Thiourea dioxide (TUD): A robust organocatalyst for oxidation of sulfides to sulfoxides with TBHP under mild reaction conditions

Article abstract of DOI:10.1016/j.tetlet.2011.04.088

Thiourea dioxide (TUD) has been reported for the first time as a highly efficient and selective organocatalyst for the oxidation of sulfides to sulfoxides in high to excellent yields by using tert-butylhydroperoxide as oxidant under mild reaction conditio

Full text of DOI:10.1016/j.tetlet.2011.04.088

Tetrahedron Letters 52 (2011) 3393–3396
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Thiourea dioxide (TUD): a robust organocatalyst for oxidation of sulfides
to sulfoxides with TBHP under mild reaction conditions
⇑
Subodh Kumar, Sanny Verma, Suman L. Jain , Bir Sain
Chemical Sciences Division, Indian Institute of Petroleum (Council of Scientific & Industrial Research), Dehradun 248005, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Thiourea dioxide (TUD) has been reported for the first time as a highly efficient and selective organocat-
alyst for the oxidation of sulfides to sulfoxides in high to excellent yields by using tert-butylhydroperox-
ide as oxidant under mild reaction conditions.
Received 15 January 2011
Revised 21 April 2011
Accepted 23 April 2011
Available online 30 April 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Organocatalyst
Thiourea dioxide
Oxidation
Sulfide
The catalysis involving small organic molecules termed as
‘organocatalyst’ has recently been recognized as the third promis-
ing catalytic process in organic synthesis.1 Unlike the conventional
biocatalysts and metal catalysts, these organocatalysts offer
numerous advantages including lower activation energy, high sta-
bility, metal-free environment, reduced toxicity, and mild reaction
conditions. There are a large number of organocatalysts, including
Lewis bases,2 Lewis acids,3 Brønsted bases,4 and Brønsted acids5
known in modern organic synthesis. Small molecules such as urea6
and thiourea derivatives7 due to their strong hydrogen-bonding
activity have also emerged as potential organocatalysts in develop-
ing a variety of synthetically important organic reactions.
Oxidation of sulfides to sulfoxides is one of the most important
transformations as they are highly useful intermediates and build-
ing blocks in the preparation of numerous chemically and biologi-
cally active compounds.8 Chiral sulfoxides are also utilised in
organic synthesis as chiral auxiliaries8c,9 and as organocatalysts.10
Table 1
Results of optimization experimentsa
Entry Cat.
(mol %)
Oxidant
Solvent Temperature
Time
(h)
Yieldb
(%)
(°C)
1
2
3
4
5
6
—
Anhyd.
TBHP
Anhyd.
TBHP
Anhyd.
TBHP
Anhyd.
TBHP
Anhyd.
TBHP
Anhyd.
TBHP
Aq. TBHP
Anhyd.
TBHP
Anhyd.
TBHP
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
rt
8.0
4.5
3.5
3.5
3.0
2.5
—
2
rt
98
98
98
82c
94c
5
rt
O
O
10
2
rt
S
50
80
NH2
H2N
TUD 1
2
7
8
2
2
CH2Cl2
THF
rt
rt
3.0
7.0
97c
—
O
S
I (2 mol%)
S
R2
R1
t-Bu-OOH
R2
R1
9
10
11
2
2
2
CHCl3
CH3CN
H2O
rt
rt
rt
8.0
5.5
6.5
78d
85
CH2Cl2
3
r.t.
2
Anhyd.
TBHP
Aq. TBHP
Scheme 1. TUD-catalyzed oxidation of sulfides to sulfoxides.
90c
a
b
c
Conditions: diphenylsulfide (1 mmol), oxidant (1.5 mmol).
Isolated yields.
Diphenylsulfone.
⇑
Corresponding author. Tel.: +91 135 2525901; fax: +91 135 2660202.
E-mail addresses: suman@iip.res.in, sumanjain@hotmail.com (S.L. Jain),
d
birsain@iip.res.in (B. Sain).
Unreacted substrate was recovered with the sulfoxide at the end of the reaction.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.04.088

