Copper-catalyzed aerobic oxidative cross-coupling reactions of vinylarenes with sulfinate salts: A direct approach to β-ketosulfones

Article abstract of DOI:10.1016/j.tetlet.2020.152794

A copper-catalyzed aerobic oxidative cross-coupling reactions for the synthesis of β-ketosulfones via formation of a C[sbnd]S bond has been demonstrated. Promoted by the crucial copper catalyst, perfect selectivity and good to excellent yields could be achieved. This method, including inexpensive copper catalyst, wide functional group tolerance, and open air conditions, make it very attractive and practical. More importantly, it also provides a versatile tool for the construction of β-ketosulfones from basic starting materials under mild conditions.

Full text of DOI:10.1016/j.tetlet.2020.152794

Tetrahedron Letters 65 (2021) 152794
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Copper-catalyzed aerobic oxidative cross-coupling reactions of
vinylarenes with sulfinate salts: A direct approach to b-ketosulfones
Yu Chen a, Lei Xu a, Biyu Wang a, Jingjing Jiang a, Yixiang Sun b, Longchun Li a,
⇑
a Department of Applied Chemistry, School of Science, Anhui Agricultural University, Hefei, Anhui, 230036, PR China
b Soil and Fertilizer Institute of Anhui Academy of Agricultural Science, Hefei, Anhui 230001, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A copper-catalyzed aerobic oxidative cross-coupling reactions for the synthesis of b-ketosulfones via for-
mation of a CAS bond has been demonstrated. Promoted by the crucial copper catalyst, perfect selectivity
and good to excellent yields could be achieved. This method, including inexpensive copper catalyst, wide
functional group tolerance, and open air conditions, make it very attractive and practical. More impor-
tantly, it also provides a versatile tool for the construction of b-ketosulfones from basic starting materials
under mild conditions.
Received 19 October 2020
Revised 14 December 2020
Accepted 17 December 2020
Available online 7 January 2021
Keywords:
Ó 2020 Published by Elsevier Ltd.
Copper-catalyzed
Aerobic oxidative
Cross-coupling
b-ketosulfones
CAS bond
Introduction
of green and sustainable chemistry, molecular oxygen is recog-
nized as an ideal oxidant due to its inexpensive, abundant, and
With growing awareness of severe global energy and environ-
mental constraints, thus, the past decades have witnessed the
emergence of transition-metal-catalyzed carbon-heteroatom
bonds formation reaction as an increasingly powerful tool in
organic synthesis, ranging from pharmaceutical to large-scale com-
modities [1]. In particular, the CAS bond formation via an oxidative
coupling process is considered as one of the most promising envi-
ronmentally friendly and sustainable approach for the transforma-
tion of organic processes owing to not only its high atom-economy
and step-economy but also readily available starting materials [2].
Thus far, a lot of efforts have been made to improve the approach
for constructing new CAS bonds[3].
environmental friendly characteristics[7].
As a class of basic scaffold with high biological value, b-ketosul-
fones have found wide applications in natural products, biologi-
cally active compounds, agrochemicals including pesticides,
fungicides, and herbicides [8]. Herein, we describe our efforts
toward the development of copper-catalyzed oxidative coupling
reaction for constructing new CAS bond: the direct approach to
b-ketosulfones via the reaction of sulfinate salts and vinylarenes
(Scheme 1). In contrast to the Pd-catalyzed [9], except for the dif-
fident product, more importantly, this method, including inexpen-
sive copper catalyst, wide functional group tolerance, and open air
conditions, make it very attractive and practical.
In the past reports, copper-catalyzed oxidative coupling reac-
tions have been arguably considered as a reliable method to con-
struct complex molecules [4]. Among these, recent achievements
have highlighted the ability of copper as a versatile reagent in
oxidative coupling reactions [5]. Compared to other transition-
metal catalysts, copper is inexpensive, abundant, insensitive to
air and water, and can be easily utilized [6]. Additionally, in view
Materials and methods
Reagent Information
Unless otherwise noted, materials were obtained from commer-
cial suppliers and used without further purification. All the olefins
were bought from Aldrich and Alfa Aesar. Some olefins were syn-
thesized from commercially available compounds by Wittig reac-
tion following literature procedures. Thin layer chromatography
⇑
Corresponding author.
E-mail address: llch75@163.com (L. Li).
https://doi.org/10.1016/j.tetlet.2020.152794
0040-4039/Ó 2020 Published by Elsevier Ltd.

