Diversity-oriented synthesis of multisubstituted olefins through the sequential integration of palladium-catalyzed cross-coupling reactions. 2-Pyridyldimethyl(vinyl)silane as a versatile platform for olefin synthesis

Article abstract of DOI:10.1021/ja016790+

A novel strategy for the diversity-oriented synthesis of multisubstituted olefins, where 2-pyridyldimethyl (vinyl)silane functions as a versatile platform for olefin synthesis, is described. The palladium-catalyzed Heck-type coupling of 2-pyridyldimethyl(vinyl)silanes with organic iodides took place in the presence of Pd₂-(dba) ₃/tri-2-furylphosphine catalyst to give β-substituted vinylsilanes in excellent yields. The Heck-type coupling occurred even with α- and β-substituted 2-pyridyldimethyl(vinyl)silanes. The one-pot double Heck coupling of 2-pyridyldimethyl(vinyl)silane took place with two different aryl iodides to afford β,β-diarylated vinylsilanes in good yields. The palladium-catalyzed Hiyama-type coupling of 2-pyridyldimethyl(vinyl)silane with organic halides took place in the presence of tetrabutylammonium fluoride to give di- and trisubstituted olefins in high yields. The sequential integration of Heck-type (or double Heck) coupling and Hiyama-type coupling produced the multisubstituted olefins in regioselective, stereoselective, and diversity-oriented fashions. Especially, the one-pot sequential Heck/Hiyama coupling reaction provides an extremely facile entry into a diverse range of stereodefined multisubstituted olefins. Mechanistic considerations of both Heck-type and Hiyama-type coupling reactions are also described.

Full text of DOI:10.1021/ja016790+

J. Am. Chem. Soc. 2001, 123, 11577-11585
11577
Diversity-Oriented Synthesis of Multisubstituted Olefins through the
Sequential Integration of Palladium-Catalyzed Cross-Coupling
Reactions. 2-Pyridyldimethyl(vinyl)silane as a Versatile Platform for
Olefin Synthesis
Kenichiro Itami, Toshiki Nokami, Yoji Ishimura, Koichi Mitsudo, Toshiyuki Kamei, and
Jun-ichi Yoshida*
Contribution from the Department of Synthetic Chemistry and Biological Chemistry, Graduate School of
Engineering, Kyoto UniVersity, Yoshida, Kyoto 606-8501, Japan
ReceiVed August 7, 2001. ReVised Manuscript ReceiVed September 25, 2001
Abstract: A novel strategy for the diversity-oriented synthesis of multisubstituted olefins, where 2-pyridyldim-
ethyl(vinyl)silane functions as a versatile platform for olefin synthesis, is described. The palladium-catalyzed
Heck-type coupling of 2-pyridyldimethyl(vinyl)silanes with organic iodides took place in the presence of Pd2-
(dba)3/tri-2-furylphosphine catalyst to give â-substituted vinylsilanes in excellent yields. The Heck-type coupling
occurred even with R- and â-substituted 2-pyridyldimethyl(vinyl)silanes. The one-pot double Heck coupling
of 2-pyridyldimethyl(vinyl)silane took place with two different aryl iodides to afford â,â-diarylated vinylsilanes
in good yields. The palladium-catalyzed Hiyama-type coupling of 2-pyridyldimethyl(vinyl)silane with organic
halides took place in the presence of tetrabutylammonium fluoride to give di- and trisubstituted olefins in high
yields. The sequential integration of Heck-type (or double Heck) coupling and Hiyama-type coupling produced
the multisubstituted olefins in regioselective, stereoselective, and diversity-oriented fashions. Especially, the
one-pot sequential Heck/Hiyama coupling reaction provides an extremely facile entry into a diverse range of
stereodefined multisubstituted olefins. Mechanistic considerations of both Heck-type and Hiyama-type coupling
reactions are also described.
Introduction
Scheme 1
Carbon-carbon double bonds are ubiquitous and essential
structural constituents in organic molecules and controlling the
geometry of CdC bond has been one of the central issues in
organic synthesis. Despite the impressive development in the
stereoselective synthesis of disubstituted olefins, the stereose-
lective synthesis of tri- and tetrasubstituted olefins lags far
behind.1 In addition, certain multisubstituted olefins have
emerged to possess interesting biological, chemical, and physical
properties. Therefore, the strategic and diversity-oriented ap-
proach for such olefins is highly called for.
