A mild, chemoselective oxidation of sulfides to sulfoxides using o-iodoxybenzoic acid and tetraethylammonium bromide as catalyst

Article abstract of DOI:10.1021/jo034483b

A mild, selective, and high-yielding method for oxidation of sulfides to sulfoxides using IBX and tetraethylammonium bromide in a variety of solvents is described. The method offers the advantage of short reaction times, no over-oxidation to sulfones, and compatibility to a wide range of functional groups.

Full text of DOI:10.1021/jo034483b

TABLE 1. Op tim iza tion of Su lfid e Oxid a tion a
A Mild , Ch em oselective Oxid a tion of
Su lfid es to Su lfoxid es Usin g
o-Iod oxyben zoic Acid a n d
Tetr a eth yla m m on iu m Br om id e a s Ca ta lyst
Vidyanand G. Shukla, Paresh D. Salgaonkar, and
Krishnacharya G. Akamanchi*
IBX
(equiv)
cat. TEAB
(mol %)
yieldb
(%)
entry
solvent
time
18 h
15 min
20 m in
24 h
36 h
30 min
12 h
1
2
3
4
5
6
7
8
CHCl3/H2O
CHCl3/H2O
CHCl3/H2O
CHCl3/H2O
PhCH3/H2O
PhCH3/H2O
DMSO/acetone
DMSO/acetone
1.1
1.1
1.1
2.2
1.1
1.1
1.1
1.1
95c
98
98
97d
5c
98
97
97
Department of Pharmaceutical Sciences & Technology,
University Institute of Chemical Technology,
Matunga, Mumbai-400 019, India
100
5
5
kgap@rediffmail.com
Received April 16, 2003
5
5
30 min
a
All reactions are run at room temperature with 5 mmol of
sulfide in 10 mL of solvent (8:2 for DMSO/acetone and 100:1 for
the rest of the entries). Reactions were also carried out using
substrate R ) Ph, R′ ) CH3 and similar results were obtained.
Abstr a ct: A mild, selective, and high-yielding method for
oxidation of sulfides to sulfoxides using IBX and tetraethyl-
ammonium bromide in a variety of solvents is described. The
method offers the advantage of short reaction times, no over-
oxidation to sulfones, and compatibility to a wide range of
functional groups.
b
Yields indicate product obtained after column chromatography.
d
c Reaction not gone for completion. Sulfoxidation was complete
in 20 min; reaction kept for 24 h to check for over-oxidation.
sulfide oxidation in variety of solvents by formation of
micellar and reverse micellar systems.5 This system was
further developed for asymmetric sulfoxidation using
both iodosobenzene (PhIO) and iodoxybenzene (PhIO2)
as oxidants.6
Though IBX finds widespread use in oxidative trans-
formations,7 to the best of our knowledge there are no
reports on IBX-mediated selective oxidation of sulfides.
In continuation of our studies on the development of
newer applications of hypervalent iodine(V) compounds,8
we wish to report the investigation leading to a new
application of IBX with catalytic amounts of tetraethyl-
ammonium bromide (TEAB) for the oxidation of sulfides
to sulfoxides.
In a preliminary experiment the sulfides were sub-
jected to oxidation using IBX in chloroform. The sulfides
underwent oxidation to the corresponding sulfoxides. The
reaction was slow and took ∼18 h to give a yield of ∼95%.
To expedite the process, the sulfoxidation was carried out
using equivalent amounts of TEAB as an IBX activator.
The oxidation was complete within 5 min in quantitative
yields. By further investigation it was found that even
catalytic amounts of TEAB (∼5 mol %) are sufficient for
facile oxidation and the reaction was complete within 30
min giving quantitative yields. In the presence of 2 equiv
Sulfoxides have fascinated organic chemist worldwide
for a longtime, owing to their varied reactivity as a
functional group for transformations into a variety of
organo sulfur compounds. These transformations are
