Metal-free, one-pot highly selective synthesis of (E)-vinyl sulfones and sulfoxides via addition-oxidation of thiols with alkynes

Article abstract of DOI:10.1016/j.tetlet.2012.01.135

We have developed a highly selective one-pot method for the synthesis of (E)-vinyl sulfones and sulfoxides from thiols with terminal alkynes. The sulfones and sulfoxides could be obtained with excellent selectivity in good isolated yields. It is simple, e

Full text of DOI:10.1016/j.tetlet.2012.01.135

Tetrahedron Letters 53 (2012) 1851–1854
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Tetrahedron Letters
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Metal-free, one-pot highly selective synthesis of (E)-vinyl sulfones and
sulfoxides via addition–oxidation of thiols with alkynes
Qicai Xue a, Zhijie Mao a, Yan Shi a, Haibin Mao a, Yixiang Cheng a, Chengjian Zhu a,b,
⇑
a School of Chemistry and Chemical Engineering, State Key Laboratory of Coordination Chemistry, Nanjing University, Nanjing 210093, China
b State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China
a r t i c l e i n f o
a b s t r a c t
Article history:
We have developed a highly selective one-pot method for the synthesis of (E)-vinyl sulfones and sulfox-
ides from thiols with terminal alkynes. The sulfones and sulfoxides could be obtained with excellent
selectivity in good isolated yields. It is simple, efficient and environmentally benign, and metal-free.
The mechanism for the formation of the (E)-vinyl sulfones was also proposed.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 28 November 2011
Revised 16 January 2012
Accepted 31 January 2012
Available online 8 February 2012
Keywords:
Thiols
Alkynes
Vinyl sulfones
Metal-free
Green chemistry
Introduction
Vinyl sulfones or sulfoxides are valuable intermediates and use-
ful building blocks in the synthesis of biologically active com-
pounds, such as cysteine proteases,1 HIV-1 integrase,2 and
antibiotic TAN-1085.3 Recently, vinyl sulfones or sulfoxides in
organic synthesis have received increasing attention.4 Owing to
the importance of these compounds, various approaches to
a,b-
unsaturated sulfones or sulfoxides have been developed.5 The
traditional methods mainly include: oxidation of vinyl sulfides,6
b-elimination,7 Knoevenagel condensation,8 Wittig reaction,9 and
Horner–Emmons reaction.10 However, these methods usually
afforded the desired products in a mixture of isomers. The develop-
ment of highly selective approaches to synthesize such compounds
is highly desirable. In this direction, some protocols have been
developed to make up for these drawbacks with the employment
of transition metal catalysts (Ru,11 Pd,12 Cu,13 Ce14). For instance,
the cross-coupling of sulfinate salts with vinyl bromides, vinyl tri-
flates, or alkenes with Pd or Cu catalysts showed an efficient route
to these compounds.12c,d,13a,b The disadvantages associated with
these methods are the utility of poisonous metals or expensive
ligands. Additionally, heavy metal impurities in drug intermediates
limit the utility of such methods.
Scheme 1. The synthesis of vinyl sulfones or sulfoxides from thiols and alkynes.
reactions involving thiols have been developed for the synthesis
of vinyl sulfides.15 However, there is no report on the synthesis
of (E)-vinyl sulfones employed alkynes and thiols as starting mate-
rials. In view of the increased attention to efficient and metal-free
methods for the formation vinyl sulfones and sulfoxides, herein we
wish to report a metal-free, one-pot highly selective approach to
(E)-vinyl sulfones or sulfoxides from hydrothiolation of alkynes
(Scheme 1).
Results and discussions
The addition–oxidation of thiols with alkynes is an attractive
approach to vinyl sulfones and sulfoxides. Various catalytic
Our initial studies were aimed at finding optimal reaction
conditions for the synthesis of (E)-vinyl sulfones. The reaction
was first attempted by using phenylacetylene (0.25 mmol) and 4-
methyl thiophenol (0.30 mmol), 0.1 mL H2O2 (30% in water) in
THF at 50 °C. To our delight, the test reaction provided (E)-isomeric
⇑
Corresponding author. Tel./fax: +86 25 83594886.
E-mail address: cjzhu@nju.edu.cn (C. Zhu).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2012.01.135