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S. Kumar et al. / Tetrahedron Letters 52 (2011) 3393–3396
Although a variety of effective methods using transition-
catalyst by using tert-butylhydroperoxide as oxidant. To the best
of our knowledge this is the only report known for organocatalyt-
ic sulfoxidation using thiourea based catalysts. However, limited
availability of the catalyst and longer reaction times (16–47 h)
make this method of inadequate applicability, leaving a great
scope for further development in this area.
metal-based catalysts with different oxygen donors have been
developed,11 toxic and expensive nature of these catalysts led to
the particular attention in developing metal-free approaches with
favorable environmental impact.12 In the recent years, while
remarkable progress has been made to develop organocatalytic
methodologies for various useful transformations, less work has
been devoted to develop organocatalytic approaches for sulfoxi-
dation.13 Recently, Russo and Lattanzi13c reported a mild and
highly chemoselective oxidation of various sulfides to sulfoxides
Thiourea dioxide (TUD)1,14 owing to its easy accessibility, stabil-
ity and strong hydrogen bonding ability, has a great potential to
activate oxygen donors through hydrogen bonding and, therefore,
can be established as promising organocatalyst for oxidation reac-
tions.15 Herein, we report the first successful application of TUD 1
by
using
(N,N0-bis[3,5-bis(trifluoromethyl)phenyl]thiourea)
Table 2
TUD I catalyzed oxidation of sulfides with TBHPa
Entry
Sulfide 2
Sulfoxide 3
Time (h)
Yieldb (%)
4.5
6.0
98
O
S
80c
S
1
3.0
5.0
98
O
85c
Me
MeO
Cl
S CH3
2
3
4
5
6
7
Me
MeO
Cl
S CH3
O
S
S CH3
CH3
3.5
96
CH3
5.75
8.5
94
O
75c
S
S CH3
O
S
S
CH2
4.5
94
CH2
8.5
12.0
70
O
40c,60d
O2N
S CH3
O2N
S CH3
O
H2C S CH2
S
4.5
6.5
92
80
H2C S CH2
S
8
O
Br
Br
Br
Br
S
O
S
9
5.0
3.5
89
95
S
S
O
10
S
S
O
11
12
3.0
3.0
93
92
S
S
O
OH
OH
S
S
S
13
14
5.5
10
80
O
O
S
30e,62d
15
16
4.0
12
90
S
S
S O
S O
15e,78d
17
18
6.5
8.0
15e,80d
30e,65d
S
S
O
OH
OH
HO
HO
S
O
S
a
b
c
Condition: sulfide (1 mmol), anhydrous TBHP (1.5 mmol), catalyst (2 mol %) at room temperature.
Isolated yields.
By using thiourea (TU) as catalyst.
Amount of unreacted substrate recovered.
Amount of sulfoxide determined by GCMS.
d
e

