Chemoselective sulfoxidation by H2O2 or HNO3 using a phosphate impregnated titania catalyst

Article abstract of DOI:10.1016/j.tetlet.2009.03.106

A variety of organosulfur compounds have been selectively oxidized to the corresponding sulfoxides by either H₂O₂ or HNO₃ using a newly developed solid acid catalyst composed of 84.5% of TiO₂ and 15.5% of [Ti₄H₁₁(PO₄)₉]·nH₂O (n = 1-4). The chemoselective oxidation of sulfides in the presence of vulnerable groups such as -CN, -C{double bond, long}C-, -CHO, or -OH, as well as sulfoxidation of substrates like benzothiazole, glycosyl sulfide, and dibenzothiophenes is some of the important attribute of the protocol. Nitric acid, under the present experimental conditions, brings about relatively better selectivity than hydrogen peroxide.

Full text of DOI:10.1016/j.tetlet.2009.03.106

Tetrahedron Letters 50 (2009) 3767–3771
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Tetrahedron Letters
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Chemoselective sulfoxidation by H2O2 or HNO3 using a phosphate
impregnated titania catalyst
Saitanya K. Bharadwaj a, Susanda N. Sharma a, Sahid Hussain a, Mihir K. Chaudhuri a,b,
*
a Department of Chemistry, Indian Institute of Technology Guwahati, Guwahati 781039, India
b Tezpur University, Tezpur 784028, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A variety of organosulfur compounds have been selectively oxidized to the corresponding sulfoxides by
either H2O2 or HNO3 using a newly developed solid acid catalyst composed of 84.5% of TiO2 and 15.5% of
[Ti4H11(PO4)9]ÁnH2O (n = 1–4). The chemoselective oxidation of sulfides in the presence of vulnerable
groups such as –CN, –C@C–, –CHO, or –OH, as well as sulfoxidation of substrates like benzothiazole, gly-
cosyl sulfide, and dibenzothiophenes is some of the important attribute of the protocol. Nitric acid, under
the present experimental conditions, brings about relatively better selectivity than hydrogen peroxide.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 2 December 2008
Revised 6 March 2009
Accepted 14 March 2009
Available online 20 March 2009
Keywords:
Heterogeneous catalysis
Chemoselective sulfoxidation
Hydrogen peroxide
Nitric acid
Selective oxidation of organic sulfides to sulfoxides is one of the
key reactions in the domain of organic oxidation chemistry espe-
cially because of the potential use of sulfoxides as synthetic inter-
mediates for construction of many chemically and biologically
active molecules including therapeutic agents such as antiulcer,
antibacterial, antifungal, and antihypertensive.1 Thus, selective
oxidation of sulfides has received continued attention leading to
the development of a number of reagents,2–4 acids,5 transition me-
tal catalysts like titanium,6–11 vanadium,12 iron,13 molybdenum,14
tungsten,15 manganese,16 copper,17,12c and zeolite-based cata-
lysts,18,19 to mention a few. While all these are important develop-
ments, there are several difficulties associated with the protocols
being used in practice, viz., non-selectivity, over oxidation, cost
effectiveness, and toxicity of catalysts. In view of the above, re-
search in this area continues in the quest of newer catalysts and
protocols for selective sulfoxidation under easy operational
conditions.
Recently, Shi et al. have reported self-catalyzed sulfoxidation
reaction at high temperature (i.e., 70 °C) with hydrogen peroxide.20
Although it is a green process, it does not work well for low volatile
sulfides, for example, dimethyl sulfide (bp. 38 °C). Moreover, Go-
mez et al. conducted a comparative study with different oxidant
and support to delineate the role of support in selectivity of sulfox-
idation, according to which acid support (amberlyst) gave sulfox-
ide selectively, basic support (basic alumina) increased the
proportion of sulfone formed.2
A great variety of titanium-containing catalysts were tested for
sufoxidation reaction with better efficiency as well as selectivity.6
Enantioselective sulfoxidation was achieved with titanium-chiral
ligand complex.8 Very recent report suggests that nanosized-TiO2
can catalyze the oxidation of sulfide to sulfone with high yield.9
Of particular relevance here are the titanium-based zeolite cata-
lysts. The selectivity of the catalyst depends on the support or its
surrounding environment. For instance, titanium silicates-1(TS-1)
and TS-2 gave
a mixture of sulfoxides and sulfones (e.g.,
PhSOMe/PhSO2Me = 78:22), whereas Ti-beta and Ti-MCM-41 gave
approximately 2:1 ratio. In addition, Ti-beta catalyst was more ac-
tive than TS-1 in the oxidation of dibutyl sulfide to dibutyl sulfone
providing 78% and 20.5% conversion, respectively.6 Other titanium-
containing zeolites are found to give moderate to high yield of sulf-
oxides and sulfones.
As a sequel to our endeavor in developing newer catalysts and
methodologies,4,21,22 a solid acid catalyst composed of 84.5% of
TiO2 and 15.5% of [Ti4H11(PO4)9]ÁnH2O (n = 1–4) has been prepared
by impregnating phosphate on titania.21 In a recent study on the
nitration of organic substrates using nitric acid with the same cat-
alyst, oxidation of sulfides predominated. This provided an impe-
tus for the present investigation. The fact that the catalyst
contains both titania and phosphate, which are known to activate
H2O2 through the formation of peroxotitanate and peroxophos-
phate intermediates, it is expected to be a potential catalyst for
the oxidation with H2O2.
Reported herein are the results of chemoselective oxidation of a
range of organic sulfides separately with H2O2 and HNO3 catalyzed
by the aforementioned catalyst. An internal comparison of the
* Corresponding author. Tel.: +91 3712 267003; fax: +91 3712 267006.
E-mail addresses: mkc@iitg.ernet.in, mkc@tezu.ernet.in (M.K. Chaudhuri).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.03.106