1852
Q. Xue et al. / Tetrahedron Letters 53 (2012) 1851–1854
Table 2
predominant vinyl sulfones in 24 h with a 70% yield (Table 1, entry
1). On the basis of this encouraging result, we investigated the
reaction in detail under various conditions, and the results were
summarized in Table 1. First, a variety of oxidants were screened.
It was observed that H2O2 (30% in water) was the most effective
(Table 1, entry 1). Other oxidants tested decreased either the selec-
tivity or the yield of 3a (Table 1, entries 2 and 3). Notably, a satis-
factory yield was obtained by increasing the loading of H2O2 (Table
1, entry 4). We then examined different solvents using 0.2 mL H2O2
as the oxidant. The results demonstrated that THF is a highly effec-
tive solvent, providing the product 3a with the highest selectivity
in a 78% isolated yield (Table 1, entry 4). Other solvents such as
EtOH, CH2Cl2, and n-hexane resulted in poorer conversion or lower
selectivity (Table 1, entries 5–7). Subsequently, the effect of addi-
tive was evaluated. After screening of various additives, it was
important to find ammonium salts that played a significant
influence on the selectivity of (E)-vinyl sulfone (Table 1, entries
8–11). In the presence of (n-C4H9)4NCl, the one-pot addition–
oxidation providing (Z)-isomeric predominant vinyl sulfones. The
reaction proceeded readily with excellent selectivity in a good
yield by using NH4Cl as an additive (Table 1, entry 11). Among
the reaction temperature examined, it turned out that 50 °C was
the most suitable. Higher temperature increased the yield, but
decreased the selectivity (Table 1, entry 13). Moreover, we also
observed that the yield could reach to 93% by prolonging time
(Table 1, entry 14). On the basis of these optimization experiments,
we decided to use 0.2 mL H2O2 as the oxidant and 1.0 equiv of
NH4Cl as the additive in THF at 50 °C for 48 h in the air as our
protocol for the one-pot selective synthesis of (E)-vinyl sulfone.
To determine the scope of the reaction, we first examined the
addition of a variety of aryl thiols to phenylacetylene (2a) under
the optimal procedure. The results were summarized in Table 2.
One-pot synthesis of (E)-vinyl sulfonesa
Entry
1
1
2
3
Yieldb E/Zc
1a 2a
1b 2a
3a
3b
93
98
>99/1
2
100/0
3
4
5
1c 2a
1a 2b
1a 2c
3c
3d
3e
81
92
82
99/1
100/0
99/1
6
1a 2d
3f
94
100/0
7
8
1a 2e
1b 2e
3g
3h
86
90
100/0
100/0
Table 1
Optimizing reaction conditions for the synthesis of 3aa
9
1b 2d
1c 2d
3i
3j
97
88
100/0
98/2
Entry
Oxidant
Solvent
Additive
T (°C)
Yieldb
E/Zc
10
1d
2d
3d
4e
5
6
7
8
9
10
11
12
13
14f
15f
16f
17f
H2O2
t-BuO2H
m-CPBA
H2O2
H2O2
H2O2
H2O2
H2O2
H2O2
H2O2
H2O2
H2O2
H2O2
H2O2
H2O2
H2O2
H2O2
THF
THF
THF
THF
EtOH
CH2Cl2
n-hexane
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
—
—
—
—
—
—
—
50
50
50
50
50
50
50
50
50
50
50
40
60
50
50
50
50
70
55
Trace
78
67
50
36
44
71
32
79
52
84
93
53
51
33
90/10
76/24
—
91/9
11
12
13
1c 2b
1a 2f
1d 2f
3k
3l
98
84
97/3
>99/1
95/5
88/12
63/35
80/20
33/67
96/4
(n-C4H9)4NCl
Et3NÁHCl
(NH4)2SO4
NH4Cl
NH4Cl
NH4Cl
NH4Cl
NH4Cl+AIBN
NH4Cl+BPO
NH4Cl+BHT
98/2
>99/1
>99/1
93/7
>99/1
>99/1
>99/1
85/15
3m 82
a
Reaction conditions: 1 (0.25 mmol), 2 (0.30 mmol), 0.2 mL H2O2 (30% in water),
0.25 mmol NH4Cl, 1.0 mL THF at 50 °C for 48 h under air.
b
Isolated yield (%).
a
Reaction conditions: 1a (0.25 mmol), 2a (0.30 mmol), solvent (1.0 mL), additive
(0.25 mmol), 50 °C, 24 h, under air.
E/Z ratio determined by 1H NMR.
c
b
Isolated yield (%).
E/Z ratio determined by 1H NMR.
c
d
0.1 mL oxidant was added.
Unless otherwise noted, adding 0.2 mL H2O2.
Stirring for 48 h, 0.25 mmol azodiisobutyronitrile (AIBN), 0.25 mmol benzoyl
e
It was discovered that a wide range of aryl thiols could afford
(E)-vinyl sulfones in good yields with excellent selectivity.
Electron-poor and electron-rich thiols were compatible for this
f
peroxide (BPO), 0.50 mmol 2,6-di-tert-butyl-4-methylphenol (BHT).