In pursuit of this objective, we had been attracted by the
potentiality of the palladium-catalyzed Mizoroki-Heck-type
coupling2 and C-M cross-coupling (Kumada-Tamao-Corriu
coupling, Negishi coupling, Migita-Kosugi-Stille coupling,
Suzuki-Miyaura coupling, and Hiyama coupling)3,4 reactions
because those reactions are usually high-yielding and stereo-
selective. The alkenylmetals (CdC-M) are extremely appealing
substrates for such reactions because both CdC and C-M
functionalities can potentially be arylated under the palladium-
catalyzed arylation conditions using aryl halides in two mecha-
nistically different modes (Scheme 1). For example, Heck-type
arylation at the CdC bond gives the substituted alkenylmetal
(Scheme 1, path a). On the other hand, arylation at C-M
functionality affords the metal-free alkene (Scheme 1, path b).
If these two functionalities were rigorously discriminated toward
the palladium-catalyzed arylation by the reaction conditions,
sequential integration of these two reactions should pave the
way for the stereoselective synthesis of multisubstituted olefins
(3) For an excellent up-to-date treatment, see: Diederich, F., Stang, P.
J., Eds. Metal-Catalyzed Cross-Coupling Reactions; Wiley-VCH: Wein-
heim, 1998.
(1) (a) Pattenden, G. In ComprehensiVe Organic Chemistry; Stoddart, J.
F., Ed.; Pergamon: Oxford, 1979; Vol. 1, p 171. (b) Denmark, S. E.;
Amburgey, J. J. Am. Chem. Soc. 1993, 115, 10386. (c) White, J. D.; Jensen,
M. S. Tetrahedron 1995, 51, 5743. (d) Creton, I.; Marek, I.; Normant, J. F.
Synthesis 1996, 1499. (e) Brown, S. D.; Armstrong, R. W. J. Am. Chem.
Soc. 1996, 118, 6331. (f) Organ, M. G.; Cooper, J. T.; Rogers, L. R.;
Soleymanzadeh, F.; Paul, T. J. Org. Chem. 2000, 65, 7959 and references
therein.
(2) (a) Mizoroki, T.; Mori, K.; Ozaki, A. Bull. Chem. Soc. Jpn. 1971,
44, 581. (b) Heck, R. F.; Nolley, J. P. J. Org. Chem. 1972, 14, 2320. For
reviews, see: (c) Beletskaya, I. P.; Cheprakov, A. V. Chem. ReV. 2000,
100, 3009. (d) Cabri, W.; Candiani, I. Acc. Chem. Res. 1995, 28, 2. (e) de
Meijere, A.; Meyer, F. E. Angew. Chem., Int. Ed. Engl. 1994, 33, 2379. (f)
Heck, R. F. In ComprehensiVe Organic Synthesis; Trost, B. M., Ed.;
Pergamon: New York, 1991; Vol. 4, Chapter 4.3.
(4) Kumada-Tamao-Corriu coupling (Mg): (a) Tamao, K.; Sumitani,
K.; Kumada, M. J. Am. Chem. Soc. 1972, 94, 4374. (b) Corriu, R. J. P.;
Masse, J. P. J. Chem. Soc., Chem. Commun. 1972, 144. (c) Yamamura,
M.; Moritani, I.; Murahashi, S. J. Organomet. Chem. 1975, 91, C39. (d)
Kumada, M. Pure Appl. Chem. 1980, 52, 669. Negishi Coupling (Zn): (e)
King, A. O.; Okukado, N.; Negishi, E. J. Chem. Soc., Chem. Commun.
1977, 683. (f) Negishi E.; Liu, F. In ref 3, Chapter 1. Kosugi-Migita-Stille
coupling (Sn). (g) Kosugi, M.; Sasazawa, K.; Shimizu, Y.; Migita, T. Chem.
