Efficient sulfonylation of ketones with sodium sulfinates for the synthesis of β-keto sulfones

Article abstract of DOI:10.1016/j.tetlet.2018.09.049

The oxidative sulfonylation of ketones with sodium sulfinates as the sulfone source and DMSO as the oxidant is reported. A series of β-keto sulfones were obtained in good to excellent yields. The advantages of this efficient protocol include the low cost of DMSO and HBr, and a broad scope.

Full text of DOI:10.1016/j.tetlet.2018.09.049

Tetrahedron Letters xxx (2018) xxx–xxx
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Efficient sulfonylation of ketones with sodium sulfinates for
the synthesis of b-keto sulfones
1
1
⇑
Siqi Deng , En Liang , Yinrong Wu, Xiaodong Tang
Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, 1023 South Shatai Road, Baiyun District,
Guangzhou 510515, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
The oxidative sulfonylation of ketones with sodium sulfinates as the sulfone source and DMSO as the oxi-
dant is reported. A series of b-keto sulfones were obtained in good to excellent yields. The advantages of
this efficient protocol include the low cost of DMSO and HBr, and a broad scope.
Ó 2018 Published by Elsevier Ltd.
Received 8 August 2018
Revised 11 September 2018
Accepted 18 September 2018
Available online xxxx
Keywords:
HBr-mediated
One-pot
Oxidative sulfonylation
DMSO
Introduction
way have been reported, they utilise strong oxidants (hypervalent
iodine reagents) [7]. Hypervalent iodine reagents are expensive
b-Keto sulfones are valuable sulfur-containing compounds, as
they exhibit a broad range of applications in synthesis. For example,
the total synthesis of lycopodine alkaloid involved a b-keto sulfone
and their use may produce significant amounts of waste. Thus, it is
still desirable to develop a mild oxidant for the synthesis of b-keto
sulfones via the direct oxidative sulfonylation of ketones.
intermediate [1]. They are also used for building
c
-sulfonyl d-lac-
Dimethyl sulfoxide (DMSO) is a versatile polar aprotic solvent
which can be used as a synthon and mild oxidant in organic trans-
formations [8]. In the past years, it has been utilized as a Me, MeS,
MeSCH2, CHO, CN, or MeSO2 source in various reactions [9]. DMSO
has been primarily used as a mild and efficient reagent to oxidize
primary and secondary alcohols to aldehydes and ketones [10].
With an emphasis on green chemistry, DMSO has been widely used
in metal-catalyzed or metal-free oxidation reactions as an inexpen-
sive and mild oxidant [11].
tones, b-sulfonyl styrenes, polyfunctionalized 4H-pyrans, quinoli-
nes, sulfonyl phenanthrenes and vinylcyclopropanes [2].
Additionally, selected b-keto sulfones possess biological activities,
including as potential anti-infectious agents [3a] and potent 11b-
HSD1 inhibitors [3b]. In light of their widespread utilities,
intensive efforts have been made to develop efficient methods for
the synthesis of b-keto sulfones. The nucleophilic substitution
reaction of an
a-haloketone with sodium sulfinates is a classical
approach [4]. Recently, new reagents and strategies have been
developed for the synthesis of b-keto sulfones. Jiang and co-workers
demonstrated a copper-catalyzed oxidative coupling of oxime acet-
ates with sodium sulfinates to generate b-keto sulfones in which the
oxime acetates acted not only as substrates but also as oxidants [5].
Various groups have developed radical processes to construct b-keto
sulfones which were initiated by the addition of sulfonyl radicals to
olefins, alkynes or diazo compounds [6]. Undoubtedly, the most
desirable method for b-keto sulfone synthesis is the direct oxidative
sulfonylation of ketones with suitable oxidants and sulfone sources
in one-pot. Although a few examples to form b-keto sulfones in this
Previously, we reported a solvent-dependent sulfonylation of
arylethynylene bromides with sodium arylsulfinates for the syn-
thesis of (E)-1,2-bis(arylsulfonyl)ethylenes and arylacetylenic sul-
fones (Scheme 1a) [12a]. We also developed
a Pd-catalyzed
desulfitative arylation for the synthesis of 2,5-diarylated oxazole-
4-carboxylates using sodium arylsulfinates as the aryl source
(Scheme 1b) [12b]. Based on our previous work, herein we report
a HBr-mediated oxidative sulfonylation of ketones for the one-
pot synthesis of b-keto sulfones with sodium sulfinates as the
sulfone source and DMSO as a mild oxidant (Scheme 1c).
Results and Discussion
⇑
Corresponding author.
E-mail address: tangxdong@smu.edu.cn (X. Tang).
These authors contributed equally to this work.
Our initial studies focused on optimizing the reaction
conditions for the synthesis of b-keto sulfone 3aa (Table 1).
1
https://doi.org/10.1016/j.tetlet.2018.09.049
0040-4039/Ó 2018 Published by Elsevier Ltd.
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2
S. Deng et al. / Tetrahedron Letters xxx (2018) xxx–xxx
Having optimized the reaction conditions, we turned our atten-
tion to investigating the scope of ketones (Table 2). A variety of
para-substituted acetophenones, bearing either electron-donating
groups (R = i-Pr, t-Bu, OMe) or electron-withdrawing groups