Y. Chen, L. Xu, B. Wang et al.
Tetrahedron Letters 65 (2021) 152794
(0.05 mmol) and 1 mL HOAc in 1 mL PEG400 in a 25 mL tube
was stirred at 60 °C for 6 h under air atmosphere and monitored
periodically by TLC. Upon completion, the crude product was
cooled to room temperature and then quenched by the addition
of 5 mL water. The aqueous solution was extracted with ethyl acet-
ate (3 Â 5 mL) and the combined extracts were dried with anhy-
drous MgSO4 . The solvent was removed under reduced pressure
by an aspirator, and the crude product was purified by silica gel
column chromatography with petroleum ether and ethyl acetate
as eluent to afford the desired product 3a.
Scheme 1. Copper-catalyzed oxidative coupling route to b-ketosulfones under air
condition.
Results and discussion
(TLC) employed glass 0.25 mm silica gel plates. Flash chromatogra-
phy columns were packed with 200–300 mesh silica gel in petro-
leum ether (bp. 60–90 °C). A gradient elution using ethyl acetate
and petroleum ether was performed, based on Merck aluminum
TLC sheets (silica gel 60F254).
Our initial efforts focused on styrene 1a and sodium benzene-
sulfinate 2a as the model reaction (Table 1). The reaction parame-
ters (i.e., catalyst, solvent, temperature, acid) were varied to
achieve this goal. To our delight, when 1a was treated with 2a,
0.5 equiv of CuCl2, and 1.0 equiv of HOAc in PEG400 under open
air at 40 °C and 6 h, the desired product 3a was obtained in 75%
yield (Table 1, Entry 9). The test reaction was carried out at differ-
ent temperatures in order to check the effect of temperature on the
reaction. It was noted that the maximum conversion occurred at
60 °C, providing the desired product 3a in 94% yield after 6 h
(Table 1, Entry 6). However, by further increasing the reaction tem-
perature (80 °C), the yield did not improve (Table 1, Entry 8). Using
other Copper(Ⅱ), such as CuBr2, Cu(SO4)2, Cu(NO3)2 and Cu(OAc)2,
also gave slightly lower yields (Table 1, Entry 4, Entry 5, Entry
14–16). Compared with Copper(Ⅱ), Copper(Ⅰ) showed ineffective
ability in this transformation (Table 1, Entry 1–3, Table S1, Entry
15–26). Unfortunately, other metal catalysts (Table S1, Entry 1–
4) and copper catalyst-free conditions (Table S1, Entry 5) proved
to be ineffective. A solvent screen showed PEG400 as most effec-
tive, other solvent loadings led to reduced yields (Table 1, Entry
7, Entry 10–13 and Table S1, Entry 6–9). Notably, 1.0 equiv of
added HOAc was important to obtain good yields (Table S1, Entry
10–12), the reaction without HOAc gave only 5% of the desired
Analytical Information
All isolated compounds were characterized by 1H, 13C NMR
spectroscopy, Copies of the 1H NMR,13C NMR can be found in the
supporting information. Unless otherwise stated, all Nuclear
Magnetic Resonance spectra were recorded on a Bruker 400 MHz
instrument with tetramethylsilane as an internal standard. All
chemical shifts (d) are reported in ppm and coupling constants
(J) in Hz. All chemical shifts are reported relative to tetramethylsi-
lane (0 ppm for 1H) and CDCl3 (77.16 ppm for 13C), respectively.
Experimental section
General Procedure for the Synthesis of b-ketosulfones
Typical procedure: The reaction mixture of styrene 1a
(0.5 mmol), sodium benzenesulfinate 2a (1.0 mmol), CuCl2
Table 1
Optimization of the Reaction Conditions
.
Entry
[Cu](equiv.)
Solvent1 mL
t[h]
T[oC]
Yield of 3a[%]
1
2
3
4
5
6
7
8
CuI
CuCl
CuBr
PEG400
PEG400
PEG400
PEG400
PEG600
PEG400
PEG600
PEG400
PEG400
PEG400
PEG400
DMF
DMA
NMP
MeOH
PEG400
PEG400
PEG400
PEG400
PEG400
PEG400
10
10
10
6
6
6
6
6
6
8
4
12
9
6
12
6
6
6
6
6
60
60
60
60
60
60
60
80
40
60
60
60
60
60
60
60
60
60
60
60
60
10
12
14
90
85
94
86
88
75
92
85
78
74
61
40
90
86
85
95[a]
0[b]
5[c]
CuBr2
CuBr2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
Cu(OAc)2
Cu(NO3)2
Cu(SO4)2
CuCl2
CuCl2
CuCl2
9
10
11
10
11
12
13
14
15
16
17
18
19
6
Reaction conditions: 1a (0.5 mmol), 2a (1.0 mmol), Cu catalyst (5.0 mol%), HOAc (0.5 mmol), PEG400 (1 mL) under air. Yields of isolated products based on 1a. [a] under O2, [b]
under N2, [c] No HOAc.
2

