Metal-free chemoselective oxidation of sulfides by in situ generated Koser's reagent in aqueous media

Article abstract of DOI:10.1016/j.tetlet.2014.01.116

Selective oxidation of sulfides was successfully performed by employing phenyliodine diacetate as an oxidant with the catalysis of TsOH in aqueous solution under mild conditions. Sulfoxides were formed with 1.1 equiv of PhI(OAc)₂ at room temperature; whereas sulfones were obtained in the presence of 2.1 equiv of PhI(OAc)₂ at 80 C under otherwise identical conditions. Notably, various sulfides were converted to corresponding sulfoxides or sulfones in good to high yields by this metal-free protocol.

Full text of DOI:10.1016/j.tetlet.2014.01.116

Tetrahedron Letters 55 (2014) 1818–1821
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Metal-free chemoselective oxidation of sulfides by in situ generated
Koser’s reagent in aqueous media
⇑
Bing Yu, Chun-Xiang Guo, Chun-Lai Zhong, Zhen-Feng Diao, Liang-Nian He
State Key Laboratory and Institute of Elemento-Organic Chemistry, Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Nankai University, Tianjin
300071, People’s Republic of China
a r t i c l e i n f o
a b s t r a c t
Article history:
Selective oxidation of sulfides was successfully performed by employing phenyliodine diacetate as an
oxidant with the catalysis of TsOH in aqueous solution under mild conditions. Sulfoxides were formed
with 1.1 equiv of PhI(OAc)2 at room temperature; whereas sulfones were obtained in the presence of
2.1 equiv of PhI(OAc)2 at 80 °C under otherwise identical conditions. Notably, various sulfides were con-
verted to corresponding sulfoxides or sulfones in good to high yields by this metal-free protocol.
Ó 2014 Elsevier Ltd. All rights reserved.
Received 12 December 2013
Revised 17 January 2014
Accepted 27 January 2014
Available online 31 January 2014
Keywords:
Phenyliodine diacetate
Sulfide
Oxidation
Aqueous reaction
Sulfoxides and sulfones are important compounds due to their
properties and reactivity. They have been widely used in the
preparation of biologically and pharmaceutically significant com-
pounds.1–3 In particular, sulfoxides have also emerged as oxotrans-
fer reagents4 and as ligands.5 On the other hand, the strong
inductive ability of the sulfone group makes it attractive in the
field of asymmetric organocatalysis.6 In this context, a considerable
effort has been devoted toward the preparation of sulfoxides and
sulfones. One of the most favored and straightforward synthetic
methods could be selective oxidation of sulfides to sulfoxides or
sulfones (Scheme 1), which has been extensively studied by using
different oxidants such as molecular oxygen,7 hydrogen perox-
ide,8,9 organic hydroperoxide,10 hypervalent iodine,11 and other
halogen derivatives.12 However, it is worth mentioning that a tran-
sition metal catalyst is often required to perform the reaction
smoothly,13,14 which may limit the application in terms of safety,
toxicity, and abolishment of heavy metals. In addition, metal-free
catalyzed processes are interesting alternatives to classical organic
transformations since they are often more economical and envi-
ronmentally friendly.
O
S
O
[O]
Cat.
O
S
or
R1
R2
S
R1
R2
R2
R1
[O] = halogen, peracids, dioxiranes, hypervalent iodine,
alkyl hydroperoxides, hypochlorites,H2O2, O2, etc.
Cat. = Os, Sc, Mo, Ti, V, Re, Ru, Cr, W, Cu, Zn, Fe etc.
Scheme 1. Catalytic oxidation of sulfides to afford sulfoxides or sulfones.
oxidation of sulfides. Togo and co-workers have prepared (diacet-
oxyiodo)arenes containing heteroaromatics as novel oxidant to
oxidize diaryl sulfides to corresponding sulfoxides.18 Kobayashi
group19 developed immobilized ruthenium catalysts for the oxida-
tion of sulfides to corresponding sulfones by using phenyliodine
diacetate (PIDA) as oxidant. In addition, Zhdankin and co-work-
ers,20 reported a sulfoxidation protocol by using oligomeric iodosyl-
benzene sulfate, which was in situ generated from PIDA and a
stoichiometric amount of sodium bisulfate, as oxidant in aqueous
solution. On the other hand, Koser’s reagent, hydroxy(tosyl-
oxy)iodobenzene, was found to be efficient in a variety of transfor-
mations such as oxytosylation, dioxytosylation, phenyliodination,
and oxidation.21 Moreover, Yusubov and Wirth disclosed the
reaction between PIDA and p-toluenesulfonic acid (TsOH), which
gave Koser’s reagent with reasonable yields.22 In view of these
precedents, sulfide oxidation involving hypervalent iodine reagents
required prior preparation of catalyst or synthesis of Koser’s re-
agent as oxidant with a stoichiometric amount of additives (e.g.
TsOH, NaHSO4). Therefore, we assumed that if the Koser’s reagent
As powerful electrophiles15 and highly selective oxidants,16
hypervalent iodine reagents have found broad application in organ-
ic chemistry due to their low toxicity, mild reactivity, ready avail-
ability, high stability, and easy handling.17 In particular,
hypervalent iodine compounds have also been employed in the
⇑
Corresponding author. Tel./fax: +86 22 23503878.
E-mail address: heln@nankai.edu.cn (L.-N. He).
http://dx.doi.org/10.1016/j.tetlet.2014.01.116
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

