Stereo- and regiospecific Cu-catalyzed cross-coupling reaction of vinyl iodides and thiols: A very mild and general route for the synthesis of vinyl sulfides

Article abstract of DOI:10.1021/ol801149n

(Chemical Equation Presented) A mild and efficient method for the copper-catalyzed formation of vinylic carbon-sulfur bonds has been developed. The desired vinyl sulfides are obtained in good to excellent yields, with full retention of stereochemistry. This method is particularly noteworthy given its mild reaction conditions, simplicity, and generality, as well as low cost of the catalyst system.

Full text of DOI:10.1021/ol801149n

ORGANIC
LETTERS
2
008
Vol. 10, No. 15
363-3366
Stereo- and Regiospecific Cu-Catalyzed
Cross-Coupling Reaction of Vinyl
Iodides and Thiols: A Very Mild and
General Route for the Synthesis of Vinyl
Sulfides
3
†
M. Shahjahan Kabir, Michael L. Van Linn, Aaron Monte, and James M. Cook*
†
‡
,†
Department of Chemistry and Biochemistry, UniVersity of WisconsinsMilwaukee,
Milwaukee, Wisconsin 53201, and Department of Chemistry, UniVersity of
WisconsinsLa Crosse, La Crosse, Wisconsin 54601
capncook@uwm.edu
Received May 30, 2008
ABSTRACT
A mild and efficient method for the copper-catalyzed formation of vinylic carbon-sulfur bonds has been developed. The desired vinyl sulfides
are obtained in good to excellent yields, with full retention of stereochemistry. This method is particularly noteworthy given its mild reaction
conditions, simplicity, and generality, as well as low cost of the catalyst system.
5
In the past few years, the efficiency of metal-catalyzed
methods for the preparation of aryl ethers and thioethers
Vinyl sulfides are used as enolate ion equivalents and
1
2
6
Michael acceptors. They are also important intermediates
in the synthesis of oxetanes, cyclopentanones, and cyclo-
pentanes. Many natural products and compounds which
exhibit interesting biological activity contain the vinyl sulfide
7
8
using both palladium and copper catalysis has increased
greatly. In contrast, metal-catalyzed preparation of vinyl
9
3
4
sulfides of synthetic and biological importance in organic
chemistry has lagged behind.
4
,10
moiety.
†
University of WisconsinsMilwaukee.
University of WisconsinsLa Crosse.
(4) (a) Sader, H. S.; Johnson, D. M.; Jones, R. N. Antimicrob. Agents
Chemother. 2004, 48, 53. (b) Johannesson, P.; Lindeberg, G.; Johanson,
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F.; Karlen, A.; Hallberg, A. J. Med. Chem. 2002, 45, 1767. (c) Ceruti, M.;
Balliano, G.; Rocco, F.; Milla, P.; Arpicco, S.; Cattel, L.; Viola, F. Lipids
2001, 36, 629. (d) Marcantoni, E.; Massaccesi, M.; Petrini, M.; Bartoli, G.;
Bellucci, M. C.; Bosco, M.; Sambri, L. J. Org. Chem. 2000, 65, 4553. (e)
Lam, H. W.; Cooke, P. A.; Pattenden, G.; Bandaranayake, W. M.;
Wickramasinghe, W. A. J. Chem. Soc., Perkin Trans. 1 1999, 847. (f)
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Kitsutaka, H.; Takahashi, A. Carcinogenesis 1991, 12, 703.
‡
(
1) (a) Tzschucke, C. C.; Murphy, J. M.; Hartwig, J. F. Org. Lett., 2007,
9
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A. V.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2005, 127, 8146. (d)
Wolter, M.; Nordmann, G.; Job, G. E.; Buchwald, S. L. Org. Lett. 2002, 4,
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Eur. J. 2006, 12, 5301. (g) Wan, Z.; Jones, C. D.; Koenig, T. M.; Pu, Y. J.;
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Synlett 2005, 11, 1767.
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(7) Morris, T. H.; Smith, E. H.; Walsh, R. Chem. Commun. 1987, 964.
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(
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Eur. J. 2006, 12, 7782. (b) Kwong, F. Y.; Buchwald, S. L. Org. Lett. 2002,
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4
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(
10.1021/ol801149n CCC: $40.75
Published on Web 07/09/2008
 2008 American Chemical Society