Lett. 1977, 301. (h) Milstein, D.; Stille, J. K. J. Am. Chem. Soc. 1978, 100,
3636. (i) Stille, J. K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508. Suzuki-
Miyaura coupling (B): (j) Miyaura, N.; Yamada, K.; Suzuki, A. Tetrahedron
Lett. 1979, 3473. (k) Suzuki, A. In ref 3, Chapter 2. Hiyama coupling (Si).
(l) Hatanaka, Y.; Hiyama, T. J. Org. Chem. 1988, 53, 918. (m) Hatanaka,
Y.; Hiyama, T. Synlett 1991, 845. (n) Hiyama, T. In ref 3, Chapter 10.
10.1021/ja016790+ CCC: $20.00 © 2001 American Chemical Society
Published on Web 10/27/2001

11578 J. Am. Chem. Soc., Vol. 123, No. 47, 2001
Itami et al.
Scheme 2
the 2-PyMe2Si group for our strategy. During the course of this
investigation, we have established that 2-pyridyldimethyl(vinyl)-
silane can be cross-coupled with various organic halides in the
above-mentioned two mechanistically different modes (Heck-
type coupling and Hiyama-type coupling) with the aid of
palladium catalyst.9,10 In this paper, we report on our strategy
for the stereoselective synthesis of multisubstituted olefins by
the sequential integration of palladium-catalyzed cross-coupling
reactions of 2-pyridyldimethyl(vinyl)silane with organic halide
(Scheme 2). The evolution of the efficient one-pot double Heck-
type coupling, mechanistic studies for Heck-type and Hiyama-
type cross-coupling reactions, and successful synthesis of
multisubstituted olefins are also described.
Results and Discussion
1-1. Palladium-Catalyzed Heck-Type Coupling of 2-Py-
ridyldimethyl(vinyl)silane with Organic Iodide. It already is
known that there are several difficulties with the Heck-type
coupling of vinylsilane.11 For example, the treatment of vinyl-
silane with aryl iodide under the typical Heck coupling
conditions affords exclusively styrene derivative as a result of
carbon-silicon bond cleavage.12 Hallberg has discovered that
the use of an equimolar amount of silver nitrate realizes the
Heck-type coupling of vinylsilane.13 Tanaka has reported the
Heck-type coupling of chloro(vinyl)silanes.14 Very recently,
Jeffery has discovered that the addition of an equimolar amount
of tetrabutylammonium acetate promotes the Heck-type coupling
of vinyltrimethylsilane.15
where alkenylmetal acts as a platform for olefin synthesis
(Scheme 2).
This strategy is an extremely flexible thus diversity-oriented
approach for the synthesis of multisubstituted olefins. The
installation of organic groups at the desired olefin carbon can
be achieved by the appropriate order of added organic halides.
Thus, the synthesis of regio- and stereoisomers of certain olefins
can be achieved by simply changing the order of addition of
organic halides. Moreover, the power of this strategy becomes
apparent when considering the singularity with respect to the
source of organic groups (i.e. organic halide). The commercial
availability of such compounds makes this approach sufficiently
diversity-oriented, thus fulfilling the recent demand for the
generation of large combinatorial chemical libraries.5 However,
the development of such integrated cross-coupling reaction lags
far behind though there are a number of catalysts and reagents
reported to date for each of the reaction types.
We have already established that the Heck-type coupling of
2-pyridyldimethyl(vinyl)silane (1) with organic iodide took place
with the aid of Pd2(dba)3/tri-2-furylphosphine (TFP)16 catalyst
On the basis of these backgrounds, we set out to establish
the general protocol of the integrated cross-coupling reactions
for the diversity-oriented synthesis of multisubstituted olefins.
At the outset, there are two critical hurdles to be overcome for
our strategy (Scheme 2) to be enlisted into service for multi-
substituted olefin synthesis: (1) the two reaction pathways of
alkenylmetal (Heck-type coupling and C-M cross-coupling)
have to be perfectly controlled and be mutually switched, ideally
with the slight changes of additive or reaction conditions
(without any switching protocols, further integration should not
be possible), and (2) a mild and efficient protocol for the double
Heck-type coupling must be established although such a process
has been known to be extremely sluggish with the typical Heck
substrates (without such protocols, our strategy would end up
in the production of disubstituted olefins).
