Imide-catalyzed oxidation system: Sulfides to sulfoxides and sulfones

Article abstract of DOI:10.1021/jo100719w

R¹SR² Imide(cat.), → Toulene or DME R ¹SOR² R¹SO₂R² A new combination system, the oxidation of sulfides using aqueous NaOCl in the presence of a catalytic amount of imide under two-phase conditions, has been developed. The combination effectively converts various sulfides to the corresponding sulfoxides and sulfones. It was deduced that the imide could react with NaOCl to produce N-chloroimide, which would play roles of both the active oxidizing reagent and phase transfer catalyst.

Full text of DOI:10.1021/jo100719w

pubs.acs.org/joc
many natural, pharmaceutical, and agricultural com-
Imide-Catalyzed Oxidation System: Sulfides to
Sulfoxides and Sulfones
pounds.1 Although numerous types of oxidation such as
the combinations of metals and co-oxidants,2 metal oxi-
des,3 and peroxy-acids4 have been developed, there are
some drawbacks in terms of safety, toxicity, operationality
of the reaction, and abolishment of heavy metals from the
standpoint of large-scale preparation. Therefore, convenient
and environmentally benign methods for the oxidation of
sulfides are still required.
Naohiro Fukuda and Tomomi Ikemoto*
Chemical Development Laboratories, CMC Center,
Takeda Pharmaceutical Company Limited, Yodogawa-ku,
Osaka 532-8686, Japan
ikemoto_tomomi@takeda.co.jp
Received April 14, 2010
SCHEME 1. Imide-Catalyzed NaOCl Oxidation of Sulfide
A new combination system, the oxidation of sulfides
using aqueous NaOCl in the presence of a catalytic
amount of imide under two-phase conditions, has been
developed. The combination effectively converts var-
ious sulfides to the corresponding sulfoxides and sul-
fones. It was deduced that the imide could react with
NaOCl to produce N-chloroimide, which would play
roles of both the active oxidizing reagent and phase
transfer catalyst.
The oxidation of sulfides to sulfoxides and sulfones is one of
the most important transformations in organic synthesis,
because these functional groups exist in the core structure of
Aqueous NaOCl as safe and inexpensive reagent is used
in the oxidation of sulfide; however, the lower solubility of
hypochlorite ions (OCl-) in organic solvents limits the
substrate as a reactant.5 Although phase transfer catalyst
increased the concentration of OCl- in the organic layer,
resulting in the oxidation of sulfide to sulfoxide in two-
phase condition, no sulfone was produced under the re-
ported condition.6 It was also reported that the oxidation
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DOI: 10.1021/jo100719w
r
Published on Web 06/03/2010
J. Org. Chem. 2010, 75, 4629–4631 4629
2010 American Chemical Society

Fukuda and Ikemoto
JOCNote
TABLE 1. Oxidation of Diphenyl Sulfide with NaOCl in the Presence
of Additive under Two-Phase Conditions
in the presence of water in an organic solvent widely con-
vert sulfide to sulfoxide or sulfone with the equivalent(s)
of resulting imide, which is tedious to remove in workup
operation.8 Meanwhile, imides react with NaOCl (Cl2 þ
NaOH) to produce N-chloroimide.9,10 From these reports,
we envisioned the new catalytic oxidation system as follows
(Scheme 1): (1) NaOCl reacts with the imide in the aqueous
layer to produce N-chloroimide, which transfers to the organic
layer; (2) N-chloroimide oxidizes the sulfide with water to yield
the oxidative product and regenerate the imide, which moves
to the aqueous layer, and this catalytic cycle repeats. Here, we
wish to report the novel imide-catalyzed oxidation of sulfide
using NaOCl under two-phase conditions.
Diphenyl sulfide 1 as a model compound was used as shown
in Table 1, although 1 is generally hard to oxidize.11 When 1
reacted with 10% aqueous NaOCl (3 equiv) for 4 h at room
temperature in toluene as a solvent, 1was recovered in 67% yield
with 1% yield of sulfone 2 and 31% yield of sulfoxide 3 (Table 1,
entry 1). The addition of a phase transfer catalyst, methyl tri-n-
octylammonium chloride (Alliquat 336, 0.1 equiv) according to
the literature6 increased the reaction rate compared with
entry 1 to give 2 in 13% yield; however, 1 also remained
(entry 2). When the sulfide reacted with NaOCl in the
presence of 0.1 equiv of cyanuric acid for 2 h, the oxidation
yield (%)a
entry
additive
solvent
time (h)
2
3
1
1
2
3
4
5
-
toluene
toluene
toluene
toluene
DME
toluene
toluene
toluene
toluene
toluene
4
2
3
2
0.5
3
4
4
4
1
31
2
67
84
alliquat 336
cyanuric acid
succinimide
succinimide
TCCA
13
98b
74
95
94b
4
23
<1
6
7c
8
cyanuric acid
acetamide
TsNH2
94
12
94
3
86
5
9
10
1
96
piperidine
4
aAssay yield by HPLC. bIsolated yield. c1.2 equiv of NaOCl was used.
of sulfide with aqueous NaOCl in diluted hydrochloric acid
or acetic acid produced the corresponding sulfone; how-
ever, these reaction conditions involve the risk of chlorine
emission.7 On the other hand, N-chloroimides such as
N-chlorosuccinimide and trichloroisocyanuric acid (TCCA)
TABLE 2. Sulfonation of Sulfide with Cyanuric Acid Catalyzed NaOCl Oxidation
aIsolated yield. bYield by 1H NMR.
4630 J. Org. Chem. Vol. 75, No. 13, 2010

