Selective and efficient oxidation of sulfides and thiols with benzyltriphenylphosphonium peroxymonosulfate in aprotic solvent

Article abstract of DOI:10.1021/jo026106p

Benzyltriphenylphosphonium peroxymonosulfate could be used for selective oxidation of aromatic and aliphatic sulfides and thiols to their corresponding sulfoxides and disulfides under nonaqueous and aprotic conditions without catalyst.

Full text of DOI:10.1021/jo026106p

to sulfoxides. Selective oxidative coupling of thiols to
disulfides is of interest from both a biological18 and a
synthetic point of view.19 Thiols are among functional
groups which can be easily over oxidized and therefore
extensive methods have been reported for their controlled
oxidation.12,20 Most of the existing methods involve the
use of metal catalysts or reagents such as halogens and
always suffer with effluents due to these reagents.
Oxone (2KHSO5‚KHSO4‚K2SO4) is an inexpensive,
water-soluble, and stable oxidizing reagent that is com-
mercially available, but this reagent is insoluble in
organic solvents and buffering is needed due to its
acidity.21 Recently, we have reported benzyltriphenylphos-
phonium peroxymonosulfate 1 (PhCH2Ph3PHSO5) as a
mild, inexpensive, and efficient oxidizing reagent for the
oxidative deprotection of trimethylsilyl and tetrahydro-
pyranyl ethers and of ethylene acetals under nonaqueous
conditions22a or microwave irradiation,22b conversion of
oximes, phenylhydrazones, 2,4-dinitrophenylhydrazones,
and semicarbazones to the parent carbonyl compounds
in aprotic solvent,22c oxidation of alcohols to aldehydes
and ketones under solvent-free22d or aprotic conditions,22e
oxidation of urazoles to triazolinediones in a solvent-free
system,22f and dethioacetalization of 1,3-dithiolanes and
1,3-dithianes.22g In the course of our studies on the
oxidation of organic sulfur compounds,14 we explored the
utility of 1 as a mild and selective oxidizing reagent for
oxidation of sulfides 2 and thiols 4 to their corresponding
sulfoxides 3 and disulfides 5 under nonaqueous condi-
tions.
Selective a n d Efficien t Oxid a tion of
Su lfid es a n d Th iols w ith
Ben zyltr ip h en ylp h osp h on iu m
P er oxym on osu lfa te in Ap r otic Solven t
Abdol R. Hajipour,* Shadpour E. Mallakpour,* and
Hadi Adibi
Pharmaceutical Research Laboratory, College of Chemistry,
Isfahan University of Technology, Isfahan 84156, Iran
haji@cc.iut.ac.ir
Received J une 27, 2002
Abstr a ct: Benzyltriphenylphosphonium peroxymonosulfate
could be used for selective oxidation of aromatic and
aliphatic sulfides and thiols to their corresponding sulfoxides
and disulfides under nonaqueous and aprotic conditions
without catalyst.
Compounds containing a sulfoxide moiety are useful
synthetic intermediates for the construction of various
chemically and biologically significant molecules.1 Oxida-
tion of sulfides is a very useful route for preparation of
sulfoxides. Several methods are available for conversion
of sulfides to sulfoxides.2-17 However, some of the existing
methods use sophisticated reagents, complex catalysts,
toxic metallic compounds, or rare oxidizing reagents that
are difficult to prepare.2-13 Otherwise overoxidation of
sulfides resulting in sulfone formation and undesired
reactions of other functional groups are common prob-
lems, particularly when preparing biologically relevant
sulfoxides. Therefore, there is a need for a simple, less
expensive, and safer method for conversion of sulfides
Benzyltriphenylphosphonium peroxymonosulfate 1, a
mild, efficient, stable, and cheap reagent, is a white
powder that is quite soluble in dichloromethane, chloro-
form, acetone, and acetonitrile and insoluble in nonpolar
solvents such as carbon tetrachloride, n-hexane, and
diethyl ether. This reagent is readily prepared by the
dropwise addition of an aqueous solution of Oxone to an
* To whom correspondence should be addressed. Fax: +98(0311)-
3912350.
(1) For recent review see: Carreno, M. C. Chem. Rev. 1995, 95, 1717.
(2) Khurana, J . M.; Panda, A. K.; Gogia, A. Org. Prep. Proced. Int.
1996, 28, 234.
(3) Orito, K.; Hatakeyama, T.; Take, M.; Suginome, H. Synthesis
1995, 1357.
(4) Breton, G. W.; Fields, J . D.; Kropp, P. J . Tetrahedron Lett. 1995,
36, 3825.
(5) Hirano, M.; Kudo, H.; Morimoto, T. Bull. Chem. Soc. J pn. 1994,
67, 1492.
