Oxidation of Organosulfides to Organosulfones with Trifluoromethyl 3-Oxo-1λ 3,2-benziodoxole-1(3 H)-carboxylate as an Oxidant

Article abstract of DOI:10.1055/s-0036-1588575

An alternative approach is described for the oxidation of organosulfides to the corresponding organosulfones by using trifluoromethyl 3-oxo-1λ ³,2-benziodoxole-1(3 H)-carboxylate as an oxidant. The oxidation of the sulfides was performed by using 2.4 equivalents of the oxidant in refluxing acetonitrile. The oxidation products were isolated in good to excellent yields.

Full text of DOI:10.1055/s-0036-1588575

SYNLETT
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© Georg Thieme Verlag Stuttgart · New York
2017, 28, A–D
letter
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S. R. Mangaonkar et al.
Letter
Synlett
Oxidation of Organosulfides to Organosulfones with Trifluoro-
methyl 3-Oxo-1λ3,2-benziodoxole-1(3H)-carboxylate as an
Oxidant
Saeesh R. Mangaonkar
Priyanka B. Kole
O
O
Fateh V. Singh*
I
OCOCF3
O
O
Chemistry Division, School of Advanced Science, VIT University,
Chennai Campus, Chennai-600127, Tamil Nadu, India
fatehveer.singh@vit.ac.in
S
S
R2
R2
(2.4 equiv)
R1
R1
MeCN, 16–20 h
8 Examples
68–91%
R1 = H, Cl or OMe;
R2 = Bn, t-Bu or CH(Et)CO2Et
Received: 02.08.2017
Accepted after revision: 29.08.2017
Published online: 21.09.2017
O
Me
Me
S
Cl
O
O
S O
DOI: 10.1055/s-0036-1588575; Art ID: st-2017-d0596-l
N
O
O
COOH
Abstract An alternative approach is described for the oxidation of or-
ganosulfides to the corresponding organosulfones by using trifluoro-
methyl 3-oxo-1λ3,2-benziodoxole-1(3H)-carboxylate as an oxidant. The
oxidation of the sulfides was performed by using 2.4 equivalents of the
oxidant in refluxing acetonitrile. The oxidation products were isolated in
good to excellent yields.
F
2: Laropiprant
1: Rofecoxib
O
O
O
N
S
O
O
Me
S
Key words oxidation, sulfides, sulfones, hypervalent iodine, oxidizing
agents
N
H
H2N
NH2
Cl
H2N
3: Dapson
4: Sulfamethoxazole
H
N
Organosulfones are important scaffolds in medicinal1
and natural-product chemistry.2 The presence of a sulfone
functionality makes these compounds more suitable as
synthetic intermediates and as chemical building blocks for
many biologically active compounds, for example 1–6 (Fig-
ure 1). Rofecoxib (Vioxx; 1) has been introduced as a COX-2
inhibitor and is a potent anti-inflammatory drug3 and an
analgesic.4 Laropiprant (2) is a prostaglandin D2 receptor
antagonist.5 Dapson (3) and sulfamethoxazole (4) have
been developed as potent antibiotics for the treatment of
leprosy and urinary infections, respectively.6,7 Glyburide (5)
has been developed as a second-generation sulfonylurea,
and is used in treating type 2 diabetes by enhancing insulin
secretion.8 Carbutamide (6) is classed as a first-generation
sulfonylurea, and is also used as an antidiabetic agent.9 In
addition, various naturally occurring garlicnins isolated
from Allium sativum L. have been shown to prevent cancer-
cell growth.2
H
N
H
OMe
O
N
S
O
O
O
O
O
O
S
Bu
N
H
N
5: Glyburide
H
H2N
6: Carbutamide
Figure 1 Structures of biologically active compounds 1–6 possessing a
sulfone moiety
derivatives, including Ti,13 Sc,10b Ru,14 Mn,15 Zr,16 Cu,17 or
Fe18 complexes. In addition, several metal-free approaches
have also been reported.19,20 Most oxidation approaches,
however, involve the use of toxic metals or harsh reaction
conditions. Recently, a synthesis of sulfones has been devel-
oped by using hypervalent iodine salts.21
In the past few decades, the chemistry of hypervalent
iodine reagents has received attention due to their favor-
able safety profile and ease of handling.22,23 1-Hydroxy-
1λ3,2-benziodoxol-3(1H)-one 1-oxide (IBX) is one of the
most common hypervalent iodine reagents, and it has been
used in various oxidation reactions.24,25 Despite being a ver-
satile oxidant, IBX has several drawbacks, such as poor solu-
Numerous procedures have been developed for the oxi-
dation of sulfides to sulfoxides and sulfones by various oxi-
dants.10–12 In most of these approaches, oxidation of sul-
fides has been achieved by using various transition-metal
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D

