Iodine-catalysed sp3 C-H sulfonylation to form β-dicarbonyl sulfones with sodium sulfinates

Article abstract of DOI:10.1039/c4ra09821h

An efficient and easily handled method for β-dicarbonyl sulfones with sodium sulfinates as the sulfonyl source was developed. This transformation was involved in the iodine-catalysed sp³ C-H sulfonylation of β-dicarbonyl compounds. This journal

Full text of DOI:10.1039/c4ra09821h

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Iodine-catalysed sp3 C–H sulfonylation to form
b-dicarbonyl sulfones with sodium sulfinates†
Cite this: RSC Adv., 2014, 4, 49329
*
*
Wen-Chao Gao, Jin-Jin Zhao, Hong-Hong Chang, Xing Li, Qiang Liu
and Wen-Long Wei
Received 4th September 2014
Accepted 29th September 2014
DOI: 10.1039/c4ra09821h
www.rsc.org/advances
An efficient and easily handled method for b-dicarbonyl sulfones with heteroaromatic compounds and C–C unsaturated bonds has
sodium sulfinates as the sulfonyl source was developed. This trans- been well established, and examples include regioselective 2-
formation was involved in the iodine-catalysed sp3 C–H sulfonylation sulfonylation of indoles with sodium sulnates,7 synthesis of
of b-dicarbonyl compounds.
sulfonated pyrazoles with sulfonyl hydrazides,8 sulfonylation of
alkenes with sulfonyl hydrazides to form alkenyl sulfones,9a
allylic sulfones,9b,c and sulfonated oxindoles,9d and sulfonyla-
tion of alkynes with sulfonyl hydrazides to synthesize b-iodo-
vinyl sulfones.9e Although these studies achieved much
progress, little attention has been paid to investigate the sul-
fonylation of sp3 C–H bond. In this regard, we described a novel
and efficient method for the synthesis of b-dicarbonyl sulfones
by iodine-catalysed sulfonylation of sp3 C–H bond with sodium
sulnates.
Initially, ethyl benzoyl acetate (1a) and sodium benzene-
sulnate (2a) were selected as model substrates to explore the
optimal reaction conditions. It was found that ethyl a-phenyl-
sulfonylbenzoylacetate (3a) was obtained in 27% yield by using
iodine (10 mol%) and tert-butyl hydroperoxide (TBHP, 1.5
equiv.) in CH3CN at 25 ꢀC (Table 1, entry 1). The yield of 3a
Sulfones belong to a known class of organosulfur compounds,
which have found diverse applications in organic synthesis,
polymer materials, and medicinal chemistry.1 Among them,
b-dicarbonyl sulfones have attracted much attention due to
their excellent biological effects, such as antimicrobial,2a anti-
coagulant2b and anti-schistosomal activities.2c Furthermore,
since b-dicarbonyl compounds are commonly used intermedi-
ates for heterocycle synthesis,3 b-dicarbonyl sulfones would
provide alternative units to construct sulfonylated hetero-
aromatic compounds in the design of potential drugs.4
Surprisingly, only a limited number of procedures was devel-
oped for the synthesis of b-dicarbonyl sulfones during last
decades. In most cases, b-dicarbonyl sulfones were prepared
through either C-acylation of b-keto sulfones with acyl halides
or C-sulfonylation of b-dicarbonyl compounds with sulfonyl
halides. These methods usually required excess amount of
strong bases (NaOMe,2a,c NaH,5 or LDA6), which are not suitable
for sensitive substrates; the acyl or sulfonyl reagents are much
reactive and moisture-sensitive, resulting in side reactions and
byproducts, especially in the synthesis of complex molecules.
Therefore, it is highly desirable to develop an efficient and easily
handled method for b-dicarbonyl sulfones with less reactive
sulfonyl sources (Scheme 1).
