Direct difunctionalization of alkenes with sulfinic acids and NBS leading to β-bromo sulfones

Article abstract of DOI:10.1016/j.tetlet.2015.02.043

A new and metal-free method has been developed for the synthesis of β-bromo sulfones through the direct difunctionalization of alkenes with sulfinic acids and NBS. This protocol provides a simple, convenient, and efficient approach to various β-bromo sulf

Full text of DOI:10.1016/j.tetlet.2015.02.043

Accepted Manuscript
Direct difunctionalization of alkenes with sulfinic acids and NBS leading to β-
bromo sulfones
Wei Wei, Xiaoxia Liu, Daoshan Yang, Ruimei Dong, Ying Cui, Fei Yuan, Hua
Wang
PII:
S0040-4039(15)00314-7
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.02.043
TETL 45912
Reference:
Tetrahedron Letters
To appear in:
Received Date:
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12 February 2015
15 February 2015
Please cite this article as: Wei, W., Liu, X., Yang, D., Dong, R., Cui, Y., Yuan, F., Wang, H., Direct
difunctionalization of alkenes with sulfinic acids and NBS leading to β-bromo sulfones, Tetrahedron Letters (2015),
doi: http://dx.doi.org/10.1016/j.tetlet.2015.02.043
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Direct difunctionalization of alkenes with
sulfinic acids and NBS leading to β-bromo
sulfones
Wei Wei, Xiaoxia Liu, Daoshan Yang, Ruimei Dong, Ying Cui, Fei Yuan and Hua Wang
A novel and metal-free method for the synthesis of β-bromo sulfones has been developed through direct
difunctionalization of alkenes with sulfinic acids and NBS

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Direct difunctionalization of alkenes with sulfinic acids and NBS leading to β-bromo
sulfones
Wei Wei, Xiaoxia Liu, Daoshan Yang, Ruimei Dong, Ying Cui, Fei Yuan, Hua Wang∗
The Key Laboratory of Life-Organic Analysis and Key Laboratory of Pharmaceutical Intermediates and Analysis of Natural Medicine, School of Chemistry and
Chemical Engineering, Qufu Normal University, Qufu 273165, Shandong, China.
ARTICLE INFO
ABSTRACT
Article history:
Received
A new and metal-free method has been developed for the synthesis of β-bromo sulfones through
the direct difunctionalization of alkenes with sulfinic acids and NBS. This protocol provides a
simple, convenient, and efficient approach to various β-bromo sulfones in moderate to good
yields with excellent selectivity, and especially does not require any catalyst or additive.
Received in revised form
Accepted
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
β-bromo sulfones
alkenes
sulfinic acids
NBS
difunctionalization
Sulfone groups are a very important class of functionalities,
which extensively exist in various bioactive compounds, natural
products, and organic functionalized materials.1 Thus, the
introduction of sulfone functionality into organic molecules to
construct various organic sulfone compounds has drawn great
interests of chemists.2 On the other hand, the difunctionalization
of alkenes, involving the formation of two new chemical bonds,
has recently become a powerful and fascinating tool for the
construction of various complex and highly valuable compounds
in organic synthesis and medicinal chemistry.3 Over the past
several years, some important difunctionalization reactions such
as diamination,4 dioxygenation,5 aminooxygenation,6 and
oxyphosphorylation7 of alkenes have been effectively developed.
Despite the significance of these reactions, difunctionalization of
alkenes to simultaneously incorporate sulfone group and other
different functional group remains a challenging but attractive
target to pursue. In 2013, Lei’s group8 reported a novel
oxysulfonylation of alkenes with dioxygen and sulfinic acids to
access β-hydroxysulfones (Scheme 1, A). Very recently, metal-
catalyzed procedures for the construction of β-ketosulfones via
oxysulfonylation of alkenes have been described (Scheme 1, A).9
Li,10a Jiao10b and our group10c also reported independently the
arylsulfonylation of activated alkenes leading to sulfonated
oxindoles (Scheme 1, B).
Scheme
1 Difunctionalization of alkenes to access sulfone-containing
compounds.
Herein, we wish to present a new and efficient synthesis
method for the direct bromosulfonylation of alkenes with sulfinic
acids and NBS to access β-bromo sulfones (Scheme 1, C).
Traditionally, β-bromo sulfones were synthesized by the
bromination
of
bis(2-phenethyl)sulfone
with
N-
bromosuccinimide in the presence of benzoyl peroxide,11 the
bromination of β-hydroxysulfones with phosphorus tribromide,12
———
∗ Corresponding author.
Tel.: +86 537 4458317; Fax: +86 537 4458317; e-mail: huawang_qfnu@126.com.