B. Yu et al. / Tetrahedron Letters 55 (2014) 1818–1821
1819
could be generated from PIDA and TsOH, then the possibility of
employing TsOH as a catalyst should be considered for the reaction
using PIDA as oxidant in the oxidation of sulfides.
the synthesis of sulfoxide 2a and sulfone 3a from sulfide 1a could
be accessed efficiently by using PIDA as oxidant, p-toluenesulfonic
acid as catalyst in water (entries 9 and 11).
As a part of our continuous interest on selective oxidation reac-
tions,23,24 we herein would like to report selective oxidation of sul-
fides in aqueous solution with the in situ formed Koser’s reagent,
from PIDA and a catalytic amount of TsOH, as reactive oxidant to
afford the corresponding sulfoxides or sulfones under mild condi-
tions (Scheme 2).
With the optimized conditions in hand, the utility and general-
ity of this transition-metal-free process for the selective oxidation
of sulfides were further examined. As shown in Table 2, a series of
aromatic sulfides can be transformed into the corresponding sulf-
oxide. Various substituents including –CH3, –OCH3, –Cl, and –CN
could be tolerated and the sulfoxides were obtained in almost
excellent yields (Table 2 entries 1–5). With sulfide 1e, the yield
was improved to 87% after increasing the reaction time to 12 h
(entry 5). In the case of diphenyl sulfide 1f, the isolated yield of
sulfoxide 2f was 78% (entry 6). However, the sulfoxidation of
dibenzothiophene sulfoxide 1g was failed, probably due to its poor
solubility in water (entry 7). Dialkyl sulfides (2h and 2i) could con-
vert to the corresponding sulfoxide in good to excellent yield under
the reaction condition for 12 h (entries 8 and 9).
The exploratory experiments started using thioanisole 1a as the
model substrate. As shown in Table 1, the oxidation of 1a using
PIDA (1.1 equiv) as oxidant in CH3CN under 80 °C for 12 h,
provided phenyl methyl sulfoxide 2a in almost quantitative yield
(Table 1, entry 1). An increase in the PIDA amount to 2.1 equiv
caused a slight increase in the yield of phenyl methyl sulfone 3a
to 7% (entry 2). Interestingly, the reaction in water gave 44% yield
of 2a and 55% yield of 3a (entry 3). The addition of a catalytic
amount of Ag2CO3, CuBr2, and FeBr2 did not lead to a significant
improvement in sulfone yield (entries 4–6). When sodium dodecyl
sulfate (SDS) was employed as phase-transfer catalyst, the yield of
3a was increased to 66% (entry 7). Moreover, 40 mol % of AcOH was
also demonstrated to be inefficient (entry 8). Surprisingly, excel-
lent conversion and selectivity were achieved in the presence of
TsOH (10 mol %) with water as a solvent (entry 9). Nevertheless,
only 12% yield of 3a was obtained in ethanol (entry 10). Compared
with other solvent, water was demonstrated to be essential for the
TsOH-catalyzed oxidation process. On the other hand, the aqueous
reaction gave 2a with 89% yield using PIDA (1.1 equiv) as oxidant
under room temperature for 5 h (entry 11). As a consequence,
We next turned our attention to the scope of sulfones’ prepara-
tion. The results have been listed in Table 3. The sulfides 1a–1d
Table 2
Oxidation of sulfides to sulfoxidesa
TsOH (10 mol%)
O
S
S
PhI(OAc)2 (1.1 equiv.)
R1
R2
R1
R2
H2O, r.t.
1a-i
2a-i
Entry Substrate
Sulfoxide
time Yieldb
(h)
(%)
S
O
S
1
2
4
5
88
1a
O
S
r.t.
2a
O
S
Cat. TsOH
PhI(OAc)2
R1
R2
S
S
R1
R2
80 oC
in H2O
O
O
85
84
1b
S
R1
R2
2b
R1, R2 = aryl, alkyl
S
O
S
Scheme 2. Chemoselective oxidation of sulfides.
3
4
5
6
5
1c
O
2c
O
Table 1
S
O
S
Optimization of the reaction conditionsa
5
85
87
78
1d
O
S
Cl
O
O
S
2d
Cl
S
PhI(OAc)2, Cat.
solvent, 80 oC, 12 h
+
S
O
S
12
5
2a
3a
Yieldb (%)
1a
1e
NC
2e
NC
Entry
Solvent
PIDA (equiv)
Cat.
Conv.b (%)
O
S
S
2a
3a
1
2
3
4
5
6
CH3CN
CH3CN
H2O
1.1
2.1
2.1
2.1
2.1
2.1
2.1
2.1
2.1
2.1
1.1
—
—
—
99
98
92
44
47
50
43
33
35
8
<1
7
1f
>99
>99
>99
>99
>99
>99
96
>99
86
>99
2f
55
52
49
56
66
60
91
12
10
S
O
S
H2O
H2O
H2O
H2O
H2O
H2O
EtOH
H2O
Ag2CO3
CuBr2
FeBr2
SDS
AcOH
TsOH
TsOH
TsOH
7
24
0
1g
7
8c
9
2g
S
O
S
1h
8
9
12
12
81
90
10
73
89
2h
11d
S
O
S
1i
a
Reaction conditions: To a glass tube equipped with a magnetic stir bar, thio-
2i
anisole (24.8 mg, 0.2 mml), indicated amount of PIDA, catalyst (10 mol %), solvent
(1.5 mL) as solvent were added, and the mixture was stirred for 12 h at 80 °C.
SDS = sodium dodecyl sulfate.
a
Reaction conditions: To a glass tube equipped with a magnetic stir bar, sulfide
(0.2 mmol), PIDA (71 mg, 0.22 mmol), p-toluenesulfonic acid (3.4 mg, 0.02 mmol),
H2O (1.5 mL) as solvent were added, and the mixture was stirred at rt for desired
time.
b
Determined by GC with area normalization.
c
40 mol % of AcOH was added.
d
b
Reaction at rt for 5 h.
Isolated yield.