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S. K. Bharadwaj et al. / Tetrahedron Letters 50 (2009) 3767–3771
Table 1
Sulfoxidation of organic sulfides with H2O2 and HNO3
Entry
Substrate
H2O2
HNO3
Time (h)
0.8
Yielda (%) sulfoxide:sulfone
Time (h)
5
Yielda (%) sulfoxide:sulfone
S
1
2
3
4
5
98 (95:5)
99 (100:0)
70 (90:10)
95 (100:0)
65 (95:5)
S
S
S
CN
6
10
73 (85:15)
90 (98:2)
20
10
C6H13
9
70 (85:15)
85, 88d (95:5)
20
8, 12d
45, 60d
90, 92d (98:2)
S
C18H37
S
6
7
13
10
10
2
75 (95:5)
45
60
55
30
30
20
15
15
90 (100:0)
90 (98:2)
92 (98:2)
58 (95:5)
50 (95:5)
90 (100:0)
95 (100:0)
99 (95:5)
S
S
S
NH2
85 (85:15)
78 (90:10)
65 (85:15)
73 (90:10)
85 (79:21)
90 (72:28)
99 (20:80)
O
O
OMe
8
9b
10b
11
12
13
CHO
OH
S
3
S
N
10
7
S
S
S
0.25
S
AcO
O
14
6
90 (95:5)
20
65 (95:5)
AcO
OAc
AcO
S
15
16
12
24
84 (75:25)
77 (75:25)
30
90
90 (100:0)c
65 (100:0)c
S