B
S. R. Mangaonkar et al.
Letter
Synlett
bility in common organic solvents26 and a tendency to ex-
plode at elevated temperatures,27 which limit its applica-
tions. We synthesized trifluoromethyl 3-oxo-1λ3,2-
benziodoxole-1(3H)-carboxylate (8) by the oxidation of 2-
iodobenzoic acid (7) with Oxone as oxidant in the presence
of TFA (Scheme 1).28 The synthesis of compound 8 has been
reported previously,29 but its oxidative properties are still
unexplored.
(entry 2). The oxidation product 10a was isolated in 56%
yield when 1.5 equivalents of reagent 8 were used (entry 3).
In this reaction, full conversion was not observed, and 40%
of the starting material was recovered. When reactions
were carried out by using 2.0 or 2.4 equivalents of 8, prod-
uct 10a was obtained 80 and 85% yield, respectively (entries
4 and 5). When the reaction was performed with 3.0 equiv-
alents of 8, no significant improvement was observed, and
10a was isolated in 86% yield (entry 6).
O
Next, our efforts were directed toward the optimization
of the solvent. Various polar and nonpolar solvents were in-
vestigated for the oxidation of sulfide 9a (Table 2). Initially,
the oxidation was performed in MeCN, and oxidation prod-
uct 10a was isolated in 85% yield (Table 2, entry 1). The oxi-
dation proceeded well in the polar aprotic solvents DMSO
and dichloromethane, giving 10a in 65 and 60% yield, re-
spectively (entries 2 and 3). In the polar protic solvents
methanol and ethanol, 10a was obtained in 50 and 52%
yield, respectively (Table 2, entries 4 and 5). When the oxi-
dation was performed in THF or 1,3-dioxane, 10a was ob-
tained in 43 and 30% yield, respectively (entries 6 and 7).
Therefore, the use of 2.4 equivalents of 8 in acetonitrile at
the reflux for 16 hours was concluded to be optimal for the
oxidation of sulfide 9a to the corresponding sulfone 10a.
I
Oxone (1.5 equiv)
O
OH
TFA–CHCl3 (3:1), r.t., 2 h
I
OCOCF3
O
8
7
Scheme 1 Synthesis of trifluoromethyl 3-oxo-1λ3,2-benziodoxole-
1(3H)-carboxylate (8) by the oxidation of 2-iodobenzoic acid (7).
Herein, we report the selective oxidation of sulfides 9 to
the corresponding sulfones 10 by using benziodoxole 8 as
an oxidant. The precursors 9a–c were synthesized by the
reaction of the corresponding thiophenols with t-butanol in
the presence of an acid.30a Other starting materials 9d–h
were synthesized by the reaction of thiophenols with alkyl
bromides in the presence of sodium ethoxide.30b
Initially, our efforts were directed at optimizing reaction
conditions for the oxidation of tert-butyl phenyl sulfide
(9a) as a model substrate. When the oxidation of sulfide 9a
was performed with 1.0 equivalents of benziodoxole 8 in
acetonitrile at room temperature for 36 hours, the oxida-
tion product 10a was not obtained (Table 1, entry 1). When
the same reaction was performed at the reflux tempera-
ture, conversion of the starting material was observed, and
tert-butyl phenyl sulfide (10a) was obtained in 40% yield
Table 2 The Optimization of Solvent for the Oxidation of Sulfide 9a to
Sulfone 10a
O
O
S
S
oxidant 8
solvent, reflux, 16–20 h
9a
10a
Entry
Solvent
Time (h)
Yield (%)
1
2a
3
4
5
6
7
MeCN
DMSO
CH2Cl2
MeOH
EtOH
16
20
20
20
20
20
20
85
65
60
50
52
43
30
Table 1 Optimization of the Stoichiometry of the Iodine(III) Reagent 8
for the Oxidation of Sulfide 9a to Sulfone10a
O
O
I
THF
O
O
OCOCF3
S
S
8
1,3-dioxane
a The reaction was performed at 100 °C.
MeCN, 16–36 h
9a
10a
A series of sulfides 9b–h was then successfully oxidized
to the corresponding sulfones 10b–h in 68–91% yield under
the optimized conditions (Table 3, entries 1–8).31 All the ox-
idation reactions proceeded well, and both electron-with-
drawing and electron-donating aromatic substituents were
tolerated. The oxidation products were isolated in slightly
better yields with substrates having electron-donating
groups on the aromatic ring in comparison to substrates
bearing electron-withdrawing groups.
Entry
Reagent 8 (equiv) Temp
Time (h)
Yield (%)
1
2
3
4
5
6
1.0
1.0
1.5
2.0
2.4
3.0
r.t.
36
24
24
16
16
16
–
reflux
reflux
reflux
reflux
reflux
40
56
80
85
86
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D