Q. Xue et al. / Tetrahedron Letters 53 (2012) 1851–1854
1853
procedure (Table 2, entries 2 and 3). To further explore the scope of
this chemistry, various commercially available alkynes were
tested. Aromatic alkynes bearing substituents such as methyl,
methoxy, and fluoro afforded good yields with excellent selectivity
(Table 2, entries 4–6). The optimized conditions were consistent
with aliphatic alkynes (Table 2, entries 7 and 8). Subsequently,
the effect of substituents on the selectivity of the desired product
3
was discussed. Aromatic thiols or alkynes with electron-
withdrawing substituents were converted into the corresponding
alkenyl sulfones with higher selectivity than electron-donating
substituents (Table 2, entries 2, 6, 8, 9 vs 5, 10, 11). 2- and 3-substi-
tuted aryl thiols or alkynes also tolerated in this protocol (Table 2,
entries 12 and 13). However, attempted synthesis of (E)-vinyl sul-
fone using aliphatic alkyne and aliphatic thiol gave an unsatisfac-
tory result under the standard conditions.
Scheme 3. Oxidation of 4a–Z and 5a–Z.
To explore the reaction pathway, the one-pot reaction of 1a
with 2a was monitored by 1H NMR spectra (Scheme 2). The
reaction of 1a with 2a at 50 °C for 1 h led to the disappearance of
acetylenic H, and instead, new peaks of vinyl sulfides (5a–E and
5a–Z) appeared. The new peaks disappeared after stirring for
12 h at 50 °C, and the sulfides were oxidated to (E)-vinyl sulfone
(3a) and sulfoxide (4a). Extending the time to 48 h, only the double
peaks of 3a can be observed. The results demonstrated that the
oxidation of sulfides to sulfones accompanies with geometric
structure transition.
To further gain insight into the mechanistic pathway, the
reaction of 1a with 2a was carried out in the presence of radical
initiator or inhibitor (Table 1, entries 15–17). It was observed that
radical initiators and inhibitors decreased the conversion. More-
over, the oxidation of 4a–Z and 5a–Z was tested (Scheme 3). The
reaction of 4a–Z led to a trace amount of vinyl sulfone, and 5a–Z
afforded the products 3a and 4a with geometric structure transi-
tion. Interestingly, no (E)-vinyl sulfone or sulfoxide was detected
in the present of radical inhibitor BHT. Thus, we presume that
the transformation of configuration (5a–Z to 4a) is the key step
for the selective synthesis of 3a via radical pathway.
Scheme 4. Plausible mechanistic pathway.
Based on this observation, a plausible mechanism was proposed
in Scheme 4. We presume that H2O2 treated with NH4Cl affords
intermediate A (with similar structure to urea hydrogen perox-
ide16). The one-pot reaction would consist of the following steps:
(1) Addition of thiol to alkyne gave anti-Markovnikov product
5.15a (2) Reaction of 5 with intermediate A give sulfur radicals (6
and 8), which resonate with the carbon-centered radical 7. Subse-
quently, the sulfur radical trapped by intermediate A affords the
(E)-vinyl sulfoxide 4. (3) The formation of (E)-vinyl sulfone from 4.
Interestingly, we found that the one-pot reaction of 1a with
2a at room temperature for 48 h proceeded smoothly to afford
Scheme 2. The monitoring 1H NMR spectra of the reaction of 1a with 2a.

1854
Q. Xue et al. / Tetrahedron Letters 53 (2012) 1851–1854
Table 3
Conclusions
One-pot synthesis of (E)-vinyl sulfoxidesa
We have developed an efficient metal-free methodology for the
preparation of substituted (E)-vinyl sulfones and sulfoxides. It is
the first example for the synthesis of vinyl sulfones or sulfoxides
in one-pot through direct addition–oxidation of thiols with al-
kynes. This new protocol is well warranted in synthetic organic,
using simple materials and easy experimental procedure. The def-
inition of the mechanism and synthetic application of this reaction
are currently under study in our laboratory.
Entry
1
1
2
4
Yieldb
94
Acknowledgments
1a
2a
4a
4b
4c
4d
We gratefully acknowledge the National Natural Science Foun-
dation of China (20832001, 20972065, 21074054, 21172106) and
the National Basic Research Program of China (2010CB923303)
for their financial support.
2
3
4
1c
1a
1a
2a
2b
2c
83
84
97
Supplementary data
Supplementary data (experimental details and the characteriza-
tion data for the compounds 3a–m and 4a–j) associated with this
article can be found, in the online version, at doi:10.1016/j.tet-
let.2012.01.135. These data include MOL files and InChiKeys of
the most important compounds described in this article.
5
1a
2d
4e
93
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a
Reaction conditions: 1 (0.50 mmol), 2 (0.60 mmol), 0.2 mL H2O2 (30% in water),
0.25 mmol NH4Cl, 1.0 mL THF at room temperature for 48 h under air.
b
Isolated yield (%).
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