S. K. Bharadwaj et al. / Tetrahedron Letters 50 (2009) 3767–3771
3769
Table 1 (continued)
Entry
Substrate
H2O2
HNO3
Time (h)
42
Yielda (%) sulfoxide:sulfone
Time (h)
360
Yielda (%) sulfoxide:sulfone
S
17
35 (80:20)
30 (100:0)c
a
Isolated yield.
Reaction was carried out at 0 °C.
Nitrated product was observed along with sulfoxide.
Reaction in 5 g scale.
b
c
d
results has been made in order to comment on the efficiency of the
chosen oxidants. A set of our results has been also compared with
those of others obtained using titanium-based catalysts to enable
us comment on the efficacy of the present protocol.
Reagent grade chemicals such as titania (Qualigens, India) and
88% phosphoric acid (E. Merck, India) were used, as purchased.
Dibenzothiophene (DBT), 4-methyl DBT, 4,6-dimethyl DBT were
purchased from Sigma Aldrich, India. Other organic sulfides were
prepared by literature procedures.
those of the hydrogen peroxide oxidation washing with water
alone was done. The ethyl acetate extract was dried with anhy-
drous Na2SO4. Evaporation of the solvent followed by column chro-
matography on silica gel using n-hexane and ethyl acetate (95:5)
as eluent afforded the corresponding sulfoxide and sulfone in the
ratio 95:5 and 98:2, respectively, for hydrogen peroxide and nitric
acid with the overall yields of 85% and 90%.
Based upon the results of trial runs, the reaction conditions
were optimized with 1 mol % of the catalyst and 1.5 mmol of oxi-
The catalyst was prepared21 by first mixing titania with phos-
phoric acid (88%), in the molar ratio of TiO2:H3PO4 as 1:1, in a silica
boat followed by heating at 200–220 °C on a hot sand bath under
stirring until the mass solidified. Heating was then discontinued
and when the temperature came down to ca. 100 °C, the catalyst
was transferred to a vacuum desiccator. Finally the catalyst was
stored in an airtight sample vial.
In a typical experiment, to a round-bottomed flask containing a
mixture of the catalyst (0.02 mmol, 1 mol %) and hydrogen perox-
ide (50%) (3 mmol, 0.204 mL) or nitric acid (70%) (3 mmol,
0.27 mL) in 3 mL of solvent, benzyl phenyl sulfide (2 mmol, 0.2 g)
was added and stirred at room temperature for the time period
specified in Table 1. While methanol was used as the solvent for
hydrogen peroxide, acetonitrile was used for nitric acid oxidations.
The reaction was monitored by TLC. After completion of the reac-
tion, the product was extracted with ethyl acetate and washed
with 5% aqueous solution of sodium bicarbonate (2.5 mL) followed
by water (5 mL) in the cases of nitric acid oxidations, whereas for
Table 3
Oxidation of benzyl phenyl sulfides with H2O2 and HNO3
Entry
Reagent
Time (h)
Yield (%)
1
2
H2O2
HNO3
36
3
25
65
Table 4
Oxidation of benzyl phenyl sulfide with different catalysts
Entry
Catalyst
H2O2
HNO3
Time (min)
Time (h)
Yield (%)
Yield (%)
1
2
3
TiO2
H3PO4
Catalyst
36
17
8
65
70
85
120
90
45
75
76
90
Table 2
Comparative reactivity of benzyl phenyl sulfide and sulfoxide
Entry
Substrate
H2O2
HNO3
Time (h)
Sulfoxide:sulfone
95:5
Time (min)
45
Sulfoxide:sulfone
98:2
S
1
2
8
O
S
24
25:75
91:9
80
45
15:85
98:2
S
3
8
O
S

