An eco-friendly oxidation of sulfide compounds

Article abstract of DOI:10.1007/s12039-016-1121-1

An improved green route has been developed for the oxidation of sulfide compounds. Albendazole is converted to ricobendazole or albendazole sulfone using H ₂O₂ as an oxidant and H ₂O as the solvent. High yields of the corresponding products were obtained by carrying out the reaction at room temperature. This synthetic method is environmentally clean and safe, operationally simple for the oxidation of other benzimidazole anthelmintics and various sulfide compounds. [Figure not available: see fulltext.]

Full text of DOI:10.1007/s12039-016-1121-1

c
J. Chem. Sci. ꢀ Indian Academy of Sciences.
DOI 10.1007/s12039-016-1121-1
An eco-friendly oxidation of sulfide compounds
RAVINDRA B WAGH, SITARAM H GUND and JAYASHREE M NAGARKAR∗
Department of Chemistry, Institute of Chemical Technology, Matunga, Mumbai 400 019, India
e-mail: jm.nagarkar@ictmumbai.edu.in
MS received 22 March 2016; revised 11 May 2016; accepted 24 May 2016
Abstract. An improved green route has been developed for the oxidation of sulfide compounds. Albendazole
is converted to ricobendazole or albendazole sulfone using H2O2 as an oxidant and H2O as the solvent. High
yields of the corresponding products were obtained by carrying out the reaction at room temperature. This syn-
thetic method is environmentally clean and safe, operationally simple for the oxidation of other benzimidazole
anthelmintics and various sulfide compounds.
Keywords. Oxidation; sulfide; sulfoxide; sulfone; benzimidazole anthelmintic.
1. Introduction
no toxic byproduct is generated. This is a simple oxida-
tion process and it is clean and safe to handle for large
scale production of benzimidazole anthelmintics.
Benzimidazoles are the bicyclic compounds with fused
benzene and imidazole rings.1 Benzimidazole anthel-
mintics are the drugs which kill internal parasites from
the body without causing significant damage to the
host.2 They are applied to treat people or animals which
are infected by helminths. These drugs include albenda-
zole, ricobendazole, albendazole sulfone, fenbendazole,
oxfendazole, fenbendazole sulfone, etc. Ricobendazole
is a very important metabolite of albendazole which
acts as an anthelmintic.3 It is therapeutically a key
anthelmintic agent with low bioavailability.4 Its low
host toxicity and broad spectrum of activity against
lungworms, tapeworms, and gastrointestinal nematodes
have made it successful as anthelmintic agent.5,6 Alben-
dazole sulfone is also used as scolicidal agents on
hydatid cysts (in vitro study).7 Efficacies of albenda-
zole sulfone against in vitro cultivated Echinococcus
multilocularis Metacestodes was also studied.8
Numerous reagents and oxidative procedures are
available for oxidation of sulfide compounds. Sulfox-
ides and sulfones are widely used in pharmaceuticals
or petrochemicals. The classical idea was to perform
the oxidation in homogenous medium but it is unsuit-
able if one of the substrates is insoluble in the reaction
medium. All the reported methods gave good to better
product yields as per their reaction conditions. How-
ever, they have some limitations such as requirement of
variable temperature, reaction medium and use of toxic
reagents. In some cases, transition metals were used
as catalysts to achieve the desired yield of the product
though these transition metals are not environmentally
friendly and are very expensive.15 20 Our method is very
simple, green and affords excellent yield of products.
Here, we propose a green protocol for the oxidation
of benzimidazole anthelmintics (Scheme 1) and also in
general for sulfide to sulfoxide or sulfone compounds.
Most of the principles of green chemistry are followed
in this protocol such as use of H2O and H2O2 and ambi-
ent temperature. This process is more efficient than
other reported methods regarding various aspects. H2O
as a green solvent and H2O2 as an ideal “green” oxidant
are used in this method. The process does not require
any catalyst or acid with solvents or electrolysis tech-
nique as reported earlier.9 14 The yield of the products
are high and H2O is generated as the only byproduct and
2. Experimental
2.1 Materials and Methods
All chemicals were purchased from Sigma Aldrich,
Loba Chemie, commercial suppliers and were used
without further purification. Hydrogen peroxide solu-
tion of 30% and 50% were procured from SD Fine
chemicals Ltd. The reaction was monitored by TLC,
GC and LCMS. The products were characterized by
LCMS (Varian Inc, USA Model: 410 Prostar Binary LC
with 500 MS IT PDA Detectors) and GCMS (Shimadzu
instrument (Rtx-17, 30 m_25 mm ID, film thickness
0.25 μm, column flow: 2 mL min−1, 80 to 240◦C at
10◦C/ min rise).1H and 13C NMR spectra were recorded
∗For correspondence