Table 1. Optimization of the Reaction Conditions
Table 2. Copper-Catalyzed Cross-Coupling of Various
E-Arylvinyl Iodides with Aromatic Thiols
catalyst
solvent
DMF
base
HPLC yield (%)
CuI
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
0
45
65
63
68
72
63
99
64
72
93
91
94
a
CuI, phen (1:2)
toluene
a
CuI/phen /PPh3 (1:1:2) toluene
CuI, L3 (1:1)
CuI, L3 (1:2)
CuI, L3 (1:2)
CuI, L3 (1:2)
CuI, L3 (1:2)
CuI, L3 (1:2)
CuI, L3 (1:2)
CuI, L3 (1:2)
CuI, L3 (1:2)
CuI, L3 (1:1)
a
toluene
toluene
iPrOH
DME
DMF
DMA
1,4-dioxane K3PO4
DMF
DMF
DMF
Cs2CO3
K2CO3
K3PO4
phen ) 1,10-phenanthroline.
Due to the importance of vinyl sulfides, a number of
methods in regard to their synthesis have been reported, each
3
,11–15
with their respective limitations.
The most important
catalytic process for the preparation of vinyl sulfides has been
reported by Venkataraman and co-workers and employs a
3
Cu(I) catalytic system. However, this process requires the
use of air- and moisture-sensitive Cu catalysts, which must
be used in a glovebox. In addition, the reaction requires the
use of harsh reaction conditions (high reaction temeperatures,
i.e., 115 °C; and long reaction times, i.e., ∼4 h) in order to
go to completion, incompatible with many substrates. These
harsh reaction conditions have proven to be inefficient for
electron rich aryl vinyl iodides in coupling reactions. For
(
10) Monte, A.; Kabir, Shahjahan, M.; Cook, J. M.; Rott, M.; Schwan,
W. R.; Defoe, L. U.S. Pat. Appl. Publ. 2007, 37 pp.
11) (a) Beauchemin, A.; Gareau, Y. Phosphorus, Sulfur Silicon Relat.
(
Elem. 1998, 139, 187. (b) Benati, L.; Capella, L.; Montevecchi, P. C.;
Spagnolo, P. J. Chem. Soc., Perkin Trans. 1 1995, 1035. (c) Benati, L.;
Montevecchi, P. C.; Spagnolo, P. J. Chem. Soc., Perkin Trans. 1 1991,
2
103. (d) Ichinose, Y.; Wakamatsu, K.; Nozaki, K.; Birbaum, J. L.; Oshima,
K.; Utimoto, K. Chem. Lett. 1987, 1647
12) (a) Sugoh, K.; Kuniyasu, H.; Sugae, T.; Ohtaka, A.; Takai, Y.;
Fanaka, A.; Machino, C.; Kambe, N.; Kurosawa, H. J. Am. Chem. Soc.
001, 123, 5108. (b) Ogawa, A.; Ikeda, T.; Kimura, K.; Hirao, T. J. Am.
.
(
2
a
b
Isolated yields, the average of at least two runs. The starting aryl
Chem. Soc. 1999, 121, 5108. (c) Koelle, U.; Rietmann, C.; Tjoe, J.; Wagner,
T.; Englert, U. Organometallics 1995, 14, 703. (d) Backvall, J. E.; Ericsson,
A. J. Org. Chem. 1994, 59, 5850. (e) Kuniyasu, H.; Ogawa, A.; Sato, K. I.
vinyl iodides contained ∼ 9-12% Z-isomer; this led to ∼ 9-12% of the
c
cis-isomer, reflected in the overall yield. Treatment with TBAF·THF
;
Ryu, I.; Kambe, N.; Sonoda, N J. Am. Chem. Soc. 1992, 114, 5902. (f)
provided the desired phenol.
Mcdonald, J. W.; Corbin, J. L.; Newton, W. E. Inorg. Chem. 1976, 15,
2
056
13) (a) Carpita, A.; Rossi, R; Scamuzzi, B. Tetrahedron Lett. 1989,
0, 2699. (b) Cristau, H. J.; Chabaud, B.; Labaudiniere, R.; Christol, H. J.
.
(
example, 3,5-dimethoxyphenyl vinyl iodide gave approxi-
mately 35% of the 3,5-dimethoxyphenylacetylene as a
byproduct when 1,10-phenanthroline was used in combina-
tion with triphenylphosphine (Table 1). Initially, 3-hydroxy-
5-methoxystyrylphenyl thioether, a potent antibacterial agent
active against drug-resistant strains of tuberculosis and
anthrax surrogates, and its 3,5-dimethoxy analogues were
prepared using the catalytic conditions of Venkataraman
Table 1). This system proved to be inefficient for the
3
Org. Chem. 1986, 51, 875. (c) Murahashi, S. I.; Yamamura, M.; Yanagisawa,
K.; Mita, N.; Kondo, K. J. Org. Chem. 1979, 44, 2408
14) (a) Aucagne, V.; Tatibouet, A.; Rollin, P. Tetrahedron 2004, 60,
.
(
10
1
8
1
817. (b) Stephan, E.; Olaru, A.; Jaouen, G. Tetrahedron Lett. 1999, 40,
571. (c) Ishida, M.; Iwata, T.; Yokoi, M.; Kaga, K.; Kato, S. Synthesis
985, 632. (d) Mikolajczak, M.; Grzejszczak, S.; Midura, W.; Zatorski, A.
Synthesis 1975, 278. (e) Kumamoto, T; Hosoi, K.; Mukaiyam, T. Bull.
Chem. Soc. Jpn. 1968, 41, 2742. (f) Zyk, N. V.; Beloglazkina, E. K.; Belova,
M. A.; Dubinina, N. S. Russ. Chem. ReV. 2003, 72, 769, and references
1
0
cited therein
.
(
(
15) Zyk, N. V.; Beloglazkina; E. K.; Belova, M. A.; Dubinina, N. S.
Russ. Chem. ReV. 2003, 72, 769, and references cited therein
.
corresponding electron-rich aryl vinyl iodides. A significant
3364
Org. Lett., Vol. 10, No. 15, 2008

