A Selective, Convenient, and Efficient Conversion of Sulfides to Sulfoxides

Article abstract of DOI:10.1055/s-2004-44387

A novel, convenient and chemoselective procedure for oxidizing sulfides to sulfoxides with 30% aqueous H₂O₂ in phenol at room temperature is described. The procedure is very simple and no strict conditions were required for the selec

Full text of DOI:10.1055/s-2004-44387

PAPER
227
A Selective, Convenient, and Efficient Conversion of Sulfides to Sulfoxides
C
W
onversion of
S
ulfides
t
e
o
Sulfoxide
i
s
Liang Xu,* Yun Zheng Li, Qing Shan Zhang, He Sun Zhu
School of Chemical Engineering and Environment, Beijing Institute of Technology, Beijing 100081, P. R. China
Fax +86(10)68913293; E-mail: xwl3831@sina.com
Received 16 October 2003; revised 28 November 2003
also easily destroyed. Thus, it is desirable to develop a
medium for the selective and convenient oxidation of sul-
Abstract: A novel, convenient and chemoselective procedure for
oxidizing sulfides to sulfoxides with 30% aqueous H O in phenol
2
2
fides to sulfoxides by aqueous H O without affecting oth-
at room temperature is described. The procedure is very simple and
no strict conditions were required for the selective conversion with-
out affecting the functional groups even including the highly reac-
tive aldehyde group. The reactions proceeded very quickly in
excellent yields. Some experimental evidences are presented de-
scribing the role of the solvent.
2
2
er functional groups.
In an extended experiment, the oxidation of methyl phe-
nyl sulfide by using aqueous 30% H O was attempted in
2
2
different solvents. When the reaction was carried out in
propan-2-ol and cyclohexanol, unreacted sulfide could be
detected even after one day. When acetic acid was adopt-
ed as the reaction medium, although the oxidation reac-
tion was enhanced, a mixture of sulfoxide and sulfone was
obtained. Eventually, the reaction was carried out in tri-
fluoroacetic acid, and it was found that the reaction was
over within one minute, and the formation rate of sulfone
was much quicker than that in acetic acid. It was obvious
that the oxidation rate increased with increasing protic
Key words: sulfide, sulfoxide, oxidation, phenol, H O
2
2
The oxidation of sulfides to sulfoxides has been the aim of
considerable research due to the importance of sulfoxides
as useful intermediates in various chemically and biolog-
1
,2
ically significant molecules. There are several reagents
3
available for this key transformation . Unfortunately,
most of these reagents are not satisfactory because they
are either harmful or expensive, and a simple procedure is
not easily available because of the over oxidation of sul-
foxides to sulfones. Despite careful control of the reaction
temperature, reaction time and the relative amount of ox-
idants, it is difficult to avoid completely such over oxida-
tion.
character of the solvent and the pK of the solvents played
a
a key role in the reaction. Unexpectedly, phenol was used
as the medium to quantitatively accomplish this oxidation
with complete selectivity. The route for the synthesis of
sulfoxide is shown in Scheme 1.
Aqueous hydrogen peroxide has attracted great attention
as oxidation reagent because of its low cost of production
and transportation, effective-oxygen content and the for-
mation of only harmless water as by-product. These obvi-
ous advantages have spurred the development of useful
Scheme 1
procedures for H O oxidation of sulfides, including the To our satisfaction, the oxidation of methyl phenyl sulfide
2
2
use of a wide range of catalysts based on metals or semi- was complete in phenol with 30% aqueous H
O
at room
2
2
4
5
metals such as H WO and H PW O + [(C H ) N]Br.
temperature within 0.5 minute and yielded the corre-
2
4
3
12 40
8
17 4
However, organic, nonmetal compounds capable of acti- sponding methyl phenyl sulfoxide as the sole product in
vating H O for the oxidation of sulfides to sulfoxides is excellent yield (99%). Prolonging the reaction to 4 hours
2
2
rather limited. The most prominent example was did not produce any sulfone. When methyl phenyl sulfox-
6
1
,1,1,3,3,3-hexafluoro-2-propanol (HFIP). The group of ide was allowed to react (14 h) with 30% aqueous H O in
2 2
Bégué successively transformed the sulfides to sulfoxides phenol at 25 °C, the starting reactant was recovered un-
with complete selectivity in HFIP. But the HFIP is poison- changed.