1820
B. Yu et al. / Tetrahedron Letters 55 (2014) 1818–1821
Table 3
Oxidation of sulfides to sulfonesa
TsOH (10 mol%)
O
R1
O
R2
PhI(OAc)2 (2.1 equiv.)
S
R1
1a-i
R2
S
H2O, 80 o
C
3a-i
Entry
1
Substrate
S
Sulfone
Time (h)
12
Yieldb (%)
86
O
S
O
1a
3a
S
O
S
O
2
3
20
20
78
80
1b
3b
S
O
O
S
1c
O
3c
O
S
O
S
O
4
5
20
36
81
40
Cl
1d
3d
Cl
S
O
O
S
1e
NC
3e
NC
S
O
O
S
6
7
20
24
42
0
1f
3f
S
S
O O
S
1g
3g
O
O
1h
8
9
24
24
89
86
S
3h
S
O
O
1i
S
3i
a
Reaction conditions: To a glass tube equipped with a magnetic stir bar, sulfide (0.2 mmol), PIDA (135 mg, 0.42 mmol), p-toluenesulfonic acid (3.4 mg, 0.02 mmol), H2O
(1.5 mL) as solvent were added, and the mixture was stirred for desired time at 80 °C.
b
Isolated yield.
were oxidized to afford the corresponding sulfones in 78–86% yield
under the conditions for 12–20 h, which revealed that the reaction
tolerated functional groups such as 4-methyl, 4-methoxyl, and 4-
halogen (entries 1–4). For 4-cyanophenylmethyl sulfide 1e and di-
phenyl sulfide 1f, low yields were obtained even with prolonged
time (entries 5 and 6). Similarly, dibenzothiophene sulfoxide 1g
was inefficient presumably owing to poor solubility in water (entry
7). Gratifyingly, aliphatic substrates (1h and 1i) displayed good
reactivity to afford the corresponding sulfones.
garded to be formed via further oxidation of the sulfoxide. In partic-
ular, the sulfoxide is rapidly formed under the reaction conditions.
On the other hand, the oxidation of the sulfoxide 2a to generate the
sulfone 3a is much slower (see Supporting information).
As outlined in Scheme 3, a possible mechanism is proposed on
the basis of the results described above. The presumed intermedi-
ate hydroxy(tosyloxy)iodobenzene is generated from phenyliodine
diacetate and p-toluenesulfonic acid in aqueous solution.16,18 The
in situ formed hypervalent iodine reagent, Koser’s reagent, could
facilitate the oxygen transfer during the oxidation of the sulfide
to the sulfoxide and further to the sulfone, which is converted to
PhI and regenerates the catalyst TsOH.
In summary, we have developed a metal-free protocol for selec-
tive oxidation of sulfides under mild conditions. The reactive oxi-
dant was proposed to be Koser’s reagent generated in situ from
readily available phenyliodine diacetate and only 10 mol % of
TsOH, which avoided the prior synthesis of Koser’s reagent with
stoichiometric additives. Notably, the transformation was achieved
in aqueous medium, resulting in the synthesis of sulfoxides and
sulfones by tuning PIDA amount and the reaction temperature.
Various sulfides worked well with this metal-free procedure under
safe and mild conditions.
To further gain insight into the reaction mechanism, 1H NMR
investigations were performed to get information about the reac-
tion intermediate (Fig. 1). In 1H NMR spectrum (A), the chemical
shift of CH3– in methyl phenyl sulfide (a, 2.25 ppm) and CH3– in
methyl phenyl sulfoxide (b, 2.74 ppm) could indicate that the sul-
fide is converted to sulfoxide efficiently without the formation of
the sulfone after stirring for 10 min at room temperature.
After reaction at 80 °C for 2 h, the signal of CH3– in methyl phe-
nyl sulfone (c, 3.10 ppm) is observed as shown in Figure 1B. More-
over, the intensity of sulfoxide signal b is declined; whereas the
sulfone signal c is augmented as the reaction going (Fig. 1B vs
1C). Consequently, the sulfone is found to be the only product with
a trace of sulfide after 24 h (Fig. 1D). As a result, the sulfone is re-