Ravindra B Wagh et al.
Scheme 1. Oxidation of albendazole.
Table 1. aOptimization of reaction parameters.
Entry
Oxidant (equiv.)
Time (h)
Yield(%)b
Sulfoxide
Sulfone
1
2
3
4
5
6
7
8
9
10
H2O2 50% (1.0)
H2O2 50% (1.2)
H2O2 50% (2.2)
H2O2 50% (2.5)
Peracetic acid (1.2)
Peracetic acid (2.5)
Oxone (1.2)
Oxone (2.5)
H2O2 30% (1.2)
H2O2 30% (2.5)
10
8
11.5
10
8
10
8
10
15
21
82
100
1
–
40
6
33
4.9
100
–
–
–
80
100
1.5
65
0.8
72
–
100
aReaction conditions: albendazole (1 mmol), oxidant, H2O (2 mL), temp. (30–35◦C); bconversion
and yield determined by LCMS.
on a Varian Mercury plus-300 spectrometer at 400 and stirred at room temperature. The progress of the reaction
100MHz in DMSO or CDCl3 as the solvent and TMS was monitored by TLC or GC. After 24 h, the product
as an internal standard.
was extracted with ethyl acetate (3 x5 mL). The organic
layer was separated, dried (Na2SO4), and concentrated
under vacuum. The crude products were purified by
column chromatography using silica gel (60-120 mesh)
with petroleum ether and ethyl acetate as solvent to get
the pure product. The pure products were analyzed by
2.2 General procedure for the oxidation of
benzimidazole anthelmintics
A mixture of alkyl or aryl derivative of albendazole
(1 mmol) and H2O (2 mL) was taken in a stoppered tube.
Then 1.2/2.5 equiv. of 50% H2O2 was added slowly to it.
The reaction mixture was stirred at room temperature
for specified time. The progress of the reaction was mon-
itored by TLCand 100% conversion of starting material
on TLC was observed. All the reactants (starting mate-
rials) as well as products are insoluble in H2O and it was
used just as medium for stirring. Therefore, the reaction
mixture was filtered after completion of the reaction and
the product was washed with distilled water followed
by acetone and dried at 100◦C. The final product was
analyzed by 13C, 1H NMR spectra.
1
13C, H NMR spectra and gas chromatography mass
spectrometer (GCMS).
3. Results and Discussion
Initially, a model reaction was carried out using alben-
dazoleas as substrate and H2O as solvent. It should be
noted that H2O is used as the medium to facilitate
the reaction. Oxidant plays a key role in this reaction.
Therefore, the reaction was carried out with H2O2,
peracetic acid and oxone as oxidants. H2O2 turned out
to be the best oxidant as it gave 100% conversion of the
products whereas other two oxidants afforded very low
yield (Table 1, entries 1-8).
2.3 General procedure for the oxidation of sulfoxide/
sulfone from sulfide compounds
In further investigations, we carried out the model
reaction with different amounts of H2O2.The reaction
A mixture of sulfide (1 mmol) and H2O (2 mL) was
taken in a stoppered tube. Then 1.2/2.5equiv. of 50% did not reach completion using less than 1.2/2.5 equiv.
H2O2 was added slowly to it. The reaction mixture was of H2O2 (Table 1, entries 1-4). As the concentration

Oxidation of sulfide to sulfoxide or sulfone compounds
Table 2. aReaction of various subtrates of benzimidazole anthelmintics.
Entry
Substrate
Product
Time (h)
Yield (%)b
1
8
98
2
8
98
3
4
5
8.5
8
97
98
96
9
aReaction conditions: Substrate (1 mmol), H2O2 50% (1.2 equiv.), H2O (2 mL), temp. (30–35◦C); bIsolated
yield.
Table 3. aReaction of various substrates of benzimidazole anthelmintics.
Entry
Substrate
Product
Time (h)
Yield (%)b
1
10.5
97
2
3
9.5
11
97
96
aReaction conditions: Substrate (1 mmol), H2O2 50% (2.5 equiv.), H2O (2 mL), temp. (30–35◦C). bIsolated
yield.