(6) Folsom, H. E.; Castrillon, J . Synth. Commun. 1992, 22, 1799.
(7) Hirano, M.; Kudo, H.; Morimoto, T. Bull. Chem. Soc. J pn. 1992,
65, 1744.
(8) Hirano, M.; Yakabe, S.; Clark, J . H.; Kudo, H.; Morimoto, T.
Synth. Commun. 1996, 26, 1875.
(9) Ali, M. H.; Stevens, W. C. Synthesis 1997, 764.
(10) Shaabani, A.; Teimouri, M. B.; Safaei, H. R. Synth. Commun.
2000, 30, 265.
(18) (a) Ogawa, A.; Nishiyama, T.; Kambe, N.; Murai, S.; Sonada,
N. Tetrahedron Lett. 1987, 28, 3271. (b) J ohnson, J . R.; Bruce, W. F.;
Dutcher, J . D. J . Am. Chem. Soc. 1943, 65, 2005.
(19) Capozzi, G.; Modena, G. In The Chemistry of Thiol Group Part
2; Patai, S., Ed.; Wiley: New York, 1974; p 785.
(20) (a) Sato, T.; Otera, J .; Nozaki, H. Tetrahedron Lett. 1990, 31,
3591. (b) McKillop, A.; Koyuncu, D. Tetrahedron Lett. 1990, 31, 5007.
(c) Meshram, H. M. Org. Prep. Proced. Int. 1993, 25, 232. (d) Iranpoor,
N.; Firouzabadi, H. Synth. Commun. 1998, 28, 367. (e) Drabowicz, J .;
Mikolajczyk, M. Synthesis 1980, 32. (f) Noureldin, N. A.; Caldwell, M.;
Hendry, J .; Lee, D. G. Synthesis 1998, 1587. (g) Movassagh, B.;
Lakouraj, M. M.; Ghodrati, K. Synth. Commun. 1999, 29, 3597. (h)
Lu, G.; Zhang, Y. Synth. Commun. 1998, 28, 4479. (i) Aida, T.;
Akasaka, T.; Furukawa, N.; Oae, S. Bull. Chem. Soc. J pn. 1976, 49,
1441. (j) Iranpoor, N.; Zeynizadeh, B. Synthesis 1999, 49. (k) Wu, X.;
Rieke, R. D.; Zhu, L. Synth. Commun. 1996, 26, 191.
(11) Fraile, J . M.; Garcia, J . I.; Lazaro, B.; Mayoral, J . A. Chem.
Commun. 1998, 1807.
(12) (a) Firouzabadi, H.; Iranpoor, N.; Zolfigol, M. A. Synth. Com-
mun. 1998, 28, 1179. (b) Firouzabadi, H.; Baltork, I. M. Bull. Chem.
Soc. J pn. 1992, 65, 1131.
(13) Drabowicz, J .; Midura, W.; Mikolajczyk, M. Synthesis 1979, 39.
(14) Hajipour, A. R.; Baltork, I. M.; Kianfar, G. Indian J . Chem.
1999, 38B, 607.
(15) (a) Hirano, M.; Yakabe, S.; Itoh, S.; Clark, J . H.; Moromoto, T.
Synthesis 1997, 1161. (b) Hirano, M.; Yakabe, S.; Clark, J . H.;
Morimoto, T. J . Chem. Soc., Perkin Trans. 1 1996, 2693.
(16) Ali, M. H.; Bohnert, G. J . Synthesis 1998, 1238.
(17) For reviews, see: (a) Madesclaire, M. Tetrahedron 1986, 42,
5459. (b) Mata, E. G. Phosphorus, Sulfur, Silicon 1996, 117, 231.
(21) For some recent work using Oxone as an oxidant, see: (a)
Hajipour, A. R. Indian J . Chem. 1997, 36B, 1069. (b) Hajipour, A. R.;
Mahboubkhah, N. Org. Prep. Proced. Int. 1999, 31, 112. (c) Meunier,
B. New J . Chem. 1992, 16, 203.
(22) (a) Hajipour, A. R.; Mallakpour, S. E.; Baltork, I. M.; Adibi, H.
Phosphorus, Sulfur Silicon 2000, 165, 155. (b) Hajipour, A. R.;
Mallakpour, S. E.; Baltork, I. M.; Adibi, H. Synth. Commun. 2001, 31,
1625. (c) Hajipour, A. R.; Mallakpour, S. E.; Baltork, I. M.; Adibi, H.
Synth. Commun. 2001, 31, 3401. (d) Hajipour, A. R.; Mallakpour, S.