useful for the synthesis of drugs and sulfur-substituted
natural products.1,2 Despite myriad of oxidants that
convert sulfides to the corresponding sulfoxides, most
reagents require careful control of the reaction conditions,
including the quantity of oxidants, to minimize the
formation of sulfones as side products.3 Selective oxida-
tions of sulfides to sulfoxides are reported with many
hypervalent iodine(III) containing reagent systems.4
However, insolubility and compatibility of these reagents
with commonly used solvents limit their use. Kita et al.
reported iodosobenzene (PhIO) in combination with
CTAB and other quarternary ammonium salts to effect
(1) Holland, H. L. Chem. Rev. 1988, 88, 473.
(2) Block, E. Angew. Chem., Int. Ed. Engl. 1992, 31, 1135.
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252-261. (b) Procter, D. J . J . Chem. Soc., Perkin Trans. 1 1999, 641.
(c) Mata, E. G. Phosphorus Sulfur Relat. Elem. 1996, 117, 231. (d)
Madesclaire, M. Tetrahedron 1986, 42, 5459.
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K. R.; Kim, K. S.; Kim, Y. H. Tetrahedron Lett. 1991, 32, 793. (c)
Imamoto, T.; Koto, H. Chem. Lett. 1986, 967. (d) Ray, D. G., III; Koser,
G. F. J . Org. Chem. 1992, 57, 1607. (e) Varvoglis, A. The Organic
Chemistry of Poly Coordinated Iodine; VCH Publishers Inc.: New York,
1992; pp 29-31. (f) Barbieri, G.; Cinquini, M.; Colorina, S.; Montanari,
F. J . Chem. Soc. C 1968, 659. (g) Ochiai, M.; Nakanishi, A.; Ito, T. J .
Org. Chem. 1997, 62, 4253. (h) Ford-Moore, A. H. J . Chem. Soc. 1949,
2126. (i) Takaya, T.; Enyo, H.; Imoto, E. Bull. Chem. Soc. J pn. 1968,
41, 1032. (j) Barton, D. H. R.; Godfrey, C. R. A.; Morzycki, J . W.;
Motherwell, W. B.; Stobie, A. Tetrahedron Lett. 1982, 23, 957. (k)
Szmant, H. H.; Lapinski, R. L. J . Am. Chem. Soc. 1956, 78, 458. (l)
Humffray, A. A.; Imberger, H. E. J . Chem. Soc., Perkin Trans. 2 1981,
382. (m) Srinivasan, C.; Chellamani, A.; Kuthalingam, P. J . Org. Chem.
1982, 47, 428. (n) Folsom, H. E.; Castrillon, J . Synth. Commun. 1992,
22, 1799. (o) Koser, G. F.; Kokil, P. B.; Shah, M. Tetrahedron Lett.
1987, 28, 5431. (p) Miyata, O.; Nishiguchi, A.; Ninomiya, I.; Naito, T.
Chem. Pharm. Bull. 1996, 44, 1285. (q) Ando, W.; Tajima, R.; Takata,
T. Tetrahedron Lett. 1982, 23, 1685. (r) Pautet, F.; Daudon, M.
Tetrahedron Lett. 1991, 32, 1457. (s) Noda, K.; Hosoya, N.; Yanai, K.;
Irie, R.; Katsuki, T. Tetrahedron Lett. 1994, 35, 1887.
(5) Tohma, H.; Takizawa, S.; Watanabe, H.; Kita, Y. Tetrahedron
Lett. 1998, 39, 4547.
(6) (a) Tohma, H.; Takizawa, S.; Watanabe, H.; Fukuoka, Y.;
Maegawa, T.; Kita, Y. J . Org. Chem. 1999, 64, 3519. (b) Tohma, H.;
Takizawa, S.; Morioka, H.; Maegawa, T.; Kita, Y. Chem. Pharm. Bull.
2000, 48 (3), 445.
(7) (a) Morales-Rojas, H.; Moss, R. A. Chem. Rev. 2002, 102, 2497.
(b) Wirth, T. Angew. Chem., Int. Ed. 2001, 40, 2812. (c) Nicolaou, K.
C.; Baran, P. S.; Zhang, Y. L. J . Am. Chem. Soc. 2001, 123, 3183. (d)
Nicolaou, K. C.; Sujita, K.; Baran, P. S.; Zhang, Y. L. Angew. Chem.,
Int. Ed. 2001, 40, 207. (e) Nicolaou, K. C.; Zhang, Y. L.; Baran, P. S.;
Sujita, K. Angew. Chem., Int. Ed. 2001, 40, 2145. (f) DeMunari, S.;
Frigerio, M.; Santagostino, M. J . Org. Chem. 1996, 61, 9272.
(8) (a) Ramanarayanan, G. V.; Shukla, V. G.; Akamanchi, K. G.
Synlett 2002, 12, 2059. (b) Chaudhari, S. S.; Akamanchi, K. G.
Synthesis 1999, 760. (c) Chaudhari, S. S.; Akamanchi, K. G. Tetra-
hedron Lett. 1998, 39, 3209.
10.1021/jo034483b CCC: $25.00 © 2003 American Chemical Society
Published on Web 05/29/2003
5422
J . Org. Chem. 2003, 68, 5422-5425

