Synthesis of (: E)-β-iodo vinylsulfones via iodine-promoted iodosulfonylation of alkynes with sodium sulfinates in an aqueous medium at room temperature

Article abstract of DOI:10.1039/c6gc03387c

An efficient molecular iodine-promoted method for the synthesis of (E)-β-iodo vinylsulfones using water as the solvent at room temperature has been developed. This green reaction is fast, operationally simple, environmentally benign and, especially, proceeds under very mild conditions to afford the target products with high regio- and stereoselectivity.

Full text of DOI:10.1039/c6gc03387c

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Synthesis of (E)-β-iodo vinylsulfones via iodine-
promoted iodosulfonylation of alkynes with
sodium sulfinates in an aqueous medium at room
temperature†
Cite this: DOI: 10.1039/c6gc03387c
Received 8th December 2016,
Accepted 23rd January 2017
DOI: 10.1039/c6gc03387c
rsc.li/greenchem
Yadong Sun,* Ablimit Abdukader, Dong Lu, Haiyan Zhang and Chenjiang Liu*
An efficient molecular iodine-promoted method for the synthesis constructing these frameworks has attracted considerable
of (E)-β-iodo vinylsulfones using water as the solvent at room interest among organic chemists. Generally, transition metal-
temperature has been developed. This green reaction is fast, oper- catalyzed addition of sulfonyl halogens to terminal alkynes
ationally simple, environmentally benign and, especially, proceeds has been considered to be the most powerful method to con-
under very mild conditions to afford the target products with high struct halo vinylsulfones (Scheme 1, eqn (1)).9 Recently,
regio- and stereoselectivity.
Nakamura10 and Li11 demonstrated iron-catalyzed chlorosulfo-
nylation of terminal alkynes with sulfonyl chloride and
sulfonylhydrazides, respectively. Despite the efficiency of
these reactions, the use of toxic metal greatly restricts the
application of these reactions in areas of the pharmaceutical
industry. More recently, Jiang and coworkers developed an
elegant NBS or NIS-promoted difunctionalization of terminal
alkynes to form β-halo vinylsulfones under metal-free con-
ditions; unfortunately, this reaction also needs the toxic com-
pound toluene as solvent (Scheme 1, eqn (2)).12 Therefore, the
development of green methods for the synthesis of β-halo
vinylsulfones with high selectivity under mild reactions is still
highly desirable. Herein we disclose a novel protocol for the
preparation of β-iodo vinylsulfones through iodine-promoted
tandem radical reactions involving C–S and C–I bond for-
mation (Scheme 1, eqn (3)).
The development of an environmentally benign and efficient
protocol for the synthesis of privileged molecular skeletons
has been a challenging task for synthetic chemists.1 Among
them, multi-component reactions (MCRs) in water have been
shown to be a helpful toolkit in organic synthesis as well as for
the requirements of green chemistry because of their conver-
gence, operational simplicity, facile automation and relevant
character.2 Recently, radical cascades have become syntheti-
cally very attractive because they enable access to highly
complex molecular frameworks in only a few synthetic steps.
In addition, because of the excellent stereo and enantiocontrol
in radical reactions, numerous highly stereoselective radical
cascade processes have been developed over recent years.3
The formation of C–S bonds is one of the fundamental
transformations in the synthesis of organosulfur compounds.4
Halo vinylsulfones represent one particularly interesting
organosulfur compound because both the vinyl halide and
vinylsulfone moiety are important intermediates in organic
chemistry. Vinylsulfone containing molecules have been found
to be widespread in biological research, such as HIV-1
inhibitors,5 cysteine protease inhibitors,6 covalent protease
inhibitors,7 and inhibitors of a transpeptidase required for cell
wall protein anchoring and virulence in Staphylococcus
aureus.8 Therefore, the development of a general method for
On the basis of recent development of iodine-mediated
reactions13 and new reactions for the formation of C–S
bonds,14 we envisioned that the multi-component reactions of
terminal alkynes, sodium sulfinates and iodine would provide
β-iodo vinylsulfones. To probe the feasibility of our assump-
tion, we started our investigation by using phenylacetylene 1a
The Key Laboratory of Oil and Gas Fine Chemicals, Ministry of Education & Xinjiang
Uygur Autonomous Region, Urumqi Key Laboratory of Green Catalysis and Synthesis
Technology, School of Chemistry and Chemical Engineering, Physics and Chemistry
Detecting Center, Xinjiang University, Urumqi 830046, P. R. China.