Y. Chen, L. Xu, B. Wang et al.
Tetrahedron Letters 65 (2021) 152794
product (Table 1, Entry 19). Alternatively, no product was formed
under nitrogen atmosphere (Table 1, Entry 18). Using pure oxygen
as the terminal oxidant provided a comparable result to that of the
reaction with air (Table 1, Entry 17). After further screening of tem-
perature, reaction time, the reaction of sodium benzenesulfinate 1a
and styrene 2a to give 3a in 94% yield using the conditions: CuCl2
(0.05 mmol), HOAc (1.0 mL), in PEG400 (1 mL) with stirring at
60 °C open to air for 6 h (Table 1, Entry 6 and Table S1, Entry
13–14). The mild reaction conditions, including shorter reaction
times (6 h), operational simplicity (open air), cost-effectiveness
and excellent yields (94%), make this protocol an alternative
method for the facile construction of numerous b-ketosulfones.
Furthermore, having identified the optimized conditions, we
investigated the scope of the reaction with respect to 2a and differ-
ent styrenes. As shown in Table 2, a range of vinylarenes, with
either electron-donating groups (R1 = Me, OMe, N, N-dimethy) or
electron-withdrawing groups (R1 = F, Cl, Br) on aromatic ring, were
viable in this transformation (Table 2, 3b-g). Electron-donating
vinylarenes (Table 2, 3b-d) displayed higher reactivity than those
bearing electron-with-drawing groups (Table 2, 3e-g). Signifi-
cantly, several functional groups (nitro, 3,4-dichloro) were well
tolerated (Table 2, 3 h-k), affording the corresponding b-ketosul-
fones in good to excellent yield. Interestingly, a nitro substituent,
which is usually unfavorable in the transformation with aerobic
oxidative cross-coupling reaction, was also well tolerated, afford-
ing the corresponding 3 h-3j in good yields. It was observed that
the electronic variation at the ortho-, meta-, para-substituents of
the aryl ring vinylarenes did not affect the transformation, gave
the corresponding 3 h, 3i and 3j in 88%, 86% and 84% yield, respec-
tively. It should be noted that 2-vinylnaphthalene was also found
to be compatible with this transformation, albeit in slightly lower
yield (Table 2, 3 l, 3u).
Additionally, to highlight the wide functional group tolerance of
this process, sulfinate salts with aliphatic and alkyl groups were
investigated under standard conditions. To our satisfaction, a vari-
ety of aryl sulfinate salts, bearing either electron-donating groups
(Table 2, 3 m-t) or electron-withdrawing groups (Table 2, 3u, 3v)
on the aryl ring, reacted smoothly with vinylarenes, affording the
corresponding b-ketosulfones in good to excellent yield. As can
be seen in Table 2, sodium p-toluenesulfinate displayed higher
reactivity than sodium 4-chlorobenzene sulfinate, although afford-
ing the corresponding b-ketosulfones in good to excellent yield. It
was interesting to note that sodium methane sulfinate, an aliphatic
sodium sulfinate, was also suitable substrate for this transforma-
tion (Table 2, 3w-z and 3Ⅰ-Ⅴ). The reaction proceeded efficiently
to afford their corresponding b-ketosulfones products in moderate
to good yields even for the substrates vinylarenes bearing func-
tional groups such as halide, Me, OMe, and nitro, especially, F, Cl
and Br group, thus further enhancing the scope of our reaction.
Because of the steric hindrance effect of ortho-position substitu-
tion, 80% of 3Ⅴwas formed, which is in contrast with the case for
3Ⅱ, where the chloro group is located on the para position of the
phenyl ring. This similar effect was then confirmed when meta-
nitro substituted vinylarene afforded 81% yield (Table 2, 3IV).
To gain preliminary mechanistic information about this proto-
col, a series of experiments were carried out to provide insight
Table 2
Substrate Scope for the Synthesis of Various b-ketosulfones under air condition
.
Entry
R1
R2
3
Yield of 3 [%]
1
2
3
4
5
6
7
8
H
Phenyl
Phenyl
Phenyl
Phenyl
Phenyl
Phenyl
Phenyl
Phenyl
Phenyl
Phenyl
Phenyl
Phenyl
4-CH3-Phenyl
4-CH3-Phenyl
4-CH3-phenyl
4-CH3-phenyl
4-CH3-Phenyl
4-CH3-Phenyl
4-CH3-Phenyl
4-CH3-Phenyl
4-Cl-Phenyl
4-Cl-Phenyl
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
3a
3b
3c
3d
3e
3f
3 g
3 h
3i
94
95
96
96
90
92
92
88
86
84
91
85
95
96
97
97
91
93
90
89
86
84
85
86
86
87
84
84
84
81
80
4-CH3
4-OCH3
4-N,N-dimethy
4-F
4-Cl
4-Br
4-NO2
3-NO2
2-NO2
3,4-dichloro
Phenyl
H
4-CH3
4-OCH3
4-N,N-dimethy
4-F
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
3j
3 k
3 l
3 m
3n
3o
3p
3q
3r
4-Cl
4-Br
3s
3t
4-NO2
Phenyl
H
4-CH3-phenyl
H
4-CH3
4-OCH3
4-F
4-Cl
4-Br
3-NO2
2-Cl
3u
3v
3w
3x
3y
3z
3Ⅰ
3Ⅱ
3III
3 IV
3Ⅴ
3