TABLE 2. Oxid a tion of Su lfid es w ith IBX Usin g TEAB (Ca t.) in CHCl3: H2O (100: 1)
entry
1
sulfoxide
time
yield (%)
98
entry
12
sulfoxide
time
yield (%)
98
20 min
30 min
2
3
20 min
20 min
98
97
13
14
3.5 h
4 h
98
97
4
5
20 min
2 h
95
93
15
16
4 h
8 h
97
96
6
7
30 min
30 min
97
97
17
18
30 min
97
90
1 h
8
9
30 min
30 min
97
97
19
20
30 h
36 h
98
96
10
11
a
30 min
2 h
97
93
21
30 min
98
b
Reactions run at room temperature using 1.1 equiv of IBX and catalytic amounts of TEAB in CHCl3/H2O (100:1). Yields indicate
isolated yields after column chromatography. c Sulfides commercially available were used as such with out further purification. Remaining
sulfides were prepared using standard available literature procedures.9 All the sulfides and sulfoxides were confirmed by their physical
d
and spectral properties (IR, NMR, and mass spectroscopy).
of IBX no over-oxidation to sulfones was observed even
after 24 h. The reactions were also carried out in different
solvents and were found to be equally good. The results
on the optimization of sulfoxidation are recorded in Table
1.
To determine functional group compatibility and
chemoselectivity of the reaction, variety of substrates
were subjected to the developed and optimized method.
As illustrated in Table 2, various functional groups,
including acids, esters, alcohols, amide, nitriles, etc., were
compatible and the sulfoxides were obtained in almost
quantitative yields. In several cases, reaction was com-
plete in 30 min to 2 h (entries 1-14). However, in case
of sterically hindered and less nucleophilic sulfides such
as diphenyl sulfide and benzyl phenyl sulfide (entries 19
and 20) unduly long reaction times were required. To
further determine the scope of the reaction, a mixed
reaction was carried out taking 1-undecene and butyl
sulfide. After 30 min, complete selective sulfide oxidation
occurred and 1-undecene remained unreacted (entry 21).
J . Org. Chem, Vol. 68, No. 13, 2003 5423