E-mail: pxylcj@126.com, syd19791016@163.com
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c6gc03387c
Scheme 1 Synthetic approaches to halo vinylsulfones.
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and sodium p-toluenesulfinate 2a as model substrates under
various conditions and the results are summarized in Table 1.
To our delight, on treatment of phenylacetylene 1a and
sodium p-toluenesulfinate 2a with iodine (1 equiv.) at room
temperature in water for 2 h, the corresponding β-halo vinyl-
sulfone 3aa was obtained in 45% yield (Table 1, entry 1).
Higher yields were obtained when 2a was employed in excess
amounts (2 equiv.) and the reaction time was prolonged from
2 to 4 h (Table 1, entries 2 and 3). Increasing the stoichiometry
of iodine from 1 equiv. to 1.5 equiv. led to a significant
increase in product yields (Table 1, entries 4 and 5). Next, the
effect of the solvent on the reaction efficiency was examined
(Table 1, entries 6–15). It was found that the solvent played a
critical role in the success of this process. Among all the sol-
vents tested, water was the most suitable solvent for the
present transformation, possibly due to an intrinsically better
solubility of the sodium p-toluenesulfinate in water. Thus, the
optimal reaction conditions were 1a (1 equiv.), 2a (2 equiv.)
and I2 (1.5 equiv.) in water at room temperature for 2 h
(Table 1, entry 4). The stereochemistry and precise configur-
ation of β-iodo vinylsulfones were unambiguously confirmed
by single-crystal X-ray analysis of 3aa (Fig. 1).
Fig. 1 X-ray crystal structure of 3aa.
Table 2 Substrate scope of alkynesa,b
With the above optimized conditions, a range of alkynes
were tested to explore the scope of the substrates, and the
results are summarized in Table 2. Generally, various aryl- and
alkyl-substituted terminal alkynes were well tolerated under
the reaction conditions and afforded the corresponding pro-
ducts in moderate to excellent yields. For the para-substituted
phenylacetylenes, the electron-donating substituents (Et, t-Bu,
MeO, and EtO) gave better reactivity than the electron-with-
drawing substituents (F, Cl, and Br). The substituents in the
para or ortho position did not affect the desired products
a Reaction conditions: 1 (0.3 mmol), 2a (0.6 mmol) and I2 (0.45 mmol)
in 2.0 mL of H2O at room temperature for 2 h. b Isolated yield.
yields, and 3ad and 3ag were obtained in 75% and 78% yields,
respectively. It should be noted that the products (3ad–3ag)
containing two carbon–heteroatom bonds enabled further
Table 1 Optimization of reactionsa
modification
to
achieve
more
complex
structures
through sequential metal-catalyzed cross-coupling reactions.
Furthermore, other heterocyclic alkynes such as 2-ethynylthio-
phene and 3-ethynylpyridine were also investigated and found
to form the desired products in 91% and 82% yields, respect-
ively. Moreover, the aliphatic terminal alkynes such as ethynyl-
cyclopropane and hex-1-yne could also be successfully
employed to afford the desired iodosulfonylation products
3am and 3an in 85% and 82% yields, respectively. To our
delight, the internal alkynes can also be successfully trans-
formed into the iodosulfonylation products 3ao–3ap in moder-
ate yields.
To expand the scope of this methodology, a series of
sodium sulfinates were also employed to react with phenyl-
acetylene under optimized conditions (Table 3). A variety of
sodium benzenesulfinates, bearing electron-donating groups
(Me, MeO) or electron-withdrawing groups (F, Cl, and Br) on
the aryl ring, reacted smoothly with phenylacetylene, affording
the corresponding β-iodo vinylsulfones 3ca–3ia in good to
excellent yields. Nevertheless, arylacetylenes bearing the same
substituents at the para, ortho, and meta positions were also
Entry I2 (equiv.) 2a (equiv.) Solvent
Time (h) Yieldb (%)
1
2
3
4
5
6
7
8
1
1
1
1
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
H2O
H2O
H2O
H2O
H2O
THF
CH3CN
Ethanol
1,4-Dioxane
DMF
DMSO
NMP
DCM
DCE
2
2
4
2
4
2
2
2
2
2
2
2
2
2
2
2
45
55
62
86
87
51
46
47
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
9
56
10
11
12
13
14
15c
16d
Trace
Trace
n.p.
n.p.
n.p.
