A stereoselective synthesis of α-halo vinyl sulfides and their applications in organic synthesis

Article abstract of DOI:10.1016/S0040-4039(01)00556-1

α-Halo vinyl sulfides have been synthesized stereoselectively via the addition of the in situ generated hydrogen halide to acetylenic thioether. α-Halo vinyl sulfides are versatile substrates that can undergo many important transformations.

Full text of DOI:10.1016/S0040-4039(01)00556-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 3771–3774
A stereoselective synthesis of a-halo vinyl sulfides and their
applications in organic synthesis†
Mei Su, Wensheng Yu and Zhendong Jin*
Division of Medicinal and Natural Products Chemistry, College of Pharmacy, The University of Iowa, Iowa City,
IA 52242, USA
Received 6 March 2001; revised 28 March 2001; accepted 2 April 2001
Abstract—a-Halo vinyl sulfides have been synthesized stereoselectively via the addition of the in situ generated hydrogen halide
to acetylenic thioether. a-Halo vinyl sulfides are versatile substrates that can undergo many important transformations. © 2001
Elsevier Science Ltd. All rights reserved.
a-Halo vinyl sulfides are an important group of com-
pounds with wide applications in organic synthesis.1
Many procedures for the preparation of a-halo vinyl
sulfides have been developed.2 Among them, the
regioselective addition of hydrogen halide (HCl, HBr,
HI) to acetylenic sulfides was the most simple and
efficient.2a Although the regioselectivity of the addition
of hydrogen halide to acetylenic sulfides was excellent,
it often resulted in the formation of both Z- and
E-isomers due to use of excess aqueous hydrogen halide
(37% HCl, 48% HBr, or 51% HI) or saturated gaseous
HX in benzene. Moreover, separation of the Z- and
E-isomers was often quite difficult. Therefore, a new
procedure is needed for the stereoselective synthesis of
a-halo vinyl sulfides.
selectivity (Scheme 1). The yield was nearly quantita-
tive. Since traces of the starting material acetylenic
sulfide 5 did not interfere with the subsequent reaction,
and the only side product, MeOTMS, could be evapo-
rated easily, neither work up nor column chromatogra-
phy was necessary.
Table 1 summarized the preparation of a variety of
a-halo vinyl sulfides using our procedure.6 Controlling
the reaction temperature was crucial to achieve high
stereoselectivity for both a-bromo and a-iodo vinyl
sulfides. If the reaction temperature was too high, a
substantial amount of the Z-isomer would be formed
along with the E-isomer. In the case of HCl, a higher
temperature (25°C) and 2 equiv. of reagents were
needed to drive the reaction to completion (Table 1,
entry 3).
Recently we have discovered that hydrogen halide gen-
erated in situ (by reaction of trimethylsilyl halide with
anhydrous methanol) can add to acetylenic ethers at
low temperature in a completely regio- and stereoselec-
tive manner with nearly quantitative yields.3 This
prompted us to investigate the possibility of the appli-
cation of this methodology for the stereoselective syn-
thesis of a-halo vinyl sulfides.
A typical procedure used in the stereoselective synthesis
of a-halo vinyl sulfides follows: To a solution of
acetylenic thioether (1 mmol) in anhydrous CH2Cl2 (2.5
mL) was added anhydrous methanol (0.99 mmol) fol-
lowed by slow addition of TMSBr (0.99 mmol) under
nitrogen at the temperature indicated. The reaction
mixture was stirred at that temperature for about 1 h,
and then was allowed to warm up to 25°C. After
removal of the solvent and the side product (MeOTMS)
by rotary evaporation, the product can be used without
any further purification.
We found that hydrogen halide generated in situ by
addition of 0.99 equiv. of trimethylsilyl halide4 to a
solution of 1.0 equiv. of acetylenic thioether5 and 0.99
equiv. of MeOH in CH2Cl2 at low temperature gave
a-halo vinyl sulfides with superior regio- and stereo-
Keywords: a-halo vinyl sulfide; acetylenic thioether.
* Corresponding author. E-mail: zhendong-jin@uiowa.edu
† Synthesis via a-halo vinyl ethers 3.
Scheme 1.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00556-1

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M. Su et al. / Tetrahedron Letters 42 (2001) 3771–3774
Table 1. A stersoselective synthesis of a-halo vinyl sulfides
The applications of a-halo vinyl sulfides in organic
synthesis were summarized in Table 2. Compounds 19,
20, and 21 (Table 2, entries 1–3) were synthesized via
a-alkylthio vinyllithium intermediates which were pre-
pared by the treatment of a-halo vinyl sulfides with
t-BuLi at −78°C.7 All reactions afforded excellent yields
with the retention of the stereochemistry of the double
bond.
a-Halo vinyl sulfides can also undergo many important
transformations catalyzed by transition metals like pal-
ladium and nickel. In the presence of a catalytic

M. Su et al. / Tetrahedron Letters 42 (2001) 3771–3774
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Table 2. Application of a-halo vinyl sulfides in organic synthesis
amount of PdCl2(PPh3)2, a-bromo vinyl sulfide 4 under-
went Stille coupling8 with tributylvinyltin to provide
1,3-diene 22 in excellent yield (Table 2, entry 4). Palla-
dium (0)-catalyzed carbonylation9 between a-bromo
vinyl sulfide 11 and CO in the presence of methanol
gave compound 23 in 91% yield with complete reten-
tion of the stereochemistry of the double bond (Table 2,
entry 5). a-Halo vinyl sulfides also coupled with Grig-
nard reagents catalyzed by an organonickel catalyst.
Compound 11 reacted with PhMgBr in the presence of
a catalytic amount of NiCl2dppp2 to give 24 in 88%
(Table 2, entry 6).10
The University of Iowa Cancer Center, a Research
Project Grant RPG-00-030-01-CDD from the Ameri-
can Cancer Society, and the Central Investment Fund
for Research Enhancement (CIFRE) at The University
of Iowa. Special thanks are due to The Center for
Biocatalysis and Bioprocessing at the University of
Iowa for providing a fellowship to W.Yu.
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In conclusion, we have successfully developed a highly
regio- and stereoselective synthesis of a-halo vinyl
sulfides. We have demonstrated that a-halo vinyl
sulfides are highly versatile substrates that can undergo
many important transformations. Application of these
methodologies to the total synthesis of natural products
is underway, and will be reported in due course.
Acknowledgements
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This work was supported by Grant No. IN-122S from
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M. Su et al. / Tetrahedron Letters 42 (2001) 3771–3774
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