Metal-free tetra-n-butylammonium bromide-mediated aerobic oxidative synthesis of β-ketosulfones from styrenes

Article abstract of DOI:10.1007/s11426-016-0284-2

An efficient and broadly applicable protocol for the aerobic coupling of styrenes with sulfonylhydrazides has been developed that affords β-ketosulfones bearing various functional groups in moderate to excellent yields. The preliminary experimental results support the involvement of active benzyl radical species, and a radical pathway was therefore proposed for the reaction.

Full text of DOI:10.1007/s11426-016-0284-2

SCIENCE CHINA
Chemistry
• COMMUNICATIONS •
doi: 10.1007/s11426-016-0284-2
Metal-free tetra-n-butylammonium bromide-mediated aerobic
oxidative synthesis of β-ketosulfones from styrenes
Xin Wan1, Kai Sun1,2* & Guisheng Zhang2*
1College of Chemistry and Chemical Engineering, Anyang Normal University, Anyang 455000, China
2School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang 453007, China
Received July 5, 2016; accepted August 15, 2016; published online October 26, 2016
An efficient and broadly applicable protocol for the aerobic coupling of styrenes with sulfonylhydrazides has been developed
that affords β-ketosulfones bearing various functional groups in moderate to excellent yields. The preliminary experimental
results support the involvement of active benzyl radical species, and a radical pathway was therefore proposed for the reaction.
styrenes, aerobic, difunctionalization, ketosulfones, transition metal-free conditions
Citation:
Wan X, Sun K, Zhang G. Metal-free tetra-n-butylammonium bromide-mediated aerobic oxidative synthesis of β-ketosulfones from styrenes. Sci
China Chem, doi: 10.1007/s11426-016-0284-2
Compounds containing a ketosulfone moiety are of value
because the skelectons are versatile organic intermediates
that have been employed in various reactions [1,2]. In light
of their widespread use, considerable efforts have been de-
voted toward the synthesis of β-ketosulfones [3–6]. Difunc-
tionalization of unsaturated compounds are a significant
class of reactions that allow for the buildup of molecular
complexity in a single procedure. From a green and sus-
tainable chemistry perspective the direct oxidative difunc-
tionalization of alkenes is therefore an ideal strategy for
constructing β-ketosulfones. In 2013, Wang and colleagues
[7] reported the first copper-catalyzed oxysulfonylation re-
action of alkenes, with dioxygen as the oxygen source and
sulfonylhydrazides as the sulfone source. Considering that
dioxygen is not only a green oxidant but also an ideal oxy-
gen source for the functionalization of organic molecules
[8], the development of new protocols for direct oxyfunc-
tionalization of alkenes with dioxygen to access a diverse
range of useful compounds is an attractive prospect. While
transition-metal-catalyzed oxidative difunctionalization of
alkenes with dioxygen has become a powerful methodology
for the construction of oxygenated compounds [9], the extra
purification required to remove residual catalyst from the
products seriously restricts their application by the pharma-
ceutical industry. The discovery of organocatalyst-mediated
aerobic difunctionalization of alkenes is an extremely at-
tractive and sustainable approach for introducing oxygen
functional groups in synthetic chemistry.
Scheme 1 Syntheses of β-ketosulfones by difunctionalization of unsatu-
rated bonds.
*Corresponding authors (email: sunk468@nenu.edu.cn; zgs6668@yahoo.com)
© Science China Press and Springer-Verlag Berlin Heidelberg 2016
chem.scichina.com link.springer.com