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S. R. Mangaonkar et al.
Letter
Synlett
Table 3 Oxidation of Sulfides 9b–h
Acknowledgements
Financial support by the DST, New Delhi, is gratefully acknowledged.
We thank the SAIF Department, VIT Vellore, for the analytical data.
O
O
I
OCOCF3
O
O
Supporting Information
S
S
R2
8 (2.4 equiv)
R2
R1
R1
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1588575.
MeCN, 16–20 h
S
u
p
p
o
nrtogI
f
rmoaitn
S
u
p
p
ortiInfogrmoaitn
10 (68–91%)
9
Entry R1
R2
t-Bu
Time (h)
Product
Yield (%)
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(31) Sulfones 10a–h; General Procedure
A mixture of the appropriate sulfide 9 (0.5 mmol) and benzio-
doxole 8 (413 mg, 2.4 equiv) in MeCN (3 mL) was refluxed for
16–20 h. When the reaction was complete (TLC), sat. aq NaHCO3
(5 mL) was added and the mixture was extracted with EtOAc (3
× 15 mL). The organic layers were combined, dried (Na2SO4), fil-
tered, and concentrated under vacuum. The crude product was
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(1:3)].
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tert-Butyl Phenyl Sulfone (10a)22b
White solid; yield: 84 mg (0.42 mmol, 85%); mp; 90–92 °C. IR
(film): 697, 725, 749, 764, 802, 996, 1021, 1076, 1130, 1277,
1294, 1449, 1475 cm–1. 1H NMR (400 MHz, CDCl3): δ = 1.23 (s, 9
H, t-Bu), 7.46 (t, J = 7.6 Hz, 2 H, ArH), 7.56 (t, J = 7.6 Hz, 1 H,
ArH), 7.77 (d, J = 7.6 Hz, 2 H, ArH). 13C NMR (100 MHz, CDCl3):
δ = 23.5, 59.7, 128.7, 130.3, 133.6, 135.2. GC/MS: m/z
(%) = 198(5), 143(25), 79(13), 77(50), 58(29), 57(100), 51(51),
41(50).
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D