ous, expensive, and volatile which severely restricted its
Although phenol has of low vapor pressure and high boil-
use in organic synthesis especially in practical organic
ing point, the purification of the product sulfoxides is not
synthesis, and in our repeated study we found that some
difficult. The workup is done by adding aqueous NaOH
reactive functional groups were easily oxidized in the re-
solution to the reaction medium once the reaction is com-
7
action. Drabowiczr reported a selective method for the
plete and extracting the product with CHCl or ethyl ace-
tate.
3
oxidation of sulfides to sulfoxides by aqueous 30% H O2
in methanol, but it was found that the reaction time was
extremely long and some other functional groups were
2
A series of sulfides was then oxidized using this remark-
ably simple procedure and the results are presented in
Table 1. As shown, all the reactions were over within a
very short time and various functional groups including
esters, amide, alcohols, nitriles, etc. were not affected, and
the sulfoxides were obtained in almost quantitative yield
SYNTHESIS 2004, No. 2, pp 0227–0232
x
x
.
x
x
.2
0
0
4
Advanced online publication: 18.12.2004
DOI: 10.1055/s-2004-44387; Art ID: F09603SS
Georg Thieme Verlag Stuttgart · New York
©

2
28
W. L. Xu et al.
PAPER
as the sole oxidation product. The cyclic ring and the car- tween the solvent and H O . The OH moiety of the solvent
2
2
bon–carbon double bond were also not affected. To fur- forms a strong hydrogen bond with H O and increases the
2
2
ther determine the scope of the reaction, a mixed reaction electrophilic ability of a peroxy oxygen atom of H O , and
2
2
was carried out with methyl phenyl sulfide and benzalde- at the same time assists the leaving group (H O) in depart-
2
hyde. After 0.5 minute, the complete selective oxidation ing from the reaction intermediate (Scheme 2) More
.
of sulfide occurred and benzaldehyde remained unreact- striking is that the solvent prevents any further oxidation
ed. Prolonging the reaction time to 5 hours did not give of sulfoxide into sulfone, because the strong hydrogen
any change. It was a significant observation that the alde- bond between the solvent and the oxygen of the sulfoxides
hyde group was not oxidized in such oxidation system. It could highly decrease the nucleophilicity of the sulfur
offered a facile, rapid, highly selective method to obtain atom of the sulfoxides.
sulfoxides with aldehyde group without any protection.
In order to further realize the oxidation reaction and sup-
To realize the essential role of phenol, the reaction prod- port the point above, some work was done with this inten-
ucts were carefully examined. No side products of phenol tion. When the oxidation reaction was carried out in water
were detected by gas chromatographic analysis. In anoth- or propan-2-ol, no significant salt effect was presented
er experiment, only aqueous 30% H O was added to the with the addition of LiNO , KNO , NaNO or Mg(ClO )
2
2
3
3
3
3 2
phenol, then hydroquinone and benzoquinone were de- even if the ionic strength varied from ca. 0.2 to 5. This
tected in the system. But when methyl phenyl sulfide was demonstrated that the oxidation of sulfides by H O was
2
2
oxidized in phenol with aqueous 30% H O by the addi- not like typical S 2 reactions involving neutral reactants
2
2
N
tion of hydroquinone and benzoquinone, no significant (Menschutkin reaction) in which significant charge sepa-
rate enhancement was observed. The intermediacy of free ration in the activated complex had taken place and would
·
–
·
·
8,9
9–11
radicals (O , HO or HO ) or other reactive oxygen spe- be sensitive to ionic strength and to solvent polarity.