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S. K. Bharadwaj et al. / Tetrahedron Letters 50 (2009) 3767–3771
Table 5
Comparison of the catalyst with other titanium-based catalysts in terms of efficiency and selectivity of methyl phenyl sulfide oxidation with H2O2
Catalyst
Solvent
Temp (°C)
Time (h)
Yield (%)
Ratio[SO:SO2]
Ref.
TS-1
TS-2
Ti-b
Ti-MCM-41
Ti(IV)-glycolate
TiO2-VO(acac)2
Present-catalyst
Acetone
Acetone
Acetone
Acetonitrile
—
Reflux
Reflux
2.5
2.5
2
5
2
98
98
85
99
71
99
98
—
78:22
—
83:17
86:14
97:3
95:5
19,24
10
11
19b
7b
23
rt
rt
rt
rt
rt
DCM
MeOH
1.5
0.8
—
dant against 1 mmol of benzyl phenyl sulfide either in acetonitrile
for HNO3 or in methanol in the case of H2O2. Whereas acetonitrile
was found to work well for HNO3, methanol appeared to be a bet-
ter solvent for the H2O2 oxidations. Coordination of alcohol to the
active site of titanium (cf. Alkoxy-Ti) presumably increases the
electrophilicity of the coordinated peroxy oxygen atom thereby
favoring the nucleophilic attack of the organic substrate, ultimately
facilitating the overall oxidation.23 The inherent acidity of the cat-
alyst might have further enhanced the reactivity.
(Table 1, entry 5) showing its prospect for preparative scale
applications.
In order to evaluate the efficiency of the catalyst, we have com-
pared the reaction of methyl phenyl sulfide and H2O2 with those of
a few other titanium-containing catalysts (Table 5). It is clear from
the results that although the yields are similar, the reaction time in
the present case is shorter and the selectivity is better than the
others. In addition, the chemoselectivity appears to be relatively
higher than its companion catalysts.
Structurally diverse sulfides were subjected to oxidation under
the optimized reaction conditions and the results are summarized
in Table 1. Evidently, both the oxidants worked well though HNO3
appeared to be comparatively better in terms of both selectivity
and efficiency (Table 1). The reagent systems chemoselectively
oxidize sulfides in the presence of other oxidation prone func-
tional groups such as –CN, –C@C–, –CHO, and –OH (Table 1, en-
tries 2, 4, 9, and 10). The protocol works efficiently in oxidizing
2-(benzylthio)benzothiazole to afford the exocyclic sulfoxide (Ta-
ble 1, entry 11). Notably, neither sulfur nor nitrogen in the het-
erocycle ring nor the benzylic position was affected in the
process. Importantly, this product is comparatively easily biode-
gradable than the substrate.24 Glycosyl sulfide is easily oxidized
to the corresponding sulfoxide (Table 1, entry 14), which is used
in chemical glycosylation.25
Though the oxidation of refractory sulfides is rather difficult,
the present protocol, however, oxidizes dibenzothiophene (DBT)
(Table 1, entry 15) and mono and disubstituted DBTs (Table 1, en-
tries 16 and 17) with reasonably good success. The ease of oxida-
tion followed the expected trend, viz. DBT > 4-methyl DBT > 4, 6-
dimethyl DBT. Steric crowding on the disubstituted DBT restricting
the approach of the active oxidant to sulfur is attributed to the dif-
ficulty in its oxidation. The presence of a very small amount of ni-
trated product was detected in each of these cases when HNO3 was
the oxidant.
The comparative reactivity of sulfide and the corresponding
sulfoxide was also studied to ensure the selectivity of the catalyst
(Table 2). The sulfides are more reactive than sulfoxides. The more
reactive sulfide competes with the sulfoxide thereby resulting in a
very low yield of sulfone.
Though hydrogen peroxide and nitric acid can themselves oxi-
dize benzyl phenyl sulfides (Table 3, entries 1 and 2), reactions
are sluggish, thereby demanding the need of catalyst for the
activation.
In separate experiments, evaluation of the catalyst and its ana-
logs was done to ensure the efficiency of the catalyst over the oth-
ers and the results are presented in Table 4. These observations
suggest that neither titania nor phosphoric acid alone is very effec-
tive to forward the desired reaction.
From the preparative point of view, it is noteworthy that the
catalyst can be efficiently recovered by evaporating the aqueous
layer and then recharging by heating on silica boat at 200–220 °C
for 30 min. Indeed, the catalyst was reused with benzyl phenyl sul-
fide for at least four reaction cycles with consistent activity and
selectivity. The reaction can be scaled up (5 g) to give good yield
In conclusion, an efficient method for the selective oxidation of
sulfides to sulfoxides under mild condition has been developed.
The catalyst-nitric acid system oxidizes simple alkyl or aryl sul-
fides more efficiently and selectively than the catalyst-hydrogen
peroxide system. However, latter one is preferable from the envi-
ronmental point of view. These processes chemoselectively oxidize
sulfur in presence of a double bond, nitrile, alcohol, aldehyde, ben-
zylic methylene and nitrogen or sulfur atom in a heterocyclic posi-
tion. Applications to the refractory sulfurs and glycosyl sulfide
make the catalytic protocols more generalized. Easy work-up and
separability are the other important attributes of the protocol.
Acknowledgment
S.K.B. is grateful to the Council of Scientific and Industrial Re-
search, India for fellowship.
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