L-proline-H2O2: A new chemoselective approach for oxidation of sulfides to sulfoxides

Article abstract of DOI:10.1080/00397910600946363

A facile and selective oxidation of sulfides to sulfoxides using an L-proline-H₂O₂ system for structurally divergent sulfide substrates with excellent yields at ambient conditions is reported. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910600946363

Synthetic Communicationsw, 36: 3761–3766, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910600946363
L-Proline–H2O2: A New Chemoselective
Approach for Oxidation of Sulfides
to Sulfoxides
K. Rajender Reddy, C. V. Rajasekhar, and A. Ravindra
Inorganic and Physical Chemistry Division, Indian Institute
of Chemical Technology, Hyderabad, India
Abstract: A facile and selective oxidation of sulfides to sulfoxides using an L-proline–
H2O2 system for structurally divergent sulfide substrates with excellent yields at
ambient conditions is reported.
Keywords: Hydrogen bonding, L-proline-H2O2, selective oxidation, sulfides, sulfoxides
INTRODUCTION
The selective oxidation of sulfides to sulfoxides is an important organic trans-
formation, and the resulting sulfoxides are versatile intermediates for the prep-
aration of biologically and medicinally important products.[1] Stoichiometric
amounts of organic or inorganic reagents were used conventionally for
these above transformations.[2,3] Because of the large volume of toxic
wastes associated with stoichiometric processes, there is a growing interest
in scientific and industrial circles for a cheap and environmentally benign
process for these transformations. A catalytic method associated with
hydrogen peroxide as the oxidizing agent is a quite attractive system for
large-scale processes from economic and environmental points of view.[4]
In recent years, several metal catalysts for selective oxidation of sulfides to
sulfoxides utilizing hydrogen peroxide as the oxidizing agent have been
Received in India May 8, 2006
Address correspondence to K. Rajender Reddy, Inorganic and Physical Chemistry
Division, Indian Institute of Chemical Technology, Hyderabad 500 007, India. E-mail:
rajender@iict.res.in
3761

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K. R. Reddy, C. V. Rajasekhar, and A. Ravindra
reported.[5] These include a number of supported heterogeneous catalysts such
as silica-supported tungsten[6] and titanium[7] derivatives, as well as tungstate-
exchanged layered double hydroxides (LDH).[8]
Another promising area that has attracted lots of attention in recent years
is organo-catalysis.[9] The metal-free nature and enzymatic compatibility of
these processes could make them potentially greener alternatives to several
conventional metal-catalyzed organic transformations, which utilize
hazardous metal ions. Organocatalytic aldol, Mannich, Diels–Alder, and
Michael reactions with high selectivity have been reported in the past five
years.[10] Similarly Bethell et al. reported selective oxidation of sulfides to
sulfoxides using chiral benzisothiazole derivative and aqueous hydrogen
peroxide as oxidant.[11] Herein, we report L-proline as an efficient catalyst
for selective oxidation of sulfides to sulfoxides using H2O2 as an oxidant.
RESULTS AND DISCUSSION
Initially we screened different amino acids and found that proline is the best
catalyst in terms of activity and selectivity (Table 1). To study the effect of
solvents, we screened different solvents and a slow conversion was
observed in dichloromethane. This might be because of the poor solubility
of the proline. On the other hand, higher conversion was observed in polar
solvents such as acetonitrile and methanol. However, acetonitrile proved to
be the best solvent in terms of conversion and selectivity (Table 1).
All further reactions were carried out in acetonitrile using a catalytic
amount (10 mol%) of commercially available L-proline with H2O2 as the
oxidizing agent at room temperature (Scheme 1). We have chosen a variety
Table 1. Selective oxidation of thioanisole using organo-catalystsa
Selectivityc
Conv.
(%)b
sulfoxide–
sulfone
Entry
Catalyst
L-proline
L-leucine
Solvent
1
2
3
4
5
6
7
CH3CN
CH3CN
CH3CN
CH3CN
98
98
98
98
—
23
98
97:3
90:10
93:7
83:17
—
L-phenyl alanine
N-benzyl-L-proline
L-proline-methyl ester CH3CN
L-proline
L-proline
CH2Cl2
MeOH
97:0
85:15
aSulfide (1 mmol), H2O2 (2.5 mmol), proline (10 mol%), acetonitrile
(2 mL), rt, 1.5 h.
bNMR yields based on sulfide.
cBased on NMR.

L-Proline–H2O2
3763
Scheme 1.
of structurally divergent aryl sulfides with a wide range of functional groups
for our study to better understand both the scope and the general applicability
of the L-proline–H2O2 system for sulfoxidation reaction (Table 1).
Thioanisole (Table 2, entry 1) and substituted thioanisoles (Table 2,
entries 2–4) undergo smooth oxidation with a small decrease in rate due to
the presence of electron-withdrawing groups (Table 2, entries 2 and 3).
Insertion of methylene group on either side of the sulfur atom of thioanisole
has a marked effect on selectivity but keeps the rate unchanged (Table 2,
entries 5 and 6). Similarly, vinyl phenyl sulfides and diallyl sulfide were
oxidized smoothly to their corresponding sulfoxides; neither sulfones nor
epoxides were detected in these reactions. Linden and coworkers reported
similar observations for oxidation of allylic and vinylic sulfides by
hydrogen peroxide using flavin as catalysts.[12] As expected, electron-rich
sulfides were oxidized faster than their electron-deficient counterparts.
The transformation mechanism is due to the formation of hydrogen
bonding between L-proline and H2O2 (Scheme 2). As shown in Table 1, quan-
titative conversions were observed with proline, leucine, and phenylalanine.
Similarly, N-benzyl proline also gave a higher conversion under similar con-
ditions (Table 1, entry 4). To our delight, there is no formation of sulfoxide
with proline ester (Table 1, entry 5). This experiment strongly suggests that
hydrogen bonding between the carboxylic group and H2O2 plays a major
role in this transformation. A similar hydrogen-bonding concept was also
proposed for flavin-catalyzed sulfoxidation[12] and for epoxidation[13] and sul-
foxidation[14] in phenolic solvents. Unfortunately, a very low enantioselectiv-
ity (4.0% ee) was observed in the case of thioanisole. When the reactions were
carried out with strong oxidizing agents such as tertiary butyl hydrogen
peroxide (TBHP), a mixture of sulfoxides and sulfones was observed.
EXPERIMENTAL
General
Analytical-grade amino acids were purchased from S. D. Fine Chemicals,
India. Aliphatic and aromatic sulfides were purchased from Aldrich or
Fluka and were used without further purification. Acme silica gel (100–200
mesh) was used for column chromatography, and thin-layer chromatography