2
2
1
cies such as O were also ruled out by ESR spectroscopy. In AcOH no decrease in rate was found on addition of the
2
–
The ESR spectrum of a solution of H O in phenol in the common ion AcO which is consistent with a neutral pro-
2
2
presence of the spin trap N-tert-butyl- -phenylnitrone (60 ton shift via molecular acid in the activated complex.
mmol) did not show typical signals arising from adducts When the oxidation reaction was carried out in CHCl and
3
·
with HO or other radicals. Thus, we could conclude that MeCN, because of the disability of formation hydrogen
the side products of phenol and the intermediacy of free bond, the reaction time was even much longer than that in
radicals or other reactive oxygen species were not respon- propan-2-ol and the sulfone was also found in the prod-
sible for the efficiency of the reaction. Moreover, no trace ucts. It was demonstrated that the hydrogen bond not only
–
3
metal catalysis of a kind sensitive to inhibition by 10 M activated the oxidation ability of H O but also controlled
2
2
EDTA was apparent for the oxidation in the phenol, which the chemoselectivity of the reaction.
excluded the participation of a metal in the reactions.
When some co-solvents such as diethyl ether, ethanol and
Although a high yield of sulfoxide was already obtained ethylenediamine that could form a strong hydrogen bond
using only 2 mol equivalents of phenol relative to sulfide, with phenol were added, the reaction rate decreased dra-
a high rate was observed using more than 2 mol equiva- matically, which proved that the hydrogen bond plays a
lents. Increasing the amount of phenol beyond 12 mol key role in the reaction. It could be easily explained by the
equivalents did not result in a further increase in the oxi- disruption of the hydrogen-bonded phenol network by the
dation rate, which demonstrated that the phenol played an co-solvents.
important role in the reaction. The degree of association of
The involvement of hydrogen bonding was further illus-
the phenol itself and with the reactants and product could
trated when the reaction was carried out in nitromethane,
dramatically affect the oxidation rate. In addition, the phe-
which has a pK value of 10.2 almost similar to phenol
a
nol was not consumed during the reaction. Thus, we could
see that although a large quantity of solvent was used, the
role of the phenol was purely catalytic.
(
pK = 10). Because of its disability to form hydrogen
a
bonds, the reaction time was much longer than that in phe-
nol. It took 8 hours to accomplish the reaction.
Regarding the mechanism of the reaction, the efficiency
of the oxidation can be explained by the interaction be-
Scheme 2
Synthesis 2004, No. 2, 227–232 © Thieme Stuttgart · New York

PAPER
Conversion of Sulfides to Sulfoxides
229
Table 1 Oxidation of Sulfides with 30% Aqueous H O in Phenol
2
2
Entry
1
Substrate
Product
Reaction Time (min)
0.5
Yield (%)
99
2
3
0.5
4
97
99
4
4.5
97
5
6
0.5
0.5
94
97
7
0.5
98
8
9
0.5
0.8
93
95
1
1
0
1
0.5
98
94
1
Synthesis 2004, No. 2, 227–232 © Thieme Stuttgart · New York

2
30
W. L. Xu et al.
PAPER
Table 1 Oxidation of Sulfides with 30% Aqueous H O in Phenol (continued)
2
2
Entry
Substrate
Product
Reaction Time (min)
1.5
Yield (%)
1
2
3
99
1
0.5
0.5
97
1
4
98
1
1
5
6
1.5
0.5
97
99
In conclusion, we have found a new, convenient and se- give the product as white solid (1.39 g, 99%) (Table 1). The phenol
could be recovered by adding HCl to the aqueous layer.
lective procedure of oxidizing sulfides to sulfoxides with
3
0% aqueous H O in phenol. The yield was excellent. All
2 2
Methyl Phenyl Sulfoxide
Solid; mp 30.0–30.5 °C.
the reagents required are cheap and easily available. The
reaction was carried out at room temperature and no strict
conditions were required for these selective oxidation.
The functional groups, even including the highly reactive
aldehyde group, were not affected. This novel oxidation
methodology should find widespread use in organic and
pharmaceutical synthesis.