2
Tetrahedron
and the bromosulfonylation of alkenes with bromine and
electron-withdrawing group could react smoothly to give the
corresponding products in good to excellent yields (3aa-3ha).
Table 2
sulfinates or sulfonyl bromide.13 Nevertheless, most of these
methods might suffer from some limitations such as the use of
stoichiometric amounts of potentially dangerous oxidants,
unreadily-available starting materials, relatively harsh reaction
conditions, and poor selectivity or low yields. Alternatively, the
present methodology provides a simple and convenient approach
to various β-bromo sulfones in moderate to good yields with
excellent stereo- and regioselectivities under the toxic metal
catalyst-free and additive-free conditions.
Results for the reactions of alkenes with sulfinic acids and NBSa
Time
(h)
Yield
(%)b
Entry
1
1
Product
8
8
83
80
79
73
1a
3aa
Table 1
2
3
4
Screening of the reaction conditionsa
1b
3ba
10
8
1c
3ca
Entry
Solvent
T(oC)
Yield (%)b
1d
3da
DCE
80
80
80
80
80
1
79
Br
SO2Ph
DME
2
38
5
10
70
1,4-dioxane
THF
3
60
1e
F
3ea
4
83
EtOAc
5
70
6
7
8
8
73
67
66
6
CH3CN
toluene
80
80
trace
trace
trace
nr
1f
1g
1h
3fa
7
8
EtOH
DMF
80
80
10
10
9
3ga
DMSO
80
10
11
12
13
nr
H2O
THF
THF
80
25
60
nr
18
3ha
33
14
15
THF
THF
80
80
75c
71d
9
10
10
10
trace
81
3ia
16
THF
80
67e
Br
O
S
a
Reaction conditions: styrene 1a (0.6 mmol), benzenesulfinic acid 2a
(0.5 mmol), NBS (0.5 mmol), solvent (2 mL), 25-80oC, 10 h (sealed
tube).
10
11
O
1a
3ab
b Isolated yields based on 2a.
75
c
1a (0.5 mmol), 2a (0.5 mmol), NBS (0.5 mmol).
1f
3fb
d 1a (0.5 mmol), 2a (0.6 mmol), NBS (0.5 mmol).
e
1a (0.5 mmol), 2a (0.5 mmol), NBS (0.6 mmol).
12
10
67
1a
3ac
3ad
In an initial experiment, styrene 1a and benzenesulfinic acid
2a, were chosen as the model substrates to optimize the reaction
conditions in the presence of NBS. Among the solvents
examined, THF was found to be the most efficient reaction
medium for this reaction (Table 1, entry 4). In contrast, only a
trace amount of product 3aa was detected when reaction was
performed in CH3CN, toluene, or EtOH (Table 1, entries 6-9).
None of product was obtained in DMF, DMSO, or H2O (Table 1,
entries 9-11). Further optimization of reaction temperature
revealed that the best yield of 3aa was obtained when reaction
was conducted at 80oC and a lower reaction temperature led to a
significantly lower yield of product (Table 1, entries 4, 12-13).
The appropriate proportion of the styrene 1a, benzenesulfinic
acid 2a, and NBS was 1.2:1:1 (Table 1, entries 14-16).
13
14
10
12
74
50
1a
1a
3ae
a
Reaction conditions: alkenes 1 (0.6 mmol), sulfinic acids 2 (0.5
mmol), NBS (0.5 mmol), THF (2 mL), 80oC, 8-120 h (sealed tube).
b Isolated yields based on 2.
Substrates bearing a methyl group in the para-, meta-, or ortho-
position of the phenyl were subjected to the optimized reaction
conditions (1b−d). The results showed that the reaction
efficiency was not obviously affected by the steric hindrance.
Moreover, halogen groups including F, Cl, and Br were
compatible with this reaction leading to the products 3ea–3ha,
which could be employed for further transformations. Only a
trace amount of desired product 3ia was obtained when 4-
vinylbenzonitrile was employed as substrate. Nevertheless, when
With the optimized reaction conditions in hand, we started to
explore the scope and limitations of the reaction of alkenes with
sulfinic acids and NBS. As demonstrated in Table 2, in general,
aromatic alkenes bearing an electron-donating group or an