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Wan et al. Sci China Chem January (2016) Vol.59 No.1
Recently, Lei et al. reported the aerobic oxidative difunc-
7–12) and CH3CN was clearly the best solvent for this cat-
alytic system, improving the yield of 3a to 67% (Table 1,
entry 9). EtOAc and EtOH were also effective solvents for
this transformation, affording the desired product 3a in sat-
isfactory yields (Table 1, entries 7 and 8). H2O and dimethyl
sulfoxide (DMSO) were found to be poor solvents for this
reaction (Table 1, entries 10 and 11). We then tested other
oxidants and this revealed that the use of anhydrous TBHP
gave a clean reaction mixture and the desired product 3a in
84% yield (Table 1, entry 12). The addition of DTBP
(di-tert-butyl peroxide), DCP (dicumyl peroxide), H2O2, and
m-CPBA (3-chloroperbenzoic acid) did not offer any further
improvements in yield (Table 1, entries 13–16). After opti-
mizing the reaction conditions, we established a highly effi-
cient route for the oxysulfonylation of styrenes to
β-ketosulfones (Table 1, entry 12).
Having acquired the optimized reaction conditions, we
investigated the scope of styrene and benzenesulfonohydra-
zide reagents compatible with this transformation. The rep-
resentative products 3b–3u are shown in Scheme 2. Various
substitutents on the benzene ring of styrene were tolerated
by the reaction, including electron-withdrawing groups
(fluoro, chloro, and bromo) and electron-donating groups
(methyl, tert-butyl, methoxy, acetate, and chloromethylene).
Some of these functional groups are useful for further syn-
thetic transformation. The chloro- and bromo-containing
substituents are particularly reactive and difficult to retain in
many transition-metal-catalyzed or organocatalytic reac-
tions [14], significantly expanding the synthetic utility of the
tionalization of alkynes to β-ketosulfones [10] and aerobic
oxysulfonylation of alkenes leading to β-hydroxysulfones
[11]. In their report, the radical oxidative functionalization
of the unsaturated bond was achieved efficiently without the
assistance of transition metals or radical initiators. In addi-
tion, Zhao et al. [12a] and Yadav et al. [12b] disclosed the
similar oxysulfonylation of olefins under metal-free condi-
tions. With the aid of an organocatalyst, we have recently
realized the iodosulfonylation and aminoiodination reac-
tions of alkenes [13c,13d]. Inspired by the work of Lei et al.
and our continuing interest in C–X (X=C, N, S, I, Se)
bond-forming reactions, we concluded that aerobic oxida-
tive difunctionalization of alkenes to form β-ketosulfones
was feasible. The following details our experimental results
on the first synthetic transformation of alkenes and sul-
fonylhydrazides to β-ketosulfones mediated by a catalytic
amount of n-Bu4NBr under mild conditions without the as-
sistance of metal salts.
All reagents were used as received from commercial
sources, unless otherwise specified or prepared as described
in the literature. All reagents were weighed and handled in
air.
1H NMR and 13C NMR spectra were respectively rec-
orded at 400 and 100 MHz, using tetramethylsilane as an
internal reference. Chemical shifts (δ) and coupling con-
stants (J) were expressed in parts per million and hertz, re-
spectively.
n-Bu4NBr (16.1 mg, 0.1 mmol) and TBHP (tert-buty-
lhydroperoxide, 46.0 mg, 1.0 mmol) were added to a solu-
tion of styrene (1a, 52.0 mg, 0.5 mmol) and benzenesul-
fonohydrazide (2a, 94.6 mg, 0.55 mmol) in acetonitrile (2.0
mL). The mixture was stirred at 60 °C for 8.0 h in a Schlenk
tube and a balloon filled with O2 was attached to the side
arm. The reaction was monitored by TLC before it was
quenched with water (10 mL) and extracted with dichloro-
methane (5×3 mL). The extracted organics were dried over
anhydrous sodium sulfate and the solvent was removed un-
der reduced pressure. The residue was purified by flash sil-
ica gel column chromatography using ethyl acetate/petro-
leum ether (1:6) as eluent to give the desired compound 3a
as a white solid (252.0 mg, 84%).
To verify our assumptions, styrene 1a and benzenesul-
fonohydrazide 2a were initially chosen to explore the reac-
tion conditions in a vessel connected to an O2 balloon.
When I2 and TBHP (70% in water) were used in combina-
tion as the catalyst, an iodosulfonylation reaction occurred,
affording the β-iodosulfone I in 81% yield, and no evidence
of the desired β-ketosulfone 3a was observed (Table 1, en-
try 1). When n-Bu4NI was then used instead of I2, a trace
amount of desired product 3a was detected (Table 1, entry
2). Various catalysts including n-Bu4NBr, n-Bu4NF,
n-Bu4NOAc, and KBr were tested and n-Bu4NBr gave a
moderate yield for 3a of 43% (Table 1, entries 3–6). Sub-
sequently, a variety of solvents were tested (Table 1, entries
Table 1 Optimization of the reaction conditions a)
Catalyst
(0.2 equiv.) (2.0 equiv.)
Oxidant
Solvent
(2 mL)
Entry
Yield (%) b)
1
2
I2
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
DTBP
DCP
THF
THF
0
14
43
0
n-Bu4NI
3
n-Bu4NBr
n-Bu4NF
n-Bu4NOAc
KBr
THF
4
THF
5
THF
22
0
6
THF
7
n-Bu4NBr
n-Bu4NBr
n-Bu4NBr
n-Bu4NBr
n-Bu4NBr
n-Bu4NBr
n-Bu4NBr
n-Bu4NBr
n-Bu4NBr
n-Bu4NBr
EtOAc
CH3OH
CH3CN
H2O
55
64
67
trace
0
8
9
10
11
12 c)
13
14
15
16
DMSO
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
84
61
23
0
H2O2
m-CPBA
22
a) Reaction conditions: 1a (0.5 mmol), 2a (0.55 mmol), catalyst (0.1
mmol) and oxidant (1.0 mmol) in 2 mL solvent, stirred at 60 °C for 8 h; b)
yield of isolated product; c) anhydrous TBHP was added instead of 70%
TBHP in water.