Y. Chen, L. Xu, B. Wang et al.
Tetrahedron Letters 65 (2021) 152794
about the reaction. First, radical trapping experiment was per-
formed, inspired by the previous reports that dioxygen activation
based processes mostly involve radical species [10]. Under the
standard reaction conditions, b-ketosulfone 3a was extremely
inhibited in the presence of TEMPO or BHT, which were well-
completing the catalytic cycle. Further studies to clearly under-
stand the reaction mechanism are ongoing in our laboratory.
Conclusions
known radical scavengers, elucidating
a
radical pathway
In summary, we have developed a copper-catalyzed aerobic
oxidative cross-coupling reactions for the synthesis of b-ketosul-
fones via formation of a new CAS bond. Notably, the method exhi-
bits wide functional group tolerance and can be operated in open
air conditions, which make it very attractive and practical. Pleas-
ingly, the success of unique transformation provides a new route
for the synthesis of b-ketosulfones under mild conditions. Applica-
tion of this methodology to ongoing research including further
mechanistic details are currently underway.
(Scheme 2a). Furthermore, demonstrating the role of air in the
reaction was very vital to unfold the intricacies of the mechanism.
The reaction was not at all formed under nitrogen (Scheme 2b).
Finally, an isotope labeling experiment was also conducted to elu-
cidate the origination of the carbonyl oxygen atom of the b-keto-
sulfone. The reaction of 1a with 2a under an 18O2/N2 (1:4)
atmosphere under the standard conditions generated the 18O-
labeled product 3a in 95% yield (Scheme 2c, Figure S1, Figure S2).
It is proved that O2 took part in this reaction and the oxygen atom
in the product came from O2.
Declaration of Competing Interest
Based on the above results and previous reports [10] (Lu et al.,
2013; Handa et al., 2014; Huang et al., 2014; Maji et al., 2014), a
plausible mechanism is proposed and illustrated in Scheme 3.
The overall sequence starts from in situ generation of free sulfinic
acid from its sodium salt and HOAc. Afterward, CuCl2/O2 catalyst
system triggers the sulfonyl radical A formation from sulfinate salt.
Then, this sulfonyl radical attacks the double bond to give vinyl
radical B, which is ultimately captured by oxygen to form peroxy
radical intermediate C. This active species C abstracted one hydro-
gen atom from HOAc generating hydroperoxo species D. Finally,
the intermediate D interacted with Cu (Ⅰ) species by single-electron
transfer (SET) and generates an enol that tautomerizes to the
desired product 3a, meanwhile regenerated Cu (II) catalyst, thus
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.
Acknowledgements
This study was financially supported by the research fund of
Anhui Agricultural University (Grant No. wd2018-03), the Natural
Science Foundation of Anhui Province (Grant No. 2008085 MB41),
the Anhui Province Key Laboratory of Chemistry for Inorganic/
Organic Hybrid Functionalized Materials, Anhui University and
finance support from Soil and Fertilizer Institute of Anhui Academy
of Agricultural Science.
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2020.152794.
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5