S. Kumar et al. / Tetrahedron Letters 52 (2011) 3393–3396
3395
as an efficient and highly selective organocatalyst for the oxidation
of sulfides 2 to sulfoxides 3 with tert-butylhydroperoxide (TBHP)
under mild reaction conditions (Scheme 1).
O
O
S
C
H
N
H
NH
H
At first we studied the oxidation of diphenylsulfide under dif-
ferent reaction conditions. The results of these optimization
experiments are summarized in Table 1. The oxidation of diphe-
nylsulfide did not occur in the absence of TUD, proving that the
presence of TUD is essential for this reaction (Table 1, entry 1).
Further, the use of higher loadings of TUD (5 mol %, 10 mol %)
did not affect the reaction to any significant extent and the yield
of the desired sulfoxides was found to be almost same (Table 1,
entries 3 and 4). The oxidation of diphenyl sulfide with aq TBHP
under identical reaction conditions, afforded the poor yield of the
sulfoxide with the formation of sulfone as major product (Table 1,
entry 7). This is probably due to the additional activation of TBHP
through hydrogen-bonding interaction with water. On the other
hand, the use of excess amount of anhydrous TBHP led to the
selective formation of sulfoxide under these reaction conditions.
All the experiments were performed at room temperature while
at higher temperature, poor yield of the sulfoxide was obtained
with the predominant formation of sulfone (Table 1, entries 6
and 7). To evaluate the effect of solvent, oxidation of diphenylsul-
fide was carried out in different solvents such as THF, CHCl3, H2O,
CH3CN and dichloromethane under described reaction conditions
(Table 1, entries 8–11). The reaction did not occur in THF,
whereas, in less polar solvents such as chloroform, the reaction
proceeded slowly and afforded the lower yield of the sulfoxide.
In protic solvents such as water, sulfone was formed predomi-
nantly under similar reaction conditions. The use of dichloro-
methane at room temperature was found to be optimum for
this reaction in terms of reactivity and selectivity.
In order to compare the catalytic efficiency of TUD with thio-
urea (TU) the oxidation of diphenylsulfide, 4-(methylphenyl)
methyl sulfide, 4-(chlorophenyl) methyl sulfide and 4-(nitro-
phenyl) methyl sulfide was carried out under identical reaction
conditions (Table 2, entries 1,2,4,6). In all the cases selective for-
mation of sulfoxides was observed and the yield of the product
was found to decrease while using TU. These findings estab-
lished the higher catalytic efficiency of TUD as compared to thio-
urea, which is probably due to strong hydrogen bonding ability
of TUD with TBHP. These findings inspired us to extend the
scope of the developed protocol and consequently, we carried
out the oxidation of a variety of sulfides under described reac-
tion conditions.16 The results are summarized in Table 2. Among
the various substrates studied, sulfides containing electron
donating groups were found to react faster and required lesser
reaction times in completion of the reaction (Table 2, entries
2,3,10–12). In case of substrates having other functional groups
such as hydroxymethyl phenyl sulfide, propargyl phenyl sulfide,
thiophene, cyclopropyl phenyl sulfide (Table 2, entries 13,14,16–
18), the reaction was found to be highly chemoselective and
gave selective formation of sulfoxides without affecting the other
functional groups. But in these cases, the reaction was found to
be slow and provided poor yield of the corresponding sulfoxides
with the recovery of the unreacted substrate at the end of the
reaction.
1
O
H
O
t-Bu
O
S
S
R1
R2
R1
R2
Scheme 2. Plausible mechanistic pathway.
In summary, we have described the first example of thiourea
dioxide promoted oxidation of sulfides to sulfoxides with TBHP
in a highly efficient and selective way. The higher activity of the
TUD is probably due to its strong hydrogen bonding ability with
the electrophilic oxygen of TBHP, which may facilitate the reaction.
A variety of sulfoxides were obtained in high to excellent yields
with excellent chemoselectivity. We believe that the use of TUD
as an organocatalyst for the present reaction is advantageous in
many ways and will open up several new possibilities for its fur-
ther use in developing many metal-free environmentally friendly
and cost effective methodologies in organic synthesis.
Acknowledgments
We are thankful to the Director, IIP for his kind permission to
publish these results. S.K. and S.V. acknowledge CSIR, New Delhi
for the award of Research Fellowship. We acknowledge Dr. Basant
Kumar and Mr. Sivakumar (analytical division) for providing the
GCMS analysis of the samples.
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16. General experimental procedure for TUD catalyzed oxidation of sulfides with TBHP:
To the stirred mixture of sulfide (1 mmol), anhydrous TBHP in dodecane
(1.5 mmol) in dichloromethane (3 ml) was added catalyst TUD (2 mol %). The
resulting mixture was stirred at room temperature for the time reported in the
Table 2. Progress of the reaction was monitored by TLC. After completion, the
reaction mixture was diluted with dichloromethane and washed with water
(3 ꢀ 15 ml). The organic layer was separated, dried over anhydrous MgSO4 and
concentrated under reduced pressure. The crude product was purified with
column chromatography (SiO2) using ethyl acetate/hexane (4:6) as eluent. The
selectivity and conversion were determined by high resolution GC–MS
analysis; however the identity of the products was confirmed by comparing
their physical and spectral data with the known compounds.