B. Yu et al. / Tetrahedron Letters 55 (2014) 1818–1821
1821
PIDA
the Doctoral Program of Higher Education (20130031110013),
MOE Innovation Team (IRT13022) of China, the ‘111’ Project of
Ministry of Education of China (Project No. B06005) for financial
support.
D2O
b
b
a
a
a
(A)
(B)
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.01.
116.
c
c
References and notes
b
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(D)
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c
a
5.5
4.5
3.5
2.5
1.5
Figure 1. 1H NMR of the oxidative reaction in D2O. (A) Reaction at rt after 10 min,
(B) the reaction at 80 °C after 2 h, (C) the reaction at 80 °C after 12 h, (D) the
reaction at 80 °C after 24 h.
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Chem. 2011, 76, 9593.
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19. Miyamura, H.; Akiyama, R.; Ishida, T.; Matsubara, R.; Takeuchi, M.; Kobayashi,
S. Tetrahedron 2005, 61, 12177.
PhI
H2O
Sulfone
PhI(OAc)2
AcOH
TsOH
Sulfoxide
or
OH
Sulfoxide
Ph I
OTs
20. Yusubov, M. S.; Yusubova, R. Y.; Funk, T. V.; Chi, K.-W.; Zhdankin, V. V. Synthesis
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Sulfide
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Scheme 3. Proposed mechanism for the oxidation of sulfide by in situ formed
Koser’s reagent.
Acknowledgments
We are grateful to the National Natural Science Foundation of
China (Nos. 21172125, 21121002), Specialized Research Fund for