Ravindra B Wagh et al.
Table 4. aOxidation of other general sulfides to sulfoxide or sulfone
compounds.
Entry
1
Substrate
Sulfoxide 6 Yield (%)b Sulfone 7 Yield (%)b
68
62
2
3
66
74
60
72
4
5
6
72
72
69
71
67
67
aReaction conditions: Substrate 5 (1 mmol), H2O2 50% = 1.2 equiv. for sul-
foxide 6, 2.5 equiv. for sulfone 7, H2O (2 mL), temp. (30–35◦C), time = 24 h.
bIsolated yield.
Figure 1. Plausible mechanism for the oxidation of sulfide compound.
of H2O2 was increased to 1.2/2.5 equiv., the time for carried out using 30% H2O2 in H2O at room tempera-
completion of reaction decreased with increased yield ture which gave 100% yield, however the time required
(Table 1, entries 2 and 4).
for this conversion was longer as compared to 50%
Sulfoxide is formed during the oxidation of sulfide H2O2 (Table 1, entries 9 and 10).
to sulfone which is less nucleophilic. Therefore the
We also carried out oxidation of starting materials
said oxidation requires higher time as rate of oxidation containing other alkyls and aryl derivatives of benz-
of sulfoxide to sulfone is slow. Hence use of excess imidazoles (Tables 2 and 3) under optimized condi-
H2O2 (2.5 equiv.) in the reaction led to the correspond- tions. The method can be extended to other benzimida-
ing sulfone via a clean reaction. The oxidation was zole anthelmintics affording excellent yields. There is
investigated in various solvents but H2O was found no significant effect on the yield of products regarding
to be the most suitable one. Model reaction was also alkyl or aryl derivative of benzimidazoles.

Oxidation of sulfide to sulfoxide or sulfone compounds
In order to explore the generality for this protocol, we Acknowledgements
further tested this selective oxidation with various sul-
Financial support from UGC, India for a research fel-
fides and the results are presented in Table 4. Aliphatic
and aromatic sulfides were treated with 50% H2O2 and
H2O. We obtained the desired sulfoxides or sulfones
(Table 4, entries 1-6). Dimethyl sulfide (5a) was oxi-
dized to sulfoxide (6a) or sulfone (7a) under optimized
reaction conditions (Table 4, entry 1). We have also oxi-
dized tetrahydrothiophene (5b) to corresponding sul-
foxide (6b) or (7b) with good yield (Table 4, entry 2).
Notably, aryl or diaryl sulfides, with or without aro-
matic rings bearing electron donating groups, were also
converted to their sulfoxides or sulfones under opti-
mized reaction conditions (Table 4, entries 3-6). This
indicates that the present protocol is very selective and
easily controllable.
Although the precise mechanism of this transforma-
tion is still uncertain, the oxidation probably involves
the nucleophilic attack of the sulfur on the peroxide
oxygen atom (Figure 1). The products (Tables 2 and 3)
were characterized by 13C, 1H NMR spectroscopy along
with liquid chromatography mass spectrometer (LCMS).
Also, the products (Table 4) were characterized by 13C,
1H NMR spectroscopy and gas chromatography mass
spectrometry (GCMS). Results confirmed the formation
ofdesiredproducts. Theexperimentalmolecularweights
matched with those of standard molecular weights of
the desired products.
lowship under BSR-SAP scheme is gratefully acknowl-
edged.
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4. Conclusions
In conclusion, a selective, controllable, cost effective,
mild and highly efficient procedure was developed for
the oxidation of synthetically important benzimidazole
anthelmintics and other sulfides. The developed proto-
col can be considered as environmentally friendly as it
avoids use of toxic oxidizing agent and other solvents
and do not produce any hazardous byproducts as well.
The corresponding products can be isolated in good to
excellent yields under metal-free conditions. The trans-
formation worked well with the solid and liquid sulfides
in spite of a heterogeneous reaction mixture. The reac-
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for large scale industrial production. High generality of
substrates demonstrate promise in broad applications of
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Supplementary Information (SI)
Supplementary Information is available at www.ias.ac.
in/chemsci.