Selective oxidation of sulfides to sulfoxides with cyanuric chloride and urea-hydrogen peroxide adduct

Article abstract of DOI:10.1016/j.tetlet.2014.05.080

Although a number of methods have been developed for the selective oxidation of sulfides to sulfoxides, the need remains for alternative efficient, reliable strategies that can be generally applied to various sulfides and that use readily available reagents under mild reaction conditions. Herein, we report the use of urea-hydrogen peroxide adduct (UHP) and cyanuric chloride in CH ₃CN at room temperature to convert sulfides to sulfoxides in excellent yields. In particular, this protocol produced sulfoxides with aromatic rings bearing electron-withdrawing groups in excellent yields.

Full text of DOI:10.1016/j.tetlet.2014.05.080

Tetrahedron Letters xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Selective oxidation of sulfides to sulfoxides with cyanuric chloride
and urea–hydrogen peroxide adduct
⇑
Heung Bae Jeon , Kyoung Tae Kim, Sang Hyun Kim
Department of Chemistry, Kwangwoon University, Seoul 139-701, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
Although a number of methods have been developed for the selective oxidation of sulfides to sulfoxides,
the need remains for alternative efficient, reliable strategies that can be generally applied to various sul-
fides and that use readily available reagents under mild reaction conditions. Herein, we report the use of
urea–hydrogen peroxide adduct (UHP) and cyanuric chloride in CH3CN at room temperature to convert
sulfides to sulfoxides in excellent yields. In particular, this protocol produced sulfoxides with aromatic
rings bearing electron-withdrawing groups in excellent yields.
Received 14 February 2014
Revised 12 May 2014
Accepted 16 May 2014
Available online xxxx
Keywords:
Selective oxidation
Sulfoxide
Ó 2014 Elsevier Ltd. All rights reserved.
Sulfide
Cyanuric chloride
Urea–hydrogen peroxide adduct (UHP)
The selective oxidation of sulfides to sulfoxides is a fundamen-
tal and important functional group transformation in organic syn-
thesis because organic sulfoxides are useful synthetic
intermediates for the construction of various chemically and bio-
logically significant molecules1 and sulfoxide reactions are signifi-
cant in medicinal chemistry and drug metabolism.2 The increasing
interest in and applications of sulfoxides have prompted investiga-
tions on novel methodologies for the preparation of these
compounds.
During the last few decades, numerous strategies have been
developed to selectively oxidize sulfides to sulfoxides because sul-
fide oxidation is considered the most direct and facile approach for
preparing sulfoxides. Among these strategies, the use of hydrogen
peroxide (H2O2) is one of the most popular methods.3 However, an
activator is essential for the success of this reaction because H2O2
alone oxidizes sulfides rather slowly. Therefore, a variety of transi-
tion metal complexes that include titanium (Ti),4 molybdenum
(Mo),5 iron (Fe),6 vanadium (V),7 tungsten (W),8 rhenium (Re),9
scandium (Sc),10 zirconium (Zr),11 manganese (Mn),12 copper
(Cu),13 and cerium (Ce)14 have been widely employed as activators
with H2O2 for the oxidation of sulfides. Other reagents such as
cyanuric chloride,15 1,3,5-triazo-2,4,6-triphosphorine-2,2,4,4,6,6-
tetrachloride,16 phosphorus oxychloride,17 organic acids,18 and
boric acid19 have also been utilized as activators. Recently, we
became interested in the oxidation and reduction of organosulfur
compounds. In our previous endeavors, sulfoxides were readily
reduced to sulfides with thionyl chloride and triphenylphos-
phine.20 However, the selective oxidation of sulfides to sulfoxides
in good yield proved difficult due to the low reactivity of diaryl sul-
fides with aromatic rings bearing electron-withdrawing groups or
because of overoxidation to sulfones (e.g., with other aryl and alkyl
sulfides). Particularly, the oxidation of diaryl sulfides with aro-
matic rings bearing electron-withdrawing groups to sulfoxides
has only been reported in a few papers and uses inconvenient
reagents, toxic and odorous reagents, or harsh reaction condi-
tions.9a,16,21 For these reasons, a need remains for alternative effi-
cient and reliable methods that utilize readily available reagents
under mild reaction conditions for the selective, general oxidation
of various sulfides to sulfoxides. Thus, we considered the use of
urea–hydrogen peroxide adduct (UHP) as an oxidant in the pres-
ence of cyanuric chloride. Both reagents are inexpensive, commer-
cially available, easy to handle, and stable during long-term
storage. Although UHP alone could not oxidize sulfides at room
temperature, sulfide oxidation can occur at high temperatures22
and in the presence of catalysts such as Ti-beta zeolite,23 metallo-
porphyrin,24 and molybdatophosphoric acid.25 In our effort to dis-
cover a novel, efficient, and reliable oxidation method using an
easily available activator with UHP under mild reaction conditions,
we report herein that cyanuric chloride is an excellent activator for
the selective oxidation of different sulfides to sulfoxides.
Initial selective oxidation experiments of a diaryl sulfide with
aromatic rings bearing electron-withdrawing groups to obtain
the corresponding sulfoxide were performed and optimized using
⇑
Corresponding author. Tel.: +82 2 940 5583; fax: +82 2 911 8584.
E-mail address: hbj@kw.ac.kr (H.B. Jeon).
http://dx.doi.org/10.1016/j.tetlet.2014.05.080
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Jeon, H. B.; et al. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.05.080

