Catalyst-free sulfonylation of activated alkenes for highly efficient synthesis of mono-substituted ethyl sulfones in water

Article abstract of DOI:10.1039/c4gc00932k

A catalyst-free sulfonylation reaction of activated alkenes with sulfonyl hydrazides was efficiently developed under mild and environmentally benign conditions, in water without any ligand or additive. The reaction gave a range of structurally diverse mono-substituted ethyl sulfones with excellent yields, in which the by-product was nitrogen. the Partner Organisations 2014.

Full text of DOI:10.1039/c4gc00932k

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Catalyst-free sulfonylation of activated alkenes for
highly efficient synthesis of mono-substituted
ethyl sulfones in water†
Cite this: Green Chem., 2014, 16,
4106
Received 21st May 2014,
Accepted 9th July 2014
Yu Yang, Lin Tang, Sheng Zhang, Xuefeng Guo, Zhenggen Zha and Zhiyong Wang*
DOI: 10.1039/c4gc00932k
www.rsc.org/greenchem
A catalyst-free sulfonylation reaction of activated alkenes with sul-
fonyl hydrazides was efficiently developed under mild and environ-
mentally benign conditions, in water without any ligand or
additive. The reaction gave a range of structurally diverse mono-
substituted ethyl sulfones with excellent yields, in which the by-
product was nitrogen.
Introduction
Green and sustainable chemistry can be defined as the design-
ing of chemically and biologically important products or pro-
cesses that minimize the use and the generation of hazardous
substances. To achieve these goals, chemists have been attri-
buted to develop green and sustainable procedures, such as
heterocatalysis,1 metal-free catalysis2 or catalyst-free synthesis.3
Particularly, the reactions under catalyst-free conditions
are attractive for their advantages of being environmentally
friendly and inexpensive.4
Sulfones display a diverse range of behaviors and possess
unique features that make them valuable to be starting
materials for numerous types of synthetic applications.5 For
example, sulfones have been described as “pluripotent” by
Fuchs et al. and as “chemical chameleons” by Trost.6 Besides,
the sulfone moiety constitutes a core structural motif for
various biologically active molecules and useful building
blocks.7 The importance of sulfones and documented difficul-
ties in their preparation have always been of considerable
interest to synthetic chemists (Scheme 1). Traditionally, allyl
aryl sulfone derivatives were prepared by the reaction
of Baylis–Hillman adducts with sulfonyl precursors such as
sulfinates,8 p-toluenesulfonylmethyl isocyanide,9 arenesulfonyl
Scheme 1 (a) Sulfone derivatives prepared by the reaction of Baylis–
Hillman adducts with sulfonyl precursors; (b) aerobic oxysulfonylation of
alkenes leading to secondary and tertiary β-hydroxysulfones; (c) copper-
catalyzed direct oxysulfonylation of alkenes with dioxygen and sulfonyl-
hydrazides; (d) preparation of mono-substituted ethyl sulfones; (e) cata-
lyst-free sulfonylation of activated alkenes.
cyanides,10 sulfinyl chlorides11 and sulfonylhydrazides12
(Scheme 1a). Recently, an aerobic oxysulfonylation of alkenes
leading to secondary and tertiary β-hydroxysulfones in the
presence of pyridine was reported by Lei et al. (Scheme 1b).13
Subsequently, a copper-catalyzed direct oxysulfonylation of
alkenes with dioxygen and sulfonyl hydrazides leading to
β-ketosulfones was reported by Wang et al. (Scheme 1c).14
However, most of them proceeded via a free radical pathway,
and a metal catalyst, an additive or a toxic organic solvent was
employed in these aforementioned reactions. In particular, few
studies involving the facile synthesis of mono-substituted ethyl
sulfones were reported. The traditional preparation of mono-
substituted ethyl sulfones includes the oxidation of sulfides15
(Scheme 1d), the alkylation of sulfinate salts16 and the alky-
lation of magnesium sulfinates.17 However, most of these
Hefei National Laboratory for Physical Sciences at Microscale, CAS Key Laboratory of
Soft Matter Chemistry & Collaborative Innovation Center of Suzhou Nano Science
and Technology, University of Science and Technology of China, Hefei, 230026,
P. R. China. E-mail: zwang3@ustc.edu.cn; Fax: (+86) 551-360-3185
†Electronic supplementary information (ESI) available: Experimental details,
characterization of catalysts and characterization of products. See DOI: 10.1039/
c4gc00932k
4106 | Green Chem., 2014, 16, 4106–4109
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procedures require multistep processes to synthesize starting (Table 1, entry 1). Subsequently, the efficiency of several nano-
materials and suffer from relatively complicated reaction con- catalyst sources was tested, the product could be obtained in
ditions with undesired by-products, which make them environ- moderate to excellent yield (Table 1, entries 2–6). To our
mentally unfavorable. Therefore, there is still a great demand delight, this reaction could also work well without any nano-
for the development of more green and sustainable catalysts, obtaining 3aa in 95% yield (Table 1, entry 7). Further
approaches to produce mono-substituted ethyl sulfones.
