A novel synthesis of aryl methyl sulfones and β-hydroxysulfones from sodium sulfinates and di-tert-butyl peroxide in H2O medium

Article abstract of DOI:10.1016/j.tetlet.2017.12.074

A novel and convenient synthetic route for aryl methyl sulfones and β-hydroxysulfones was developed via the radical reaction between sodium sulfinates and di-tert-butyl peroxide (DTBP). Without any catalysts and additives, the synthetic process could be smoothly carried out to afford the target products in good to excellent yields in H₂O medium, demonstrating its promising application. In the present system, H₂O could act not only as a green solvent but also as a reactant.

Full text of DOI:10.1016/j.tetlet.2017.12.074

Accepted Manuscript
A novel synthesis of aryl methyl sulfones and β-hydroxysulfones from sodium
sulfinates and di-tert-butyl peroxide in H2O medium
Junyi Lai, Gaoqing Yuan
PII:
S0040-4039(17)31605-2
https://doi.org/10.1016/j.tetlet.2017.12.074
TETL 49576
DOI:
Reference:
Tetrahedron Letters
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Received Date:
Revised Date:
Accepted Date:
24 October 2017
21 December 2017
25 December 2017
Please cite this article as: Lai, J., Yuan, G., A novel synthesis of aryl methyl sulfones and β-hydroxysulfones from
sodium sulfinates and di-tert-butyl peroxide in H2O medium, Tetrahedron Letters (2017), doi: https://doi.org/
10.1016/j.tetlet.2017.12.074
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A novel synthesis of aryl methyl sulfones and
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Junyi Lai, Gaoqing Yuan*

1
Tetrahedron Letters
A novel synthesis of aryl methyl sulfones and β-hydroxysulfones from sodium
sulfinates and di-tert-butyl peroxide in H2O medium
Junyi Lai, Gaoqing Yuan*
Key Laboratory of Functional Molecular Engineering of Guangdong Province, School of Chemistry and Chemical Engineering, South China University of
Technology, Guangzhou 510640, China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A novel and convenient synthetic route for aryl methyl sulfones and β-hydroxysulfones was
developed via the radical reaction between sodium sulfinates and di-tert-butyl peroxide (DTBP).
Without any catalysts and additives, the synthetic process could be smoothly carried out to
afford the target products in good to excellent yields in H2O medium, demonstrating its
promising application. In the present system, H2O could act not only as a green solvent but also
as a reactant.
Available online
2009 Elsevier Ltd. All rights reserved.
.Keywords:
Radical reaction
Aryl methyl sulfones
β-Hydroxysulfones
H2O solvent
Introduction
aryl methyl sulfones and β-hydroxysulfones via a radical reaction
in water medium without additional catalysts and additives
Sulfone derivatives are versatile synthetic intermediates and
potent inhibitors of several enzymes, such as HIV-1 reverse
transcriptase, γ-secretase and matrix metalloproteinase.1 For
example, some aryl methyl sulfones and β-hydroxysulfones have
been confirmed to have anti-inflammatory, anti-fungicidal and
biological activities (Scheme 1).2 Due to their great value in
pharmaceuticals, the synthesis of sulfones and β-hydroxysulfones
has attracted much attention over the past decades. The common
methods for the synthesis of sulfones mainly include the
oxidation of sulfides and sulfoxides,3 the sulfonylation of arenes,4
the reaction of aryl boronic acids with sulfonyl halides,5 and the
coupling reaction between sodium sulfinates and aryl halides or
aryl boronic acids.6 Recently, our group successfully achieved
the synthesis of aryl methyl sulfones from aryl halides and
DMSO via copper-catalyzed aerobic oxidation.7 For the synthesis
of β-hydroxysulfones, the classical methods are based on the
chemical or bioreduction of ketosulfones,8 and the reaction of
epoxides with sulfinate salts.9 Lei et al. recently developed a
novel method to construct β-hydroxysulfones by aerobic
oxysulfonylation of alkenes with sulfinic acids.10 Taniguchi
reported the synthesis of β-hydroxysulfones from sodium
sulfinates and alkenes.11 Although considerable advances in this
field have been made over the past decades, green and convenient
synthetic strategies are still necessary for the synthesis of aryl
methyl sulfones or β-hydroxysulfones.
(Scheme 2). The present work provides a green and convenient
method for the synthesis of aryl methyl sulfones and β-
hydroxysulfones.
Scheme 1. Some drugs containing aryl methyl sulfone or β-
hydroxysulfone motif.
During the last few decades, a radical reaction has played an
important role in the development of modern organic synthesis.12
Up to now, most of radical reactions were carried out in organic
solvents. From both economical and environmental points of
view, to develop a radical process in a water medium seems to be
attractive and interesting. Herein, we report a novel synthesis of
Scheme 2. A novel synthesis of aryl methyl sulfones and β-
hydroxysulfones.