87
H2O
H2O
85
a Conditions: 1a (0.30 mmol) in the indicated solvent (2.0 mL) at room
temperature. n.p. = No product. b Isolated yield. c Under N2 in a sealed
tube. d The reaction was carried out in a dark background.
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Table 3 Substrate scope of sodium sulfinatesa,b
Scheme 4 Control experiments.
5 were obtained in 87% and 82% yields via Sonogashira and
Suzuki–Miyaura reactions, respectively.15 We also performed
dehydrohalogenation reactions of 3aa for the synthesis of
alkynyl sulfone 6, which as we know, is a versatile and essen-
tial building block in organic and polymer chemistry.
a Reaction conditions: 1a (0.3 mmol), 2 (0.6 mmol) and I2 (0.45 mmol)
To explore the reaction mechanism, several control experi-
ments were conducted (Scheme 4). The existence of radical
scavenger BHT did not prohibit this reaction (Scheme 4, eqn
(1)). However, the reaction was completely inhibited in the
presence of TEMPO (Scheme 4, eqn (2)), which indicated that
this transformation should involve a radical pathway. On the
in 2.0 mL of H2O at room temperature for 2 h. b Isolated yield.
effective substituents in this transformation furnishing the
corresponding products (3fa, 3ha, and 3ia) in good yields. To
our delight, apart from aromatic sodium sulfinates, less reac-
tive aliphatic sodium sulfinates such as sodium methanesulfi-
nate, sodium ethanesulfinate, and sodium cyclopropanesulfi-
nate were also good substrates for this reaction, giving the
desired products 3ja–3la in good yields. However, our attempts
to employ sodium trifluoromethanesulfinate, sodium 4-nitro-
benzenesulfinate, sodium 2-nitrobenzenesulfinate, and hetero-
aromatic sulfinate salts including sodium thiophene-2-sulfi-
nate and sodium pyridine-3-sulfinate as substrates turned out
to be ineffective, which might be caused by the instability of
the corresponding sulfone radicals.
basis of control experiment results and previous reports,9–12
a
possible mechanism is proposed in Scheme 5. The sulfinate
sodium salt reacts with iodine to give a sulfonyl iodide inter-
mediate that could undergo homolytic cleavage to yield a sul-
fonyl radical A. Addition of the sulfonyl radical A to the term-
inal alkyne takes place chemoselectively to form the vinyl
sulfone radicals B and C. Subsequently, sulfonyl iodide, mole-
cular iodine, or iodine radical may approach the vinyl sulfone
radical C more readily than vinyl sulfone radical B to avoid a
steric repulsion from the sulfonyl group to provide the difunc-
tionalization products.16
Moreover, this iodosulfonylation reaction could be scaled
up to 20 mmol without a significant decrease in the yield and
stereoselectivity of the product, illustrating its potential indus-
trial applications in the future (Scheme 2).
To further demonstrate the synthetic application of our
developed protocol, we performed experiments using 3aa as
the starting material for further functionalization (Scheme 3).
The corresponding alkynylation and arylation products 4 and
In summary, we have developed an efficient metal-free syn-
thesis of (E)-β-iodo vinylsulfones through iodine-promoted
tandem radical reactions of alkynes and sodium sulfinates.
The molecular iodine plays a dual role as both a trigger and
iodine source in this radical process. Notable features of this
transformation include metal-free, room temperature, water as
the environmentally friendly solvent, and high regio- and
stereoselectivity, which render it a powerful complement to
traditional methods for the synthesis of β-halo vinylsulfone
derivatives. The expansion of the synthetic application of this
reaction is currently ongoing in our laboratory.
The authors thank the National Natural Science Foundation
of China (21662032, 21562039, 21572915 and 21262035),
Xinjiang Natural Science Foundation (2015211C264) and
Xinjiang University Doctoral Science Foundation (BS150225)
for financial support.
Scheme 2 Large scale experiment.
Scheme 3 Synthetic transformations of the β-iodo vinylsulfone (3aa).
Scheme 5 Possible reaction mechanism.
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