2
H. B. Jeon et al. / Tetrahedron Letters xxx (2014) xxx–xxx
bis(4-nitrophenyl) sulfide to determine suitable reaction condi-
tions (i.e., oxidant, additive, and solvent) (Table 1). No reaction
occurred when 30% hydrogen peroxide (H2O2) was used in the
absence of an additive and in the presence of 0.1 equiv of cyanuric
chloride (CC) (entries 1 and 2). The use of 1.5 equiv of cyanuric
chloride as an additive with 30% H2O2 afforded the desired sulfox-
ide in 5% yield (entry 3). Activation with cyanuric chloride may
have been less effective because of interference by H2O in 30%
H2O2. Accordingly, we determined to change the oxidant to UHP
from 30% H2O2 to perform the reaction in organic solvents. When
1.5 equiv of UHP was employed as the oxidant in the presence of
1.5 equiv of cyanuric chloride in THF, sulfoxide was obtained in
38% yield (entry 4). After obtaining this promising result, we per-
formed the reactions in different solvents, including CH3CN (entry
5), THF/CH3CN (entry 6), CH2Cl2 (entry 7), CHCl3 (entry 8), EtOAc
(entry 9), acetone (entry 10), and DMF (entry 11). Surprisingly,
using CH3CN as the solvent increased the yield of the desired prod-
uct to 80% (entry 5). When we used 2 and 2.5 equiv of UHP with 2
and 2.5 equiv of cyanuric chloride in CH3CN to obtain better yields,
the desired sulfoxides were produced in 88% yield (entries 12 and
13). When the amount of cyanuric chloride was reduced to 1 equiv,
the yield of the desired product decreased to 80% (entry 14). As
expected, the reaction did not occur in the presence of UHP with-
out cyanuric chloride (entry 15). These results indicate that UHP
and cyanuric chloride can be employed as an oxidant and activator,
respectively, in the selective oxidation of diaryl sulfides with aro-
matic rings bearing electron-withdrawing groups to afford the cor-
responding sulfoxides, providing a new efficient oxidation method
using mild reaction conditions. In addition, when the reaction of
UHP and cyanuric chloride with thianthrene 5-oxide was per-
formed to examine the high selectivity for sulfoxide as a predom-
inant product, Xso value was 0.03.26 This value means that UHP/
cyanuric chloride system is a powerful selective oxidation method
to sulfoxide working as electrophilic oxidant.
cyanuric chloride (2 equiv) in CH3CN at room temperature. All
diaryl sulfides with aromatic rings bearing electron-withdrawing
groups, including acetyl- (entry 2), cyano- (entry 3), trifluoro-
methyl- (entry 4), fluoro- (entry 5), and methoxycarbonyl-groups
(entry 6), were converted to their corresponding sulfoxides in
excellent yields. With methyl 4-acetylphenyl sulfide (entry 7)
and methyl 4-nitrophenyl sulfide (entry 8), which have an
aromatic ring bearing an electron-withdrawing group, the selec-
tive oxidation reactions produced the corresponding sulfoxides
in yields of 92% and 88%, respectively, under the same reaction
conditions as those used for bis(4-nitrophenyl) sulfide (entry
1). When methyl phenyl sulfide, which does not possess an elec-
tron-withdrawing group, was oxidized under the same reaction
conditions, the desired sulfoxide was obtained in only 57% yield
and the rapid generation of an undesired sulfone was observed
(entry 9). To reduce sulfone formation (i.e., overoxidation), we
varied the amounts of UHP and cyanuric chloride. As a result,
the reaction of methyl phenyl sulfide with 1 equiv of UHP and
1 equiv of cyanuric chloride produced the desired sulfoxide in
96% yield. Other aryl methyl sulfides with aromatic rings bearing
methyl- (entry 10), methoxy- (entry 11), and chloro-groups
(entry 12) were converted to their corresponding sulfoxides in
excellent yields under the same reaction conditions. When
diphenyl sulfide (entry 16) and dialkyl sulfides, such as dioctyl
sulfide (entry 13), dibenzyl sulfide (entry 14), and difurfuryl
sulfide (entry 15), were treated with UHP (1 equiv) and cyanuric
chloride (1 equiv), the desired sulfoxides were obtained in
excellent yields. Clearly, the use of UHP and cyanuric chloride
produced the desired sulfoxides from all types of sulfides with
excellent yields. Our results prove that cyanuric chloride is a
good activator and that UHP is a more reactive oxidant than
aqueous H2O2 when utilized with cyanuric chloride.
In conclusion, we obtained the desired sulfoxides in excellent
yield when aliphatic and aromatic sulfides were treated with
UHP and cyanuric chloride in CH3CN at room temperature and
we found that UHP is more powerful oxidizing agent than aqueous
H2O2 when they are employed with cyanuric chloride as an
activator. Notably, diaryl sulfides with aromatic rings bearing
electron-withdrawing groups were also converted to their
Next, the generality of this UHP/cyanuric chloride combina-
tion as reagents for the selective oxidation of sulfides into
sulfoxides was investigated, as shown in Table 2.27 First, a
variety of diaryl sulfides with aromatic rings bearing electron-
withdrawing groups were treated with UHP (2 equiv) and
Table 1
Oxidation of bis(4-nitrophenyl)sulfide to bis(4-nitrophenyl)sulfoxide using various reaction conditionsa
O
S
oxidant
S
additive
solvent
O2N
NO2
20 oC
O2N
Solvent
NO2
Entry
Oxidant (equiv)
Additive (equiv)
Timeb (h)
Yieldc (%)
1
2
3
4
5
6
7
8
H2O2 (5)
H2O2 (2)
H2O2 (2)
UHP (1.5)
UHP (1.5)
UHP (1.5)
UHP (1.5)
UHP (1.5)
UHP (1.5)
UHP (1.5)
UHP (1.5)
UHP (2)
12
12
12
12
3.5
5
12
12
12
4.5
4
NR
NR
5
38
80
80
5
CC (0.1)
CC (1.5)
CC (1.5)
CC (1.5)
CC (1.5)
CC (1.5)
CC (1.5)
CC (1.5)
CC (1.5)
CC (1.5)
CC (2)
CH3CN
CH3CN
THF
CH3CN
THF/CH3CN
CH2Cl2
CHCl3
EtOAc
Acetone
DMF
CH3CN
CH3CN
CH3CN
CH3CN
H2O
12
8
9
10
11
12
13
14
15
16
57
37
88
88
80
NR
10
3
UHP (2.5)
UHP (2)
UHP (2)
CC (2.5)
CC (1)
2.5
3.5
12
12
Oxone (1)
a
b
c
UHP means urea–hydrogen peroxide adduct and CC means cyanuric chloride.
12 h means slow reaction without generation of sulfone and other reaction times mean the reaction was stopped when sulfone was observed on TLC.
Isolated yields and NR means no reaction.
Please cite this article in press as: Jeon, H. B.; et al. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.05.080