2
Tetrahedron Letters
Result and discussion
phenylmethanesulfinate, sodium thiophene-2-sulfinate and
sodium methanesulfinate could also give satisfactory results
(Table 2, 3r–3t).
In the absence of any catalysts and additives, sodium
benzenesulfinate (1a) reacted with di-tert-butyl peroxide DTBP
(2a) to afford the product phenyl methyl sulfone (3a) in 42%
yield at 110 ˚C when H2O was used as the solvent (Table 1, entry
1). If the amount of 2a was increased to 1 or 2 equivalent from
0.5 equivalent, the yield of 3a was dramatically improved (Table
1, entries 2 and 3). When reaction temperature was declined from
110 ˚C to 100 ˚C, 2-methyl-1-(phenylsulfonyl)propan-2-ol (4a)
was also observed besides 3a (Table 1, entry 4). With the decline
in reaction temperature, the yield of 4a increased gradually
(Table 1, entries 5 and 6). At 70 ˚C, 4a became almost a sole
target product (Table 1, entry 7). Thus, reaction temperature has
a great effect on the formation of 3a or 4a. In addition, it is
noteworthy that 3a or 4a was not detected when H2O was
replaced by organic solvents such as N,N-dimethylformamide
(DMF), dimethylacetamide (DMA), CH3CN, toluene, anhydrous
EtOH and DMSO (Table 1, entries 11–19). This means that H2O
solvent plays an important role in the reaction. In the present
system, H2O solvent may take part in the reaction process.
Table 2
Synthesis of aryl methyl sulfones under the optimum
conditions.a,b
,
Table 1
Optimization of reaction conditions.a
Entry
2a
(equiv)
0.5
1
2
2
2
2
2
2
1
0.5
2
2
2
2
2
2
Solvent
Temp.
(˚C)
110
110
110
100
90
80
70
60
70
Time
(h)
12
12
12
12
12
12
16
16
16
16
12
12
12
12
12
12
16
16
16
Yield b
(3a/4a, %)
42/0
82/0
93/0
80/7
47/45
8/60
trace/75
0/53
0/60
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15c
16d
17
18
19d
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
a Reaction conditions: 1 (0.5 mmol), 2a (1 mmol), H2O (2.5 mL), 12 h under
air in a sealed tube.
H2O
70
0/44
N D
N D
N D
b Isolated yield based on sodium sulfinates.
DMF
DMA
CH3CN
toluene
EtOH
DMSO
DMF
CH3CN
DMSO
110
110
110
110
110
110
70
Table 3
Synthesis of β-hydroxysulfones under the optimum conditions.a,b
N D
trace/0
trace/0
N D
N D
0/trace
2
2
2
70
70
a Reaction conditions: 1a (0.5 mmol), solvent (2.5 mL), under air in a sealed
tube.
b Isolated yields based on 1a.
c
Anhydrous EtOH.
dAnhydrous DMSO.
Under the optimal reaction conditions, a series of sodium
sulfinates were examined to evaluate the generality of this
synthetic route. As shown in Table 2, sodium sulfinates with both
electron-withdrawing and electron-donating groups could be
smoothly converted to the corresponding aryl methyl sulfones in
good to excellent yields at 110 ˚C (Table 2, 3a–3m, and 3p).
Various functional groups at para-position of the aromatic ring
were well tolerated under the standard conditions, such as
halogen, methyl, ethyl, phenyl, tertiary butyl, –OCH3, and –
COCH3 groups. Moreover, the substituted group at different
positions on the phenyl ring of sodium sulfinates had no obvious
effect on the reaction (Table 2, 3f, 3l and 3p, 3c and 3m). In
addition, polyaryl substrates such as sodium naphthalene-1-
sulfinate and sodium naphthalene-2-sulfinate are suitable for this
reaction to provide the corresponding aryl methyl sulfones in
good yields (Table 2, 3n and 3o). Notably, even sodium
a Reaction conditions: 1 (0.5 mmol), 2a (1 mmol), H2O (2.5 mL), 16 h under
air in a sealed tube.
b Isolated yield based on sodium sulfinates.