–
1
IR (KBr): 1034 cm .
1H NMR (CDCl3): = 2.73 (s, 3 H), 7.48–7.58 (m, 3 H), 7.61–7.69
(
m, 2 H).
Dibutyl Sulfoxide
Solid; mp 34.0–34.5 °C.
–
1
IR (KBr): 1041 cm .
1H NMR (CDCl3): = 0.95 (t, 6 H, J = 7.4 Hz), 1.41–1.57 (m, 4 H),
IR spectra were obtained on a Tensor27 spectrometer and are re-
–
1
1
ported in wave numbers (cm ). H NMR spectra were recorded on
a Jeol JNMA 400 NMR spectrometer at 400 MHz. TLC were per-
formed with 0.2–0.25 mm precoated silica gel plates (GF-254). El-
emental analyses were performed on Vario EL instrument.
1
.70–1.79 (m, 4 H), 2.59–2.73 (m, 4 H).
Diphenyl Sulfoxide
Solid; mp 72.0–73.5 °C.
–
1
IR (KBr): 1031 cm .
Oxidation of Methyl Phenyl Sulfide in Phenol; Methyl Phenyl
Sulfoxide (Entry 1); Typical Procedure
To a stirred solution of methyl phenyl sulfide (1.24 g, 10 mmol) in
1
H NMR (CDCl ): = 7.41–7.49 (m, 6 H), 7.62–7.66 (m, 4 H).
3
phenol (11.28 g, 120 mol) at 25 °C was added 30% aq H O (2.25
2
2
Benzyl Phenyl Sulfoxide
Solid; mp 122.0–123.5 °C.
mL, 20 mmol). The progress of the reaction was followed by TLC.
After complete disappearance of the reactant (0.5 min), the excess
H O was quenched with sat. aq Na SO solution. The phenol was
–
1
IR (KBr): 1030 cm .
2
2
2
3
neztralized with 10% aq NaOH solution (43.5 mL). The two phases
were separated and the aqueous layer was back extracted with
EtOAc (3 × 50 mL). The combined organic layers were washed
with H O, dried (MgSO ) and the EtOAc was removed in vacuo to
1H NMR (CDCl3): = 3.98 (d, 1 H, J = 12.6 Hz), 4.10 (d, 1 H,
J = 12.6 Hz), 6.95–7.02 (m, 2 H), 7.20–7.33 (m, 3 H), 7.35–7.53 (m,
5 H).
2
4
Synthesis 2004, No. 2, 227–232 © Thieme Stuttgart · New York

PAPER
Conversion of Sulfides to Sulfoxides
231
1
Allyl Methyl Sulfoxide
H NMR (CDCl ): = 2.71–3.08 (m, 4 H), 7.53 (m, 5 H).
3
Oil.
Anal. Calcd for C H NOS: C, 60.34; H, 5.28; S, 17.88. Found: C,
60.35; H, 5.30; S, 17.84.
9
9
–
1
IR (KBr): 1647, 1050 cm .
1H NMR (CDCl3): = 2.03 (s, 3 H ), 3.14 (dt, 2 H, J = 7.0, 1.1 Hz),
4
Oil.
-(1-Methoxyethyl)phenyl Methyl Sulfoxide
5
5
.08 (dq, 1 H, J = 1.5, 17.0 Hz), 5.09 (dq, 1 H, J = 1.1, 10.2 Hz),
.78 (ddt, 1 H, J = 7.1, 10.3, 16.9 Hz).
–
1
IR (KBr): 1218, 1047 cm .
4
Oil.
-Acetylphenyl Methyl Sulfoxide
1H NMR (CDCl3): = 1.32 (d, 2 H, J = 6.0 Hz ), 2.60 (s, 3 H), 3.19
(
s, 3 H), 4.12 (q, 1 H, J = 6.5 Hz), 7.30–7.65 (m, 4 H).
–
1
IR (KBr): 1692, 1045 cm .