TABLE 3. Ch em oselectivity Stu d ies Usin g
3-(P h en ylth io)bu ta n -1-ol 1a
SCHEME 1
TEAB
(mol %)
yieldb
(%)
entry
solvent
time
3 h
1 h
24 h
product
1
2
3
4
DMSO/acetone (8:2)
DMSO/acetone (8:2)
CHCl3/H2O
3
96
c
c
5
5
m ixtc
m ixtc
2
CHCl3/H2O
30 min
97
a
Reactions run at room temperature using 1.1 equiv of IBX.
Yields indicate isolated yields after removal of solvent. c No
b
chemoselectivity was observed and yield not determined.
This study clearly shows that the double bond also
remains unaffected.
Chemoselectivity of sulfide oxidation over alcohol is a
significant observation with this system (Table 2, entries
17 and 18). Further investigation on this chemoselectivity
was undertaken. Ease of alcohol oxidation by IBX is
highly dependent on the solvent employed.10 Therefore,
the substrate 1 (Table 3) was subjected to oxidation in
two different solvents and in the presence and absence
of catalyst. The results are summarized in Table 3. It is
interesting to find that by changing the solvent, selectiv-
ity can be shifted from sulfide to alcohol oxidation (Table
3, entries 1 and 4).
(B) Sulfides prepared by Michael addition of thiophenol
to R,â-unsaturated aldehydes (viz. crotonaldehyde), when
subjected to oxidation, did not give the expected sulfoxide
but instead the double bond got introduced to give R,â-
unsaturated aldehydes. Further work is in progress.
We would like to suggest the mechanism as depicted
in Scheme 1. The oxidation may involve the initial
polarization of the IdO bond by TEAB then a nucleophilic
attack of sulfur on the hypervalent iodine(V) center
followed by a concerted oxygen transfer to give sulfoxides.
Over-oxidation to sulfones does not occur and this could
be attributed to the low nucleophilicity of sulfoxide.
In summary, we have developed an efficient, fast
procedure for sulfoxidation using o-Iodoxybenzoic acid
(IBX) in the presence of TEAB as catalyst. This method
possesses increased compatibility to different functional
groups, mild and neutral conditions. Further applications
of this reagent combination are under investigation in
our laboratory.
The following investigations were also carried out on
the developed method:
(A) The residue (solid) obtained on the completion of
oxidation was separated by filtration and characterized
by physical and spectral properties.11 As expected, it was
hypervalent iodine(III) compound 1-hydroxy-1,2-benzio-
doxol-3(1H)-one (o-iodosylbenzoic acid). o-Iodosylbenzoic
acid obtained from the reduction of IBX can be recycled
by oxidation to IBX.12 It is known that o-iodosylbenzoic
acid converts sulfides to sulfoxides;4n,6a hence, one reac-
tion was carried out on ethyl sulfide using 1 molar equiv
of the residue in the presence of catalytic amounts of
TEAB. Indeed, sulfoxidation occurred, however, the reac-
tion was sluggish and gave 95% yield in 6 h. The residue
obtained on completion of oxidation for this reaction was
identified as o-iodobenzoic acid, which can be reused for
the preparation of IBX.13 A reaction was carried out using
0.5 molar equiv of IBX on ethyl sulfide. As expected,
initially the oxidation proceeded quite rapidly but overall
reaction took 6 h to give 94% yield of the sulfoxide.
Exp er im en ta l Section
Gen er a l Met h od s. All NMR spectra were recorded on 60
MHz. Chemical shifts are expressed in δ units relative to
tetramethylsilane (TMS) signal as internal reference in CDCl3.
IR spectra were recorded in CHCl3 or as a KBr pellet. Mass
spectra were recorded by EI (70 eV) ionization. IBX was freshly
prepared by standard procedure:14 mp ) 230 °C (HAZARD!
Explodes) (lit.14 mp ) 232-233 °C). All the solvents were
purchased from commercial sources and used with out further
purification. Wherever necessary the solvents were dried by
standard literature procedures.
Gen er a l Exp er im en ta l P r oced u r e. To a stirred suspension
of IBX (1.1 equiv) in CHCl3/H2O (100:1) was added TEAB (5 mol
%) followed by the addition of sulfide (1.0 equiv) in one portion.
The mixture was stirred at room temperature for 20 min until
complete consumption of starting material as observed by TLC.
The residual solids were filtered off and washed thoroughly with
CHCl3. The combined filtrate was washed successively with 10%
sodium bisulfite solution (2 × 15 mL), saturated sodium
(9) (a) Gasparrini, F.; Giovannoli, M.; Misti, D. J . Org. Chem. 1990,
55, 1323 and references therein. (b) Herriott, A. W.; Picker, D.
Synthesis 1975, 447. (c) Baliah, V.; Uma, M. Tetrahedron 1963, 19,
455.
(10) More, J . D.; Finney, N. S. Org. Lett. 2002, 4 (17), 3001.
(11) Baker, G. P.; Mann, F. G.; Sheppard, N.; Tetlow, A. J . J . Chem.
Soc. 1965, 37721.
(12) (a) Surendra, K.; Krishnaveni, S.; Arjun Reddy M.; Nageswar,
Y. V. D.; Rama Rao K. J . Org. Chem. 2003, 68, 2058. (b) Frigerio, M.;
Santagostino, M.; Sputore, S. J . Org. Chem. 1999, 64, 4537.
(13) Dess, D. B.; Martin, J . C. J . Am. Chem. Soc. 1991, 113, 7277.
(14) Varvoglis, A. Hypervalent Iodine In Organic Synthesis; Aca-
demic Press Inc.: New York, 1997; p 17.
5424 J . Org. Chem., Vol. 68, No. 13, 2003

bicarbonate solution (2 × 15 mL), water (2 × 15 mL), and brine
(1 × 15 mL). The organic layer was dried over sodium sulfate
and concentrated under vacuo. Purification by silica gel column
chromatography (50% EtOAc/hexane) afforded the sulfoxide.
Su p p or tin g In for m a tion Ava ila ble: Experimental de-
tails. Selected IR, 1H NMR, and mass spectral data of
intermediates and sulfoxides. This material is available free
of charge via the Internet at http://pubs.acs.org.
Ack n ow led gm en t. We thank CSIR, New Delhi, for
financial support.
J O034483B
J . Org. Chem, Vol. 68, No. 13, 2003 5425