3
We further screened the scope of sodium sulfinates toward the
synthesis of β-hydroxysulfones at 70 ˚C. As shown in Table 3,
sodium benzene sulfinates with different substitued groups, such
as halogen atoms F, Cl, and Br as well as methyl, tertiary butyl,
and methoxyl, were suitable for this reaction and afforded the
desired β-hydroxysulfones in moderate to good yields (Table 3,
4a–4g). Moreover, this reaction could be applicable to sodium 3-
bromo-5-methylbenzenesulfinate and sodium thiophene-2-
sulfinate (Table 3, 4i and 4j). However, with TBHP (tert-butyl
hydroperoxide) to replace DTBP as the substrate, the target
product 3a or 4a was not observed at all under the same
conditions.
Scheme 4. A total equation for the formation of 3a or 4a.
Based on the above mentioned analyses and the previous
literatures, possible reaction mechanism is depicted in Scheme 5.
Initially, DTBP is split into tert-butoxyl radical A under the
heating condition.13 And then, the tert-butoxyl radical A reacts
with benzenesulfinate anions in H2O solvent to afford a sulfonyl
radical B,14 tert-butyl alcohol and OH–. Meanwhile, the tert-
butoxyl radical A further decomposes to a methyl radical C and
acetone at 110 ˚C.13 Subsequently the cross-coupling of the
sulfonyl radical B with the methyl radical C leads to the
formation of the product 3 (Path a).15 If the reaction is carried
out at 70 ˚C, the tert-butoxyl radical A can be converted into a
radical D by an intermolecular hydrogen atom transfer process
among the tert-butoxyl radicals. Then, the sulfonyl radical B is
combined with the radical D to generate the product 4 (Path b).
According to the isotope labelling experiments (Scheme 3, eqs 4
and 5), the product 3 or 4 could further exchange hydrogen
atoms with H2O solvent to give the target product eventually.
In the presence of
a
radical scavenger 2,2,6,6-
tetramethylpiperidine-1-oxyl (TEMPO), the formation of 3a or
4a was completely suppressed under standard conditions
(Scheme 3, eqs 1 and 2), indicating that the formation of 3a or 4a
undergoes a radical process. For the peroxide DTBP, the O–O
bond is easily broken to produce tert-butoxyl radical.13 High
reaction temperature (110 ˚C) may further lead to the C–C bond
cleavage of the tert-butoxyl radical to yield a methyl radical.
When D2O was used as the solvent, the reaction at low
temperature (70 ˚C) afforded the deuterium substituted product
4a' in 74% yield (Scheme 3, eq 3). This isotope labelling result
indicates that the H atom of –OH group corresponding to the
product 4a β-hydroxysulfone originates from DTBP instead of
H2O solvent. Therefore, we deduce that the formation of 4a
undergoes the iso-configuration of the tert-butoxyl radical from
DTBP via an intramolecular hydrogen atom transfer process (C–
H
bond cleavage). In addition, the reaction of sodium
benzenesulfinate (1a) with DTBP (2a) could smoothly be carried
out to give the target product 3a or 4a in H2O solvent but failed
in organic solvents (Table 1). The reason may be that H2O
solvent could take part in the reaction process. During the
synthesis of 3a or 4a, it was observed that the pH value of the
reaction solution was obviously changed to 10.9 (after the
reaction) from 7.8 (before the reaction), which is due to H2O
solvent participating in this reaction to form the base (NaOH). A
total formation equation of 3a or 4a could well explain H2O
solvent involving in the reaction (Scheme 4).
Scheme. 5 Possible reaction mechanism.
Conclusions
In conclusion, we have developed a novel and facile method
for the synthesis of aryl methyl sulfones and β-hydroxysulfones
in water medium in the absence of any additives and catalysts.
Reaction temperature and water medium have a great impact on
the reaction. It is reasonable to believe that this method could
find its application in organic and pharmaceutical synthesis due
to its simplicity, convenience and environmental friendliness.
Acknowledgments
This work was supported by the National Natural Science
Foundation of China (21572070) and the National Key Research
and Development Program of China (2016YFA0602900).
Scheme 3. Control experiments.

4
Tetrahedron Letters
References
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5
Highlights
 The synthetic route does not need additional
catalysts and additives.
 H2O could act not only as a green solvent but
also as a reactant.
 The formation of the target products undergoes
a radical process.
 The radical reaction depends greatly on
reaction temperature.