Recently, iodine or tetrabutylammonium iodide has
emerged as a promising alternative to catalyse oxidative sulfo-
nylation due to their high efficiency, mild reaction conditions
and metal-free features. Especially, the sulfonylation of
College of Chemistry and Chemical Engineering, Taiyuan University of Technology,
Taiyuan, 030024, P. R. China. E-mail: gaowenchao@tyut.edu.cn; changhonghong@
tyut.edu.cn; Tel: +86 0351 6018534
Scheme 1 Different methodologies for the synthesis of b-dicarbonyl
† Electronic supplementary information (ESI) available: Details of experimental
procedures and characterization data of products. See DOI: 10.1039/c4ra09821h
sulfones.
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Table 1 Optimization of reaction conditionsa
Table 2 The scope of b-dicarbonyl compoundsa
Yieldb (%)
Entry
Catalyst
Oxidant
Solvent
T (ꢀC)
Yieldb (%)
Entry
b-Dicarbonyl compound
Product
1
2
3
I2
I2
I2
I2
I2
—
I2
KI
Bu4NI
KIO3
I2
I2
I2
I2
I2
I2
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
—
TBHP
TBHP
TBHP
H2O2
Oxone
TBHP
TBHP
TBHP
TBHP
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
THF
25
45
65
Reux
65
65
65
65
65
65
65
65
65
65
65
65
27
73
94
94
89
0
21
85
66
0
49
17
87
85
38
Trace
1
2
3
4
5
6
R1 ¼ C6H5, R2 ¼ OEt, R3 ¼ H
R1 ¼ 4-BrC6H4, R2 ¼ OEt, R3 ¼ H
R1 ¼ 2-MeC6H4, R2 ¼ OEt, R3 ¼ H
R1 ¼ 4-MeOC6H4, R2 ¼ OEt, R3 ¼ H
R1 ¼ 2-naphthyl, R2 ¼ OEt, R3 ¼ H
R1 ¼ 2-furyl, R2 ¼ OEt, R3 ¼ H
R1 ¼ 2-thienyl, R2 ¼ OEt, R3 ¼ H
R1 ¼ C6H5, R2 ¼ OEt, R3 ¼ Me
R1 ¼ iPr, R2 ¼ OEt, R3 ¼ H
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
94
87
71
87
93
71
82
9
66
51
66
54
48
81
4
5c
6
7d
8
7
8c
9
9
10
11
12
13
14d
R1 ¼ tBu, R2 ¼ OEt, R3 ¼ H
10
11
12
13
14
15
16
R1 ¼ CO2Me, R2 ¼ CO2Me, R3 ¼ H
R1 ¼ CO2Et, R2 ¼ CO2Et, R3 ¼ H
t
t
R1 ¼ CO2 Bu, R2 ¼ CO2 Bu, R3 ¼ H
R1 ¼ C6H5, R2 ¼ C6H5, R3 ¼ H
EtOAc
CHCl3
CH3COOH
a
Reaction conditions: 0.5 mmol of 1, 0.6 mmol of 2a, 0.05 mmol of I2,
0.75 mmol of TBHP (70% in water), in 2 mL of MeCN at 65 ꢀC, for 1–4 h.
a
Isolated yield. c Conversion: 38%. d Solvent: THF (2 mL).
b
Reaction conditions: 0.5 mmol of 1a, 0.6 mmol of 2a, 0.05 mmol of
b
catalyst, 0.75 mmol of oxidant, in 2 mL of solvent for 1 h. Isolated
yield. The reaction was run under N2. The reaction was run with
1.0 equiv. of iodine.
c
d
donating or electron-withdrawing group on the phenyl ring gave
the corresponding products in good to high yields (3b–d). Other
aromatic rings such as naphthyl, furyl, and thienyl groups could
also be tolerated, and delivered the corresponding products 3e–
g in good to excellent yields. It was noteworthy that the location
of a methyl group at the a-position of b-keto esters impeded the
reaction process, and the desired product 3h was only furnished
in 9% yield. Furthermore, the aliphatic b-keto esters were also
attempted and gave the corresponding products in moderate
yields (3i, 3j). As for the different b-diesters, the reaction also
proceeded well, and gave the desired products 3k, 3l and 3m in
moderate yields. The b-diketone such as dibenzoylmethane was
proved to be a good substrate for this transformation, and the
product 3n was obtained in 81% yield.