(R = F, Cl, Br, NO2) on the aryl ring were applicable to this transfor-
mation, affording the corresponding products 3ba–ja in moderate
to good yields. The ortho-substituted, meta-substituted and
3–4-disubstituted acetophenones reacted well with sodium
p-toluenesulfinate (Table 2, 3ka–na). Furthermore, propiophe-
none, 2-phenylacetophenone and 3,4-dihydronaphthalen-1(2H)-
one could also be used to afford the desired products 3oa, 3pa
and 3qa in 97%, 84% and 75% yields, respectively. In addition, other
aromatic ketones including naphthalene, thiophene and furfuran,
resulted in formation of the corresponding products in satisfactory
yields (Table 2, 3ra–ta). Gratifyingly, the method was suitable for
alkyl ketones such as 3-pentanone and cycloheptanone, and the
desired products were obtained in 66% and 57% yield, respectively
(Table 2, 3ua, va).
Subsequently, the scope of the reaction was explored with dif-
ferent sodium sulfinates, which were treated with acetophenone
(1a) under the optimized reaction conditions (Table 3). Sodium
benzenesulfinate and substituted benzenesulfinates bearing vari-
ous substituents such as F, Cl, Br and OMe at the para-position of
the aryl ring gave the target products in good to excellent yields
(Table 3, 3ab–af). When sodium 2-methylbenzenesulfinate,
2-chlorobenzenesulfinate and 3-fluorobenzenesulfinate were
used as substrates, the yields were 87%, 76% and 81%,
respectively (Table 3, 3ag–ai). Gratifyingly, the method was also
suitable for sodium 2-naphthylsulfinate and methanesulfinate
(Table 3, 3aj–ak).
Scheme 1. Our previous work and the current work.
Acetophenone (1a) and sodium p-toluenesulfinate (2a) were cho-
sen as model substrates for examining the acids, oxidants, solvents
and reaction temperature (Table 1). Gratifyingly, when the reaction
was performed with 1a (0.3 mmol), HBr (0.36 mmol) and DMSO
(0.36 mmol) in EtOAc (1.5 mL) at 60 °C for 6 h, followed by the
addition of 2a (0.6 mmol) and (HOCH2)2 (1.0 mL) at 80 °C for
17 h, the desired product 3aa was obtained in 96% yield (Table 1,
entry 1). When other acids such as HCl, HOAc and TsOH were used
to replace HBr, product 3aa was not detected or was formed in very
low yield (Table 1, entries 2–4). Next, different oxidant such as O2,
H2O2, K2S2O8, PhI(OAc)2 and DTBP were screened (Table 1, entries
5–9). These oxidants did not give better yields than DMSO.
Furthermore, other solvents, including DMSO, DMF, CH3CN, H2O,
CH3OH and EtOH were tested, but they were not better than
(HOCH2)2 (Table 1, entries 10–15). The yield was decreased to
65% when the second stage of the reaction was performed at
60 °C (Table 1, entry 16). In addition, the yields were significantly
reduced upon decreasing the amount of 2a (Table 1, entries 17–18)
In order to understand the reaction mechanism, some control
experiments were performed (Scheme 2). When we directly used
Br2 as a reagent, the yield of 3aa was 94% [Eq. (1)]. In addition,
when we used 2-bromoacetophenone 4 as the substrate, product
3aa was obtained in 95% yield [Eq. (2)]. Based on the control exper-
iments and previous reports of DMSO as an oxidant [11], a possible
mechanism was proposed (Scheme 2). Br2 or DMSÁBr2 was formed
via the oxidation of HBr by DMSO. Next, 2-bromoacetophenone
was produced by the bromination of acetophenone with Br2 or
Table 1
Optimization of the reaction conditions.a
Table 2
Substrate scope of various ketones.a
Entry
Acid
Oxidant
Solvent
Yield 3aa (%)
1
2
3
4
5
6
7
8
HBr
HCl
DMSO
DMSO
DMSO
DMSO
O2
(HOCH2)2
(HOCH2)2
(HOCH2)2
(HOCH2)2
(HOCH2)2
(HOCH2)2
(HOCH2)2
(HOCH2)2
(HOCH2)2
DMSO
96
n.d.
n.d.
<10
n.d.
74
40
29
42
18
37
61
n.d.
81
80
65
58
66
HOAc
TsOH
HBr
HBr
HBr
HBr
HBr
HBr
HBr
HBr
HBr
HBr
HBr
HBr
HBr
HBr
H2O2
K2S2O8
PhI(OAc)2
DTBP
9
10
11
12
13
14
15
16b
17c
18d
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
CH3CN
H2O
CH3OH
EtOH
(HOCH2)2
(HOCH2)2
(HOCH2)2
a
Reagents and conditions: 1a (0.3 mmol), acid (0.36 mmol), oxidant
(0.36 mmol), EtOAc (1.5 mL), 60 °C, 6 h, then TsNa (0.6 mmol), solvent (1.0 mL),
80 °C, 17 h. Isolated yield.
b
a
Reaction was conducted at 60 °C for 17 h.
TsNa (0.36 mmol) was used.
Reagents and conditions: ketone
1 (0.3 mmol), HBr (0.36 mmol), DMSO
c
(0.36 mmol), EtOAc (1.5 mL), 60 °C, 6 h, then TsNa (0.6 mmol), (HOCH2)2 (1.0 mL),
80 °C, 17 h. Isolated yield.
d
TsNa (0.45 mmol) was used.
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S. Deng et al. / Tetrahedron Letters xxx (2018) xxx–xxx
3
Table 3
Foundation of China (21702096), and Guangdong Natural Science
Foundation (2017A030310546) for financial support.
Substrate scope of various sodium sulfonates.a
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2018.09.049.
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In conclusion, we have developed an efficient approach for the
oxidative sulfonylation of ketones with sodium sulfinates using
the simple DMSO/HBr system. This reaction exhibited a wide range
of functional-group tolerance and various b-keto sulfones were
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Please cite this article in press as: S. Deng et al., Tetrahedron Lett. (2018), https://doi.org/10.1016/j.tetlet.2018.09.049