screening of the solvents without catalyst revealed that the
From a “green and sustainable chemistry” perspective, yield of the desired product largely decreased when organic
water is a cost-effective and environmentally safe solvent solvents were applied instead of water (Table 1, entries 8–15).
in synthetic chemistry.18 Water, as a hydrogen source, is In addition, raising the temperature had no effect on the yield,
undoubtedly one of the most suitable and promising routes while lowering the reaction temperature decreased the yield of
for constructing compounds. Besides, alkenes, as versatile the desired product (Table 1, entries 16–18). After the screen-
and readily available building blocks, are extensively used in ing, 1a with 2a in the presence of air at 65 °C using water as
organic synthesis.19 In consideration of the importance of the solvent was established as the optimal reaction conditions.
sulfone derivatives and related scaffolds,7,20 we developed a
With the optimal conditions in hand, we then examined
highly efficient sulfonylation of activated alkenes with sulfonyl the scope of this sulfonylation process. The optimized reaction
hydrazides to afford mono-substituted ethyl sulfones via an conditions were found to be applicable to a broad range of
anion process instead of a free-radical pathway (Scheme 1e). substrates (Table 2). The effect of substituents on the aryl ring
All these transformations can be smoothly performed in water of the sulfonylhydrazides on the sulfonylation was first exam-
under mild conditions. The reaction didn’t involve any cata- ined. Gratifyingly, a variety of aryl sulfonylhydrazides, bearing
t
lyst, additive, ligand or organic solvent. Moreover, the by- either electron-donating groups (R = Me, Bu, OMe, OCF3) or
product was nitrogen.
electron-withdrawing groups (R = CH3CONH, CF3, NO2, F, Cl,
Br) on the aryl ring,22 could be converted to the desired pro-
ducts 3aa–3al in excellent yields. The sterically hindered ortho-
nitro substituted benzene-sulfonylhydrazides gave the corres-
ponding 3am in 54% yield. Notably, disubstituted benzene-
Results and discussion
Initially, we chose Pd/DNA as the catalyst in the presence of
4-methylbenzenesulfonohydrazide (1a) and ethyl acrylate (2a)
at 65 °C under air atmosphere in water to optimize the reac-
tion conditions since we have been focusing on heterogeneous
catalysts for a long time1,21 (Table 1). Pleasingly, the desired
β-sulfone ester product 3aa was observed in 93% yield
Table 2 Synthesis of β-sulfone esters/amides from sulfonyl hydrazidesa
Table 1 Optimization of the reaction conditionsa
Entry
R1
R2
Product
Yieldb (%)
1
2
3
4
5
6
7
8
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OMe
OPh
NH-isopropyl
NHPh
NHtBu
4-CH3C6H4
Ph
3aa
3ab
3ac
3ad
3ae
3af
3ag
3ah
3ai
95
94
94
93
91
87
97
91
93
90
91
98
54
99
93
99
96
92
91
99
70
99
99
92
4-tBuC6H4
4-CH3OC6H4
4-CF3OC6H4
4-CH3CONHC6H4
4-CF3C6H4
4-FC6H4
4-ClC6H4
4-BrC6H4
4-NO2C6H4
3-NO2C6H4
2-NO2C6H4
3-F,4-CH3C6H3
3-NO2,4-ClC6H3
3-Br,5-CF3C6H3
2-Naphthalene
2-Thiophene
PhCH2
4-CH3C6H4
4-CH3C6H4
4-CH3C6H4
4-CH3C6H4
4-CH3C6H4
Entry
Catalyst
Solvent
T (°C)
Yieldb (%)
1
2
3
4
5
6
7
8
Pd/DNA
Pd/C
Pd/TiO2
Au/TiO2
Au/DNA
Pt/C
—
—
—
—
—
—
—
—
—
—
—
—
H2O
H2O
H2O
H2O
H2O
H2O
H2O
EtOH
DMSO
DMF
Toluene
CH3CN
DCE
THF
1,4-Dioxane
H2O
65
65
65
65
65
65
65
65
65
65
65
65
65
65
65
80
50
35
93
95
76
51
94
90
95
25
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
3aj
3ak
3al
3am
3an
3ao
3ap
3aq
3ar
3as
3ba
3ca
3da
3ea
3fa
9
30
36
10
11
12
13
14
15
16
17
18
Trace
Trace
Trace
Trace
Trace
94
H2O
H2O
76
22
a Reaction conditions: activated alkenes (0.5 mmol) and sulfonyl
a Reaction conditions: 1a (0.5 mmol), 2a (0.25 mmol), catalyst (2 mol%), hydrazides (0.25 mmol) in 1 mL of H2O, 65 °C, under air, 24 h.