1H NMR (CDCl3): = 2.58 (s, 3 H), 2.71 (s, 3 H), 7.61 (d, 2 H,
Anal. Calcd for C H O S: C, 60.61; H, 7.07; S, 16.16. Found: C,
1
0
14
2
60.67; H, 7.02; S, 16.21.
J = 8.5 Hz), 7.97 (d, 2 H, J = 8.5 Hz).
4
Oil.
-Acetamidophenyl Ethyl Sulfoxide
Anal. Calcd for C H O S: C, 59.34; H, 5.49; S, 17.58. Found: C,
9
10
2
5
9.28; H, 5.51; S,17.60.
–
1
IR (KBr): 3310, 3271, 3001, 1670, 1211, 1038 cm .
3
Oil.
-Hydroxy-1-methylpropyl Phenyl Sulfoxide
1
H NMR (CDCl ): = 0.99 (t, 3 H, J = 7.40 Hz), 2.11 (s, 3 H), 2.56–
.95 (q, 2 H, J = 7.40 Hz), 7.20–7.75 (m, 4 H), 8.71 (s, 1 H).
3
2
–
1
IR (KBr): 3393, 1214, 1030 cm .
Anal. Calcd for C H NO S: C, 56.87; H, 6.16; S, 15.17. Found: C,
56.83; H 6.18; S, 15.14.
1
0
13
2
1
H NMR(CDCl ): = 0.99 (d, 3 H, J = 6.9 Hz), 1.63–2.33 (m, 2 H),
3
2
.84–3.22 (m, 2 H), 3.81 (m, 2 H), 7.55 (m, 5 H).
2
Oil.
-Ethoxycarbonylethyl Phenyl Sulfoxide
Anal. Calcd for C H O S: C, 60.61; H, 7.07; S, 16.16. Found: C,
10
14
2
6
0.63; H, 7.11; S, 16.09.
–
1
IR (KBr): 1735, 1220, 1039 cm .
2
-Cyclopentenyl Benzyl Sulfoxide
1H NMR (CDCl3): = 1.05 (t, 3 H, J = 7.10 Hz), 2.49–2.72 (m, 2
H), 2.88–3.26 (m, 2 H), 3.86–4.24 (q, 2 H, J = 7.06 Hz), 7.38–7.66
(m, 5 H).
Solid; mp 66.0–68.5 °C.
–
1
IR (KBr): 1030 cm .
1H NMR (CDCl3): = 1.80–1.90 (m, 2 H), 2.16–2.21 (m, 2 H),
Anal. Calcd for C H O S: C, 58.41; H, 6.19; S, 14.16. Found: C,
11
14
3
2
(
7
.21–2.31 (m, 2 H), 2.50–2.53 (m, 2 H), 2.65–2.79 (m, 2 H), 3.97
d, 1 H, J = 12.8 Hz), 4.05 (d, 1 H, J = 12.8 Hz), 5.36–5.38 (m, 1 H),
.27–7.41 (m, 5 H).
58.44; H 6.17; S, 14.19.
References
Anal. Calcd for C H OS: C, 71.79; H, 7.69; S, 13.67. Found: C,
1
4
18
7
1.84; H, 7.62; S,13.59.
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1
Oil.
-Phenylsulfinylpropan-2-one
–
1
(2) Ravikumar, K. S.; Barbier, F.; Bégué, J.-P.; Bonnet-Delpon,
D. J. Fluorine Chem. 1999, 95, 123.
(3) (a) Martin, S. E.; Rossi, L. I. Tetrahedron Lett. 2001, 42,
IR (KBr): 1710, 1036 cm .
1
H NMR (CDCl ): = 2.24 (s, 3 H), 3.80 (d, 1 H, J = 13.7 Hz), 3.86
d, 1 H, J = 13.7 Hz), 7.52–7.58 (m, 3 H), 7.65–7.68 (m, 2 H).
3
(
7174. (b) Ali, M. H.; Stevens, W. C. Synthesis 1997, 764.