E.; Adibi, H. Chem. Lett. 2000, 460. (e) Hajipour, A. R.; Mallakpour,
S. E.; Adibi, H. Phosphorus, Sulfur Silicon 2000, 167, 71. (f) Hajipour,
A. R.; Mallakpour, S. E.; Adibi, H. Chem. Lett. 2001, 164. (g) Hajipour,
A. R.; Mallakpour, S. E.; Baltork, I. M.; Adibi, H. Phosphorus, Sulfur
Silicon 2002, in press.
10.1021/jo026106p CCC: $22.00 © 2002 American Chemical Society
Published on Web 11/02/2002
8666
J . Org. Chem. 2002, 67, 8666-8668

TABLE 1. Oxid a tion of Meth yl P h en yl Su lfid e w ith
Differ en t Am ou n ts of Rea gen t 1 a t Reflu x Aceton itr ilea
TABLE 3. Oxid a tive Cou p lin g of Th iols 4 to Disu lfid es 5
w ith Rea gen t 1 in Reflu xin g Aceton itr ilea ,b
substrate/oxidant
entry
(equiv)
time (h)
yield (%)
1
2
3
4
1/1
18
18
10
2
66
71
85
1/1.2
1/1.3
1/1.5
100
a
Monitored by TLC and 1H NMR analysis.
TABLE 2. Oxid a tion of Su lfid es 2 to Su lfoxid es 3 w ith
Rea gen t 1 in Reflu xin g Aceton itr ilea ,b
entry
R1
R2
Me
n-Bu
PhCH2
Me
n-Bu
Me
Me
time (h)
yieldc (%)
1
2
3
4
5
6
7
8
Ph
Ph
Ph
2
2.5
12
6
6
3
91
92
88
90
90
86
89
78
PhCH2
PhCH2
4-MeC6H4
4-ClC6H4
C4H9
3
12
C4H9
a
b
Confirmed by comparison with authentic samples.2-17 Sub-
strate/oxidant (1:1.5). c Yield of isolated pure products.
a
b
Confirmed by comparison with authentic samples.12,20 v-
Substrate/oxidant (1:1). c Yield of isolated pure products. Sub-
d
SCHEME 1
strate/oxidant (1:1.5).
SCHEME 2
aqueous solution of benzyltriphenylphosphonium chloride
in quantitative yield at room temperature and could be
stored for months without losing its potency.22 The
amounts of HSO5- in this reagent have been determined
by an iodometric titration method23 and the measure-
ments are consistent with almost 99 wt % of active
oxidizing agent.
At first, the oxidation of methyl phenyl sulfide as the
model compound in various solvents was examined. The
solvents examined were dichloromethane, chloroform,
and acetonitrile. The reactions were carried out by
stirring the model compound with 1.5 molar amount of
1 at reflux condition. Dichloromethane and chloroform
were inferior solvents to acetonitrile because the reaction
stopped at lower conversions in these solvents than that
in acetonitrile. Next, the effects of the amount of the
oxidant 1 were examined with the model compound (1
mmol) under nonaqueous conditions in refluxing aceto-
nitrile without catalyst. The results are summarized in
Table 1.
The optimum ratio of sulfide to oxidant 1 (1:1.5) is
found to be ideal for complete conversion of sulfides 2 to
sulfoxides 3 while the reaction remains incomplete with
lesser ratio of substrate and oxidant, for example 1:1 and
1:1.2. By using this oxidation system, a wide variety of
alkyl aryl and dialkyl sulfides 2 were oxygenated to their
corresponding sulfoxides 3 in high yields within mild
reaction periods (Table 2 and Scheme 1). In this method,
oxidation of a sulfide is achieved by stirring a mixture of
a sulfide and the reagent 1 under reflux condition. The
reaction time is usually between 2 and 12 h. The
sulfoxides are isolated by filtering the reaction mixture
and washing the filter cake with appropriate solvent.
Evaporation of filtrate under vacuum often produces pure
sulfoxide without any purification. All the reactions
occurred with complete selectivity for sulfoxide formation,
no overoxidation products such as sulfones were detected
in the reaction mixtures. This method offers a simple,
general, selective and highly efficient route for converting
sulfides to the corresponding sulfoxides in the absence
of complex catalyst.