3
an aliphatic alkene such as 1-octene was used as the substrate,
none of the desired product was obtained. In addition to
benzenesulfinic acid, substituted benzenesulfinic acids containing
either electron-rich or electron- deficient groups were all suitable
for this reaction to generate the corresponding products in good
yields (3ab-3ad). The sterically-hindered substituted arylsulfinic
acids such as 2-(trifluoromethyl) benzenesulfinic acid could also
be smoothly transformed to the desired β-bromo sulfone (3ae).
Interestingly, when α-methyl styrenes such as prop-1-en-2-
ylbenzene 1i, 1-fluoro-4-(prop-1-en-2-yl)benzene 1j, and 1-
chloro-4-(prop-1-en-2-yl)benzene 1k were used as the substrates,
the corresponding allylic sulfones 4ia-4ka were obtained in good
yields (Scheme 2). Therefore, this reaction system offers a useful
and attractive strategy for the construction of allylic sulfone
structural motifs, which are exceptionally valuable and versatile
building blocks in synthetic and pharmaceutical chemistry.14
Subsequently, sulfonyl radical 5 interacted with NBS to give
sulfonyl bromide 6. Finally, the addition of sulfonyl bromide
6 to alkene 1 would lead to the formation of the desired β-
bromo sulfone 3.
Scheme 4 Postulated reaction pathway.
In conclusion,
a novel and efficient method has been
developed for the contruction of β-bromo sulfones through the
direct difunctionalization of alkenes with sulfinic acids and NBS.
This protocol, which utilizes simple and readily available starting
materials and catalyst-free conditions, provides a convenient and
highly attractive route to various β-bromo sulfones. Further
studies on the scope and application of this reaction are underway.
Acknowledgements
This work was supported by the National Natural Science
Foundation of China (No. 21302109, 21302110, and 21375075), the
Taishan Scholar Foundation of Shandong Province, the Excellent
Middle-Aged and Young Scientist Award Foundation of Shandong
Province (BS2013YY019), National Training Programs of
Scheme 2 Method for the synthesis of allylic sulfones.
Innovation
and
Entrepreneurship
for
Undergraduates
Considering that sulfonyl radicals were easily formed from
sulfinic acids under air,8,9d,10b,c,15 we supposed a radical
pathway might be involved in this reaction system. As shown
in Scheme 3 (Eq. 1), the model reaction was completely
inhibited when 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO,
a well-known radical scavenger) was added into the reaction
system, suggesting that a radical pathway could be involved
in the present transformation. Moreover, when the reaction of
benzenesulfinic acid 2a with NBS was conducted in the
absence of styrene, benzenesulfonyl bromide 6a was obtained
in 76% yield (Scheme 3, Eq. 2). Furthermore, treatment of
benzenesulfonyl bromide 6a with styrene 1a under the
standard procedure led to the formation of desired product
3aa (Scheme 3, Eq. 3). The above results indicated that
sulfonyl bromide might be the critical intermediate in the
present reaction system.
(201410446018), and the Scientific Research Foundation of Qufu
Normal University (BSQD 2012020).
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1a (0.5 mmol)
(0.5 mmol)
O
O
O
O
S
THF
80oC
S
+
Ph
Ph
Br
6a (0.25 mmol)
1a (0.3 mmol)
3aa (54%)
Scheme 3 Investigation into the reaction mechanism
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the present stage, based on the above experiments and
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proposed as described in Scheme 4. Firstly, the sulfonyl
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4
Tetrahedron
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