3764
K. R. Reddy, C. V. Rajasekhar, and A. Ravindra
a
Table 2. Selective oxidation of sulfides to sulfoxides using L-proline-H2O2
Time
(h)
Conv.
(%)b
Selectivityc sulfoxide–
sulfone
Entry
1
Sulfides
1.5
98
95:5
2
3
4
3.0
92
77:23
3.0
2.5
98
96
93:7
96d
5
6
7
3.0
3.5
4.0
98
98
95
82:18
98d
84:16
8
9
(CH3-(CH2)3)2S
3.0
3.0
3.0
98
98
90
98d
98
10
90
aSulfide (1 mmol), H2O2 (2.5 mmol), proline (10 mol%), acetonitrile (3 mL), rt.
bNMR yields based on sulfide.
cBased on NMR.
dNo sulfone peaks observed in NMR.
(TLC) was performed on Merck precoated silica-gel 60-F254 plates. All the
other solvents and chemicals were obtained from commercial sources and
were purified using standard methods.
Typical Experimental Procedure for Sulfoxidation
A 10 mL round-bottom flask was charged with sulfide (1 mmol), L-proline
(10 mol%), and aqueous 30% H2O2 (2.5 mmol). The reaction mixture was
stirred at room temperature, and the progress of the reaction was monitored

L-Proline–H2O2
3765
Scheme 2.
by TLC. After completion of the reaction, the excess H2O2 was quenched with
a saturated Na2SO3 solution and purified by silica-gel chromatography using
hexane–ethyl acetate to obtain the pure product. NMR spectra were compared
with the reported systems.[8,15]
ACKNOWLEDGMENT
We thank CSIR, India, for financial support under Task Force Project CMM-
0005. C. V. Rajasekhar and A. Ravindra thank CSIR for the award of research
fellowship.
REFERENCES
1. For recent reviews, see (a) Carreno, M. C. Chem. Rev. 1995, 95, 1717;
(b) Prilezhaeva, E. N. Russ. Chem. Rev. 2001, 70, 897.
2. (a) Drust, T. J. Am. Chem. Soc. 1969, 91, 1034; (b) Leonard, N. J.; Johnson, C. R.
J. Org. Chem. 1962, 27, 282; (c) Davis, F. A.; Jenkins, R. Jr.; Yocklovich, S. G.
Tetrahedron Lett. 1978, 5171.
3. (a) Gokel, G. W.; Gerdes, H. M.; Dishong, D. M. J. Org. Chem. 1980, 45, 3634;
(b) Edward, D.; Stenlake, J. B. J. Chem. Soc. 1954, 3272; (c) Khurana, J. M.;
Panda, A. K.; Ray, A.; Gogia, A. Org. Prep. Proced. Int. 1996, 28, 234.
4. (a) Sato, K.; Aoki, M.; Noyori, R. Science 1998, 281, 1646; (b) Brink, G. T.;
Arends, I. W. C. Science 2000, 287, 1636.
5. (a) Yadollahi, B. Chem. Lett. 2003, 32, 1066; (b) Matteucci, M.; Bhalay, G.;
Bradley, M. Org. Lett. 2003, 5, 235.
6. Karimi, B.; Nezhad, M. G.; Clark, J. H. Org. Lett. 2005, 7, 625.
7. Fraile, J. M.; Garcia, J. I.; Lazaro, B.; Mayoral, J. A. Chem. Commun. 1998, 1807.

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K. R. Reddy, C. V. Rajasekhar, and A. Ravindra
8. (a) Lakshmi Kantam, M.; Veda Prakash, B.; Bharathi, B.; Venkat Reddy, C. J. Mol.
Catal. A 2005, 226, 119; (b) Choudary, B. M.; Bharathi, B.; Venkat Reddy, C.;
Lakshmi Kantam, M. J. Chem. Soc., Perkin Trans. 1 2002, 2069.
9. List, B. Tetrahedron 2002, 58, 5573.
10. See the special issue on asymmetric organocatalysis, Acc. Chem. Res. 2004, 37 (8),
for related references.
11. Bethell, D.; Bulman Page, P. C.; Vahedi, H. J. Org. Chem. 2000, 65, 6756.
12. Linden, A. A.; Kruger, L.; Backvall, J. E. J. Org. Chem. 2003, 68, 5890.
13. Wahlen, J.; Devos, D. E.; Jacobs, P. A. Org. Lett. 2003, 5, 1777.
14. Xu, W. L.; Li, Y. Z.; Zhang, Q. S.; Zhu, H. S. Synth. Commun. 2004, 231.
15. Kim, S. S.; Nehru, K.; Kim, S. S.; Kim, D. W.; Jung, H. C. Synthesis 2002, 2484.