amount of arylacetylenes (approximately 30-35%) were
observed as byproducts in the reaction mixture. Arylacetylene
formation has been reported in Cu-catalyzed cross-coupling
reactions of unfunctionalized aryl vinyl iodides using nitrogen
based bidentate ligands, although this system was success-
Table 4. Copper-Catalyzed Cross-Coupling of Various E-Aryl
Vinyl Iodides with Alkyl Thiols
1
f
fully applied to nitrogen and oxygen nucleophiles.
However, the scope and functional group tolerance of these
cross-coupling reactions had not been fully explored. Therefore,
it was felt that a copper-based process might be readily extended
to the synthesis of vinyl sulfides, including the cases where the
aforementioned problems existed. A potential solution would
Table 3. Copper-Catalyzed Cross-Coupling of Various
E-Arylvinyl Iodides with Heterocyclic Thiols
a
b
Isolated yields, the average of at least two runs. The starting aryl
vinyl iodides contained ∼ 9-12% Z-isomer; this led to ∼ 9-12% of the
c
cis-isomer, reflected in the overall yield. Reaction mixuture was heated
d
for 8 h. Treatment with TBAF·THF provided the desired phenol.
optimization conditions. The optimized reaction conditions
utilized 10 mol % of Cu(I), 20 mol % of cis-1,2-cyclohexanediol
3 4
(L3), and 1.5 equiv of K PO in reagent grade DMF (without
drying or degassing), as illustrated in Table 1. Moreover, DME,
i-PrOH, and 1,4-dioxane proved to be inefficient solvent systems
at lower temperature; they required longer reaction times and
produced a significant amount of alkyne byproduct. The
formation of arylacetylenes was observed under many condi-
tions in Table 1. The catalytic conditions with CuI and L3
proved to be the best in the formation of the desired sulfides.
This provided a very active catalyst, presumably due to the
proper geometry of the copper complex.
a
b
Isolated yields, the average of at least two runs. The starting aryl
vinyl iodides contained ∼ 9-12% Z-isomer; this led to ∼ 9-12% of the
c
cis-isomer, reflected in the overall yield. Reaction mixture was heated for
d
8
h. Treatment with TBAF·THF provided the desired phenol.
These reaction conditions were applied to the coupling of
various aryl vinyl iodides and aryl thiols, some of which were
prone to yield a considerable amount of elimination byproduct
with other catalytic systems. Thus, highly electron rich aryl vinyl
iodides containing methoxy groups at the 3- and 5- positions
gave coupling products in excellent yield, even with ortho-
hindered functional groups (entries 1-5, Table 2). Deprotection
of the silyl protected, phenolic vinyl iodides occurred at higher
be to employ an alternative Cu-catalytic system which would
take place under very mild conditions. By taking advantage of
mild reaction conditions, the scope of the reaction could be
extended, permitting the use of a wide variety of functional
groups. The catalytic system required should be both inexpen-
sive and easily handled under atmospheric conditions. Herein,
a mild, stereo- and regiospecific copper-based process for the
cross-coupling of vinyl iodides with thiols is reported. A broad
substrate scope provided good to excellent yields with the
catalytic system developed here.
3
temperatures under the previously reported reaction conditions.
In the latter case, isolation of the desired product had proven
to be difficult. The silyl function remained intact under the
newly developed catalytic system which provided the vinyl
sulfides in high yield. Deprotection of the silyl group was then
carried out in the same reaction vessel using TBAF·THF (entries
The 3,5-dimethoxyphenyl vinyl iodide and thiophenol were
used as the prototypical substrate combination for preliminary
Org. Lett., Vol. 10, No. 15, 2008
3365