Wan et al. Sci China Chem January (2016) Vol.58 No.1
3
zide, such as thiophene-2-sulfonohydrazide, also gave the
desired β-ketosulfone 3u in 83% yield. However, when
ethanesulfonohydrazide was used instead of benzenesul-
fonohydrazides, hydroxysulfonylation occurred, and no
β-ketosulfone was detected.
To demonstrate the synthetic utility of this oxysulfonyla-
tion reaction, we conducted a gram-scale reaction under the
optimized conditions using 1a and 2a, which gave the de-
sired product 3a in an isolated yield of 69% (Scheme 3).
To understand the reaction mechanism, radical trapping
experiments were conducted by employing 2,2,6,6-tetrame-
thyl-1-piperidinyloxy (TEMPO, 2 equiv.) and 2,4-di-tert-
butyl-4-methylphenol (BHT, 2 equiv.) to determine whether
the reactions involved radical species [15]. The reactions
were found to be completely inhibited by the addition of
TEMPO and no desired product 3a was detected even after
extended reaction times (Scheme 4(a)). However, we iso-
lated the coupling product H (Scheme 4(b)) of BHT with
the proposed benzyl radical intermediate C (Scheme 5) in
51% yield. These results supported the presence of radical
intermediates during this transformation.
There are three potential oxygen sources in the reaction
system: molecular oxygen; traces of water in the solvent;
and the peroxides. The reaction was found to proceed with-
out adding TBHP, but the yield of 3a was only 13% (Sche-
me 4(c)). Based on this result, we supposed that TBHP was
Scheme 3 Gram-scale synthesis of the β-ketosulfone 3a.
Scheme 2 Reactions of alkenes with sulfonohydrazides. Reaction condi-
tions: 1 (0.5 mmol), 2 (0.55 mmol), n-Bu4NBr (0.1 mmol) and TBHP (1.0
mmol) in 2 mL CH3CN, stirred at 60 °C for 6–12 h. The values are yield of
isolated product.
protocol described in this work. Styrenes with substituent
groups at different positions (such as 2-, 3-, and 4-fluorosty-
rene) were also efficiently transformed into their corre-
sponding β-ketosulfones (3b, 3d, and 3i). The influence of
electronic effects is not clear from these results, with
3-methylstyrene 1c, 3-fluorostyrene 1d, 4-methylstyrene 1e,
and 4-fluorostyrene 1i all giving the corresponding products
3c, 3d, 3e, and 3i in high yields. A range of benzenesulfon-
ohydrazides with electron-donating or electron-withdrawing
substituents on the aromatic ring were also reacted. Various
functional groups commonly used in synthetic chemistry
including fluoro (2n), chloro (2j), bromo (2k), and nitro
(2q) were all compatible with the reaction conditions pre-
sented, affording the corresponding products (3n, 3o, 3p,
and 3q) in high yields. Heterocycle-based sulfonylhydra-
Scheme 4 Reactions determining the reaction mechanism.

4
Wan et al. Sci China Chem January (2016) Vol.59 No.1
simplicity, inexpensive catalysts, readily available materi-
als, and mild and environmentally benign conditions, this
novel catalytic system provides a highly attractive approach
for producing β-keto-sulfones. Further studies into the
mechanism of this process are underway in our laboratory.
Acknowledgments This work was supported by the National Natural
Science Foundation of China (U1504210), the China Postdoctoral Science
Foundation funded project (2015M572110) and Jilin Province Key Labor-
atory of Organic Functional Molecular Design & Synthesis (130028651).
Conflict of interest The authors declare that they have no conflict of
interest.
Supporting information The supporting information is available online
at http://chem.scichina.com and http://link.springer.com/journal/11426.
The supporting materials are published as submitted, without typesetting or
editing. The responsibility for scientific accuracy and content remains
entirely with the authors.
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undergo beta scission to form carbonyl group and hydroxyl
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for the unprecedented synthesis of β-ketosulfones through
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moderate to high yields. Taking into account the operational

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