H. B. Jeon et al. / Tetrahedron Letters xxx (2014) xxx–xxx
3
Table 2
Oxidation of various sulfides to sulfoxides under optimized reaction conditionsa
O
S
UHP, CC
S
R1
R2
CH3CN, 20 o
C
R1
R2
Entry
1
Substrate
Amount of UHP (equiv)
2
Amount of CC (equiv)
2
Reaction timeb (h)
3
Yieldc (%)
88
S
S
O2N
NO2
2
2
2
3
87
O
NC
O
S
3
4
5
6
2
2
2
2
2
2
2
2
3.5
1.5
1
85
88
85
84
CN
S
F3C
CF3
S
F
F
S
4
MeO2C
CO2Me
S
S
7
2
2
2
2
1.5
1.5
92
88
O
8
9
O2N
S
2
2
1
1
2
1
2
1
1.5
6
2.5
2.5
57
90
86
96
S
10
11
1
1
1
1
2
2
94
95
H3C
CH3O
Cl
S
S
12
13
1
1
1
1
6
92
98
S
1.5
S
14
15
1
1
1
1
4
3
90
87
O
O
S
S
16
1
1
2.5
94
a
b
c
UHP means urea–hydrogen peroxide adduct and CC means cyanuric chloride.
Reaction time means the reaction was stopped when sulfone was observed on TLC.
Isolated yields.
sulfoxides in excellent yield under mild reaction conditions using
the UHP and cyanuric chloride. Due to the ease of operation, mild
reaction conditions, use of inexpensive reagents, and high general-
ity of substrates, this protocol demonstrates promise in broad
applications in organic synthesis.
Acknowledgments
We are grateful for support from Basic Science Research Pro-
gram through the National Research Foundation of Korea (NRF)
funded by the Ministry of Education, Science and Technology
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4
H. B. Jeon et al. / Tetrahedron Letters xxx (2014) xxx–xxx
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and UHP (2.0 or 1.0 mmol according to the sulfide) in CH3CN (20 mL) was
added cyanuric chloride (2.0 or 1.0 mmol according to the sulfide). The
resulting solution was stirred until the sulfone was generated by TLC
monitoring at room temperature and then quenched with H2O. The reaction
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Please cite this article in press as: Jeon, H. B.; et al. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.05.080