solvent (1 mL), under air, 24 h. b Isolated yields based on 2a.
b Isolated yields based on sulfonyl hydrazides.
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sulfonylhydrazides could also be employed as reaction sub-
strates, furnishing the desired products 3an–3ap in excellent
yields. More importantly, the naphthalene substrate 2q, the
thiophene substrate 2r and aliphatic substrate 2s could also be
converted into interesting products 3aq–3as with excellent
yields.
On the other hand, the scope of the activated alkenes was
screened. The acrylates with various functional groups such as
ethyl and methyl were successfully transformed into the desired
product 3aa and 3ba in excellent yields.23 It is noteworthy that
the phenol ester can be used as the reaction substrate in this
reaction (entry 21, Table 2), giving 3ca with a yield of 70%.
Other alkenes with electron-withdrawing groups, such as some
acrylamides, also gave the corresponding products in excellent
yields (3da–3fa).
Scheme 3 The proposed mechanism for the reaction.
Further, the sulfur-centered anion 7 is selectively added to
the activated alkene 1a leading to the oxygen-centered anion 8,
which can resonate with the carbon-centered anion 9. Finally,
the intermediate 9 affords β-sulfone ester/amide 3aa by a sub-
sequent proton transfer (PT) from hydronium ions.
Studies on the reaction mechanisms
To get an insight into the mechanism of the sulfonylation
process, several controlled experiments were conducted.
First, radical trapping experiments were conducted to elucidate
whether the reaction involves radical species. When the radical
Conclusions
A remarkably mild catalyst-free sulfonylation of activated
alkenes in water was developed, affording β-sulfone esters/
amides in excellent yields. The sulfonylation proceeded under
very environmentally benign conditions without any catalyst,
additive, ligand or organic solvent, and the by-product was
nitrogen. Moreover, the reaction has a broad scope of reaction
substrates, a variety of functional groups can tolerate the reac-
tion conditions well. Ongoing research, including further
mechanistic details, expanding the substrate scope and appli-
cations in organic synthesis are currently underway.
scavenger 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO;
2
equiv.) was employed under standard conditions, the reaction
afforded 3aa in 81% yield (Scheme 2b), which implied that
the transformation did not proceed via a free-radical
pathway.23,24 Subsequently, when D2O (1 mL) was used as the
solvent under standard conditions, the reaction afforded a
deuterium generation product in a 94% yield (Scheme 2a),
which indicated that the origin of the α-hydrogen atom of
β-sulfone esters derived from water. Furthermore, β-sulfone
ester 3ab could be isolated from the reaction of 1a with
sodium benzenesulfinate 5 (Scheme 2c),13 suggesting that
benzenesulfinic acid should be an intermediate in this reaction.
It is noteworthy that the reaction mixture was weak acidic at
the end of the reaction, which indicated that a small amount
of acid was produced.
On the basis of the aforementioned investigations and pre-
vious reports,16,22 a possible reaction pathway was proposed and
depicted in Scheme 3. Initially, sulfonylhydrazide is quickly
transformed into an sulfinyl anion 6, which can resonate
with the sulfur-centered anion 7 in the presence of water, with
the generation of hydronium ions and the release of N2.
Experimental
A mixture of arylsulfonyl hydrazides (0.25 mmol) and activated
alkenes (0.5 mmol) in water (1 mL) was put into an oil bath at
65 °C under magnetic stirring for 24 h under air. After the
reaction was complete, the mixture was extracted with EtOAc
(3 × 15 mL) and then the combined organic extract was
washed with brine (15 mL), dried over sodium sulfate, and fil-
tered. The solvent was removed under reduced pressure and
the residue was purified by flash column chromatography
(hexane–ethyl acetate = 4 : 1) to give compound 3.
Acknowledgements
We are grateful to the National Nature Science Foundation of
China (2127222, 91213303, 21172205).
Notes and references
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