The different sodium sulnates were also evaluated for this
transformation (Table 3). Arylsulnic acid sodium salts bearing
electro-donating or electro-withdrawing substituents on the
phenyl ring could smoothly react with ethyl benzoylacetate to
give the corresponding products in high yields (3o, 3p).
Furthermore, the aliphatic sulnic acid sodium salts like
sodium methanesulnate were also suitable for this reaction,
and coupled with b-keto esters or b-diketones in moderate
yields (3q, 3r). Besides, the reactions of b-diketones with
different kinds of aromatic sulnic acid sodium salts also pro-
ceeded smoothly, and provided the b-diketo sulfones in high to
excellent yields (3s–u).
could be increased when the reaction temperature was raised
(entries 1–3), and the best result (94% yield of 3a) was obtained
when heating the reaction mixture to 65 ꢀC (entry 3), while a
higher temperature could not give a better result (entry 4). 3a
was obtained in slightly lower yields when the reaction was run
under N2 atmosphere (entry 5). Control experiments indicated
that the desired product 3a could not be determined in the
absence of iodine catalyst (entry 6), and only 21% yield of 3a was
obtained even using stoichiometric amount of iodine in the
absence of TBHP (entry 7). Other catalysts such as KI, Bu4NI,
and KIO3 were examined but found less effective than iodine:
for KI and Bu4NI, 3a was just afforded in 85% and 66% yields
separately (entries 8 and 9); while no desired product was
detected when using potassium iodate as the catalyst (entry 10).
Two commonly used oxidants (H2O2 and Oxone) were also
tested for this transformation, while 3a was produced in inferior
yields (entries 11 and 12). Other different solvents were also
attempted for this transformation but they failed to provide a
more favorable outcome (entries 13–16). For example, 3a could
be produced in high yield in the solvents like THF and EtOAc
(entries 13 and 14), while low yields of 3a were obtained when
using CHCl3 or AcOH as the solvent (entries 15 and 16).
With the optimal reaction conditions in hand (Table 1, entry
3), a series of b-dicarbonyl compounds (1) was then investigated
to couple with sodium benzenesulnate (2a). It was found that
various b-dicarbonyl compounds including b-keto esters,
b-diesters and b-diketones were suitable for this transformation
(Table 2). Ethyl benzoylacetate derivatives bearing electro-
The mechanism of the present transformation is worth dis-
cussing. Several control experiments were carried out in order to
obtain some insight of the possible mechanism. In the reaction
of ethyl benzoylacetate with sodium benzenesulnate, the a-
iodinated ester 4a was detected at the rst few minutes. 4a
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Table 3 The scope of sodium sulfinatesa
Entry
Sodium sulnate
Product
Yieldb (%)
1
2
3
R3 ¼ 4-OMeC6H4
R3 ¼ 4-BrC6H4
R3 ¼ Me
3o
3p
3q
85
89
43
4c
5c
6c
7c
R3 ¼ Me
3r
3s
3t
57
82
89
95
R3 ¼ 4-FC6H4
R3 ¼ 2-naphthyl
R3 ¼ 4-MeC6H4
Scheme 3 The proposed mechanism.
3u
a
Reaction conditions: 0.5 mmol of 1, 0.6 mmol of 2, 0.05 mmol of I2,
0.75 mmol of TBHP (70% in water), in 2 mL of MeCN at 65 ꢀC, for 1–4
h. b Isolated yield. c Solvent: THF (2 mL).
In summary, we have developed a novel method for the
synthesis of b-carbonyl sulfones with sodium sulnate as the
sulfonyl source under metal-free conditions. This trans-
formation was catalysed by molecule iodine through the
sulfonylation of sp3 C–H bond, and the a-iodinated b-dicarbonyl
compounds were believed as the key intermediates. The ready
availability of starting materials, broad substrate scope, high
efficiency and operational simplicity make the present method
attractive to construct b-dicarbonyl sulfones and the derived
biologically active molecules.
Acknowledgements
We gratefully acknowledge the Natural Science Foundation of
Shanxi Province (2012021007-2 and 2011011010-2) and the
Qualied Personnel Foundation of Taiyuan University of Tech-
nology (no. tyut-rc201307a).
Scheme 2 Control experiments for mechanism studies.
Notes and references
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