Fukuda and Ikemoto
JOCNote
completed to give 2 in 96% yield, as expected (entry 3).
Comparatively, the addition of succinimide as a catalyst for 2 h
afforded a mixture of 2 and 3 in 74% and 23% yield, respec-
tively, while the same reaction for 0.5 h in 1,2-dimethoxy-
ethane (DME) converted 1 to 2 in 95% yield (entries 4 and 5).
The use of TCCA as an additive provided almost the same
result as using cyanuric acid (entry 6). These results show
that the active species could be N-chloroimide as shown in
Scheme 1. These differences from cyanuric acid and succi-
nimide could be explained by the solubility of N-chloro-
succinimide and N-chlorinated cyanuric acid as the
active species in the organic solvents.12 When 1.2 equiv
of NaOCl in the presence of cyanuric acid was used, 3 was
selectively obtained in 94% yield (entry 7). The other
additives were also examined. Although both acetamide
and tosylamide accelerated these oxidation rates, these
were slower than that with cyanuric acid (entries 8 and 9).
Meanwhile, piperidine inhibited the oxidation to retain
most of 1 (entry 10).
Subsequently, the NaOCl oxidation catalyzed by cyanuric
acid in toluene was applied to various sulfides 4 to sulfones 5 as
shown in Table 2. The oxidation of dialkyl sulfides 4a and 4b
provided the corresponding sulfones in 96% yield, respectively
(entries 1 and 2). Benzyl phenyl sulfide 4c mainly gave sulf-
oxide 7 chlorinated at the benzylic position of sulfoxide 6
(entry 3). The reaction of allyl phenyl sulfide 4d gave 5d in
moderate yield (entry 4). A variety of functional groups were tole-
rated in methyl phenyl sulfide bearing the ether, nitro, and halogen
groups (entries 5-8). Methylsulfanyl benzothiazole 4i was selecti-
vely oxidized at the 20-position to afford 5i in almost quantitatively
yield (entry 9). Methyl pyridyl sulfide 4j yielded a mixture of 5j and
trichloromethyl sulfone 8, while the sulfide containing cyano group
on the pyridine ring 4k selectively afforded 5k in 95% yield without
chlorination on the methyl group (entries 10 and 11). It was
supposed that the pummerer rearrangement could be inhibited by
the electron-withdrawing effect of the cyano group.
In conclusion, a novel and versatile combination system
for the imide-catalyzed NaOCl oxidation of sulfide to
sulfone and sulfoxide has been developed. To our know-
ledge, this is the first reaction with imide as a catalyst. This
methodology is applied to various sulfides including other
functional groups. The noteworthy feature is that this reaction
can be carried out with an inexpensive reagent under safe and
environmentally friendly conditions. Moreover, we are free of
concern over metal residues in the desired product.
Experimental Section
General Procedure for the Imide-Catalyzed Oxidation of
Sulfide: Oxidation of Diphenyl Sulfide 1 (Table 1, Entry 3). To
a solution of 1 (10.00 g, 53.69 mmol) and cyanuric acid (0.69 g,
5.37 mmol) in toluene (100 mL) was added 10% (w/w) aqueous
NaOCl (119.90 g, 161.07 mmol), and the mixture was stirred
for 3 h at ambient temperature. Ethyl acetate (200 mL) and
sodium sulfite (6.77 g, 53.69 mmol) were added to the reaction
mixture, and the whole mixture was stirred for 0.5 h at
ambient temperature. After being separated, the organic layer
was washed with aqueous NaOH solution (0.3 M, 100 mL)
and concentrated in vacuo. The resulting residue was crystal-
lized in ethanol to afford 2 (11.35 g, 98%). IR (ATR) 427, 559,
583, 681, 688, 698, 725, 759, 999, 1067, 1104, 1152, 1295, 1308,
1
1317, 1447 cm-1; H NMR δ 7.42-7.65 (6H, m), 7.90-7.99
(4H, m); 13C HMR δ 127.7, 129.3, 133.2, 141.7; mp 123.4-
124.1 °C. Anal. Calcd for C12H10O2S: C, 66.03; H, 4.62.
Found: C, 65.95; H, 4.63.
6-(Methylsulfonyl)pyridine-2-carbonitrile (5k): IR (ATR) 440,
496, 537, 671, 733, 768, 822, 851, 943, 972, 988, 1077, 1114, 1151,
1171, 1221, 1304, 1438, 1551, 1579, 2929, 3015, 3081 cm-1; 1H
NMR δ 3.32 (3H, s), 7.92-8.00 (1H, m), 8.14-8.23 (1H, m),
8.27-8.33 (1H, m); 13C HMR δ 39.7, 115.7, 123.8, 131.6, 133.8,
140.0, 159.8; MS (ESI): m/z [M þ H]þ 283; mp 119.5-120.5 °C.
Anal. Calcd for C7H6N2O2S: C, 46.14; H, 3.32; N, 15.38. Found:
C, 46.09; H, 3.25; N, 15.45.
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Acknowledgment. The authors would like to thank Mr. Toru
Ishida and Dr. Masahiro Kajino for helpful discussions.
Supporting Information Available: Experimental proce-
dures and compound characterization data. This material is
available free of charge via the Internet at http://pubs.acs.org.
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