Table 5. Copper-Catalyzed Cross-Coupling of E-Cylohexylvinyl
Iodides with Various Thiols
Table 6. Copper-Catalyzed Cross-Coupling of
Z-Ethyl-3-iodoacrylate with Various Thiols
a
b
Isolated yields, the average of at least two runs. The starting aryl
vinyl iodides contained ∼ 9-12% Z-isomer; this led to ∼ 9-12% of the
cis-isomer, reflected in the overall yield.
6-9, Table 2; entries 3-4, Table 3; entry 3, Table 4). Nitrile
functionalized, electron-poor aryl vinyl iodides were also
employed for the coupling reactions and these provided excel-
lent yields of the sulfides under the same catalytic conditions
a
Isolated yields, the average of at least two runs.
(entries 10-12, Table 2; entries 5-6, Table 3; entries 4-5,
Table 5).
iodide (ethyl cis-3-iodoacrylate) and various thiols. Analysis
of the results indicated the catalytic system worked well for
Z-vinyl iodides with aryl-, alkyl-, and heterocyclic thiols in
excellent yields with complete retention of stereo- and
regiochemistry (Table 6).
Since many compounds of biological interest contain
heterocycles,
4,10
it was decided to subject heterocyclic thiols
to the Cu-catalyzed cross-coupling reaction (Table 3). A
range of heterocyclic thiols produced the desired sulfides in
high yield. Relative to alkyl and aryl thiols, these coupling
reactions were slower (4-6 h) and required slightly elevated
temperatures (60 °C).
Alkyl thiols were also found to be effective nucleophiles
under these reaction conditions with various aryl vinyl
iodides (Table 4). Moreover, selective S-vinylation over
O-vinylation was observed when 6-mercaptohexanol was
used as the substrate (Table 4, entries 2 and 5).
In summary, an efficient, regio- and stereospecific copper-
catalyzed system has been developed for the synthesis of
vinyl sulfides. This method is useful because of the mild
reaction conditions, broad functional group tolerance, sim-
plicity in operation, and low cost. Further investigation of
the utility of this catalytic system is currently in progress
and will be reported in due course.
The ability to couple alkyl vinyl iodides was also
investigated with aryl, alkyl, and heterocylic thiols. This
proved to be an excellent catalytic sytem for alkyl vinyl
iodides as well (Table 6).
The retention of regio- and stereochemistry in all products
was observed in the cases of E-aryl vinyl iodides. To ensure
the coupling reaction proceeded in a regio- and stereospecific
fashion, the coupling reaction was investigated using Z-vinyl
Acknowledgment. We thank Dr. Steven H. Bertz for
helpful discussions, Matthew E. Dudley and Terry Clayton
UWM) for technical support, as well as the Research Growth
Initiative of the University of WisconsinsMilwaukee and
UW-System Applied Research Grants Program for financial
support.
(
OL801149N
3366
Org. Lett., Vol. 10, No. 15, 2008