Anal. Calcd for C H O S: C, 59.53; H, 5.49; S, 17.58. Found: C,
(c) Batigalhia, F.; Zaldini-Hernandes, M.; Ferreira, A. G.;
Malvestiti, I.; Cass, Q. B. Tetrahedron 2001, 57, 9669.
9
10
2
5
9.48; H, 5.43; S, 17.40.
(d) Lindén, A. A.; Krüger, L.; Bäckvall, J.-E. J. Org. Chem.
Phenyl Ethyl Sulfoxide
Oil.
2003, 68, 5890. (e) Iranpoor, N.; Firouzabadi, H.; Pourali,
A.-R. Tetrahedron 2002, 58, 5179. (f) Khurana, J. M.;
Panda, A. K.; Ray, A.; Gogia, A. Org. Prep. Proced. Int.
–
1
IR (KBr): 1045 cm .
1996, 28, 234. (g) Varma, R. S.; Saini, R. K.; Meshram, H.
1H NMR(CDCl3): = 0.98 (t, 3 H, J = 7.29 Hz), 2.48–2.91 (m, 2 H),
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Fields, J. D.; Kropp, P. J. Tetrahedron Lett. 1995, 36, 3825.
7
.05–7.44 (m, 5 H), 7.52–7.58 (m, 3 H).
(
i) Mckillop, A.; Tarbin, J. A. Tetrahedron Lett. 1983, 24,
(
Z)-1-Phenylsulfinyl-2-heptylethene
1505. (j) Leonard, N. J.; Johnson, C. R. J. Org. Chem. 1962,
27, 282. (k) Goheen, D. W.; Bennett, C. F. J. Org. Chem.
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J. A. Tetrahedron Lett. 1983, 24, 1505. (n) Trost, B. M.;
Curran, D. P. Tetrahedron Lett. 1981, 22, 1287.
Oil.
–
1
IR (KBr): 2860, 1455, 1039 cm .
1H NMR (CDCl3): = 0.86–0.90 (m, 3 H), 1.23–1.36 (m, 10 H),
2
.52–2.67 (m, 2 H), 6.18–6.24 (m, 1 H), 6.62 (dt, 1 H, J = 6.8, 15.5
Hz), 7.45–7.52 (m, 5 H).
(o) Kennedy, R. J.; Stock, A. M. J. Org. Chem. 1960, 25,
Anal. Calcd for C H OS: C, 72.00; H, 8.80; S, 12.80. Found: C,
1901. (p) Djerassi, C.; Engle, R. R. J. Am. Chem. Soc. 1953,
75, 3838. (q) Fringuelli, F.; Pellegrino, R.; Piermatti, O.;
Pizzo, F. Synth. Commun. 1994, 24, 2665.
1
5
22
7
2.08; H 8.84; S, 12.77.
2
Oil.
-Cyanoethyl Phenyl Sulfoxide
(4) Schultz, H. S.; Freyermuth, H. B.; Buc, S. R. J. Chem. Soc.
1963, 1140.
(
5) Collins, F. M.; Lucy, A. R.; Sharp, C. J. Mol. Catal., A:
Chem. 1997, 117, 397.
–
1
IR (KBr): 2256, 1219, 1047 cm .
Synthesis 2004, No. 2, 227–232 © Thieme Stuttgart · New York

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W. L. Xu et al.
PAPER
(
(
(
6) Ravikumar, K. S.; Bégué, J.-P.; Bonnet-Delpon, D.
Tetrahedron Lett. 1998, 39, 3141.
7) Drabowicz, J.; Mikojajczyk, M. Synth. Commun. 1981, 11,
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(10) (a) Kosower, E. M. J. Am. Chem. Soc. 1958, 80, 3253.
(b) Kosower, E. M. J. Am. Chem. Soc. 1958, 80, 3267.
(11) Watanabe, M.; Fuoss, R. M. J. Am. Chem. Soc. 1956, 78,
527.
1025.
8) Parker, A. J. J. Chem. Soc. 1961, 1328.
Synthesis 2004, No. 2, 227–232 © Thieme Stuttgart · New York