Benzyltriphenylphosphonium peroxymonosulfate 1 was
also used to transform thiols 4 to disulfides 5 at reflux
condition. A variety of aromatic and aliphatic thiols were
converted into symmetrical disulfides 5 upon simple
admixing with the reagent 1. The process involves
stirring the thiol 4 with reagent 1 in acetonitrile under
reflux condition. In most cases investigated, the optimum
mole ratio between the thiol and the oxidant is found to
be 1:1, which produces pure disulfides 5 in high yields
(Table 3 and Scheme 2). Aromatic thiols could be selec-
tively oxidized within 1h to the corresponding disulfides
in quantitative yields. Thiophenol, 4-chlorothiophenol
and 4-methylthiophenol (Table 3, entries 1-3) exhibited
a similar reactivity leading to the corresponding disul-
fides respectively, in high yields with no detectable
influence of the substituent. Benzylthiol underwent
oxidation with 1 in refluxing acetonitrile to afford diben-
zyl disulfide in quantitative yield (Table 3, entry 4). The
aliphatic thiols (Table 3, entries 5 and 6) afforded only
traces of disulfides 5 even after 12 h under these
(23) Trost, B. M.; Braslau, R. J . Org. Chem. 1988, 53, 532.
J . Org. Chem, Vol. 67, No. 24, 2002 8667

0.124 g) in acetonitrile (5 mL) in a 25 mL round-bottomed flask
which was equipped with a condenser and a magnetic stirrer
was added reagent 1 (1.5 mmol, 0.7 g). The reaction mixture
was refluxed for 2 h. After disappearance of the starting sulfide
monitored by TLC using EtOAc/cyclohexane (2:8), the mixture
was filtered through a sintered glass funnel and the solid residue
was washed with acetonitrile (10 mL). Evaporation of the
filtrates gave methyl phenyl sulfoxide as a colorless oil in 91%
yield as revealed from 1H NMR analysis: mp 30-32 °C (lit.16
mp 32-33 °C); 1H NMR (CDCl3, 90 MHz) δ 2.7 (s, 3H), 7.48-
7.56 (m, 3H), 7.64-7.67 (m, 2H); IR (film) ν 692, 754, 954, 1046,
conditions. These reactions could be completed, however,
by increasing the oxidant/thiol ratio (Table 3). The
presented oxidative coupling of thiols by reagent 1 is a
convenient alternative to the reported reagents in terms
of the reaction time, the yields of the disulfides, mild
reaction conditions, no necessary to catalyst and the
amount of the oxidant required.20 In addition to the
greater safety in handling and ease use of 1, the product
can be isolated by simple filtration and removal of the
solvent. To demonstrate the utility of the procedure
described here, a 10-fold scale oxidation was carried out
with 1 for the oxidative coupling of thiophenol, and the
corresponding disulfide was obtained in 99% yield within
1 h.
In conclusion, this new method for converting sulfides
and thiols to their corresponding sulfoxides and disulfides
offers the following advantages: (a) the reagent 1 is a
cheap, selective, and safe oxidant, (b) the procedure is
simple and occurs in aprotic solvent, (c) the yield of
sulfoxide and disulfide is high, and (d) unlike previous
oxygenation methods, this one requires neither an alde-
hyde nor a transition metal complex.
1092, 1415, 1446, 1477, 2915, 3000, 3062 cm-1
.
Typ ica l P r oced u r e for 10-F old Sca le Oxid a tive Cou -
p lin g of Th iols 4 to Disu lfid es 5 w ith Rea gen t 1. In a round-
bottomed flask (250 mL) equipped with a condenser and a
magnetic stirrer was prepared a solution of thiophenol (10 mmol,
1.1 g) in acetonitrile (50 mL). Reagent 1 (10 mmol, 4.66 g) was
added to the solution, and the resulting mixture was stirred
magnetically under reflux conditions for 1 h. After completion
of the reaction, monitored by TLC using EtOAc/cyclohexane (2:
8), the reaction mixture was filtered and the solid material was
washed with acetonitrile (50 mL). The removal of solvent under
reduced pressure afforded pure diphenyl disulfide in 99% yield
without any purification: mp 59-61 °C (lit.12b mp 58-61 °C);
1H NMR (CDCl3, 90 MHz) δ 7.62-7.48 (m, 4H), 7.42-7.20 (m,
6H); IR (KBr) ν 459, 470, 687, 734, 1435, 1474, 1572, 3050 cm-1
.
Exp er im en ta l Section
Yields refer to isolated pure products. The oxidation products
were characterized by comparison of their spectral (IR, 1H NMR)
and physical data with the authentic samples. All 1H NMR
spectra were recorded at 90 MHz. All reactions were carried out
in refluxing acetonitrile. The reagent 1 was prepared according
to our previously reported procedures.22
Ack n ow led gm en t. We are thankful of the Isfahan
University of Technology (IUT), IR Iran, for financial
support. Further financial support from Center of
Excellency in Chemistry Research (IUT) is gratefully
acknowledged.
Typ ica l P r oced u r e for Oxid a tion of Su lfid es 2 to Su l-
foxid es 3 w ith Rea gen t 1. To a solution of thioanisole (1 mmol,
J O026106P
8668 J . Org. Chem., Vol. 67, No. 24, 2002