Recently, we have been engaged in the development of
removable directing groups,6 which control the metal-mediated
and -catalyzed processes by complex-induced proximity effect
(CIPE).7 We have established that a 2-pyridyldimethylsilyl (2-
PyMe2Si) group efficiently functions as such a removable
directing group for various organometallic reactions.8 Therefore,
we began by addressing the above-mentioned issues by utilizing
(7) For excellent reviews on CIPE, see: (a) Beak, P.; Meyers, A. I. Acc.
Chem. Res. 1986, 19, 356. (b) Snieckus, V. Chem. ReV. 1990, 90, 879. (c)
Beak, P.; Basu, A.; Gallagher, D. J.; Park, Y. S.; Thayumanavan, S. Acc.
Chem. Res. 1996, 29, 552. See also: (d) Hoveyda, A. H.; Evans, D. A.;
Fu, G. C. Chem. ReV. 1993, 93, 1307.
(8) (a) Yoshida, J.; Itami, K.; Mitsudo, K.; Suga, S. Tetrahedron Lett.
1999, 40, 3403. (b) Itami, K.; Mitsudo, K.; Yoshida, J. Tetrahedron Lett.
1999, 40, 5533. (c) Itami, K.; Mitsudo, K.; Yoshida, J. Tetrahedron Lett.
1999, 40, 5537. (d) Itami, K.; Nokami, T.; Yoshida, J. Org. Lett. 2000, 2,
1299. (e) Itami, K.; Nokami, T.; Yoshida, J. Tetrahedron 2001, 57, 5045.
(f) Itami, K.; Kamei, T.; Mitsudo, K.; Nokami, T.; Yoshida, J. J. Org. Chem.
2001, 66, 3970. (g) Itami, K.; Mitsudo, K.; Yoshida, J. Angew. Chem., Int.
Ed. 2001, 40, 2337. (h) Itami, K.; Koike, T.; Yoshida, J. J. Am. Chem. Soc.
2001, 123, 6957. (i) Itami, K.; Kamei, T.; Yoshida, J. J. Am. Chem. Soc.
2001, 123, 8773. (j) Yoshida, J.; Itami, K. J. Synth. Org. Chem. Jpn. In
press. (k) Itami, K.; Mitsudo, K.; Nishino, A.; Yoshida, J. Chem. Lett. In
press. See also: (l) Itami, K.; Nokami, T.; Yoshida, J. Angew. Chem., Int.
Ed. 2001, 40, 1074.
(9) Itami, K.; Mitsudo, K.; Kamei, T.; Koike, T.; Nokami, T.; Yoshida,
J. J. Am. Chem. Soc. 2000, 122, 12013.
(10) Itami, K.; Nokami, T.; Yoshida, J. J. Am. Chem. Soc. 2001, 123,
5600.
(11) For an excellent review on the 1,2-additions of organopalladium
reagents to heteroatom-substituted olefins, see: Daves, G. D., Jr.; Hallberg,
A. Chem. ReV. 1989, 89, 1433.
(12) (a) Hallberg, A.; Westerlund, C. Chem. Lett. 1982, 1993. (b)
Karabelas, K.; Hallberg, A. J. Org. Chem. 1989, 54, 1773. (c) Alvisi, D.;
Blart, E.; Bonini, B. F.; Mazzanti, G.; Ricci, A.; Zani, P. J. Org. Chem.
1996, 61, 7139.
(5) (a) Schreiber, S. L. Science 2000, 287, 1964. (b) Valler, M. J.; Green,
D. Drug DiscoVery Today 2000, 5, 286. (c) Arya, P.; Chou, D. T. H.; Baek,
M. G. Angew. Chem., Int. Ed. 2001, 40, 339.
(6) For the use of removable directing group in metal-catalyzed reactions,
see: (a) Evans, D. A.; Fu, G. C.; Hoveyda, A. H. J. Am. Chem. Soc. 1988,
110, 6917. (b) Breit, B. Angew. Chem., Int. Ed. Engl. 1996, 35, 2835. (c)
Jun, C. H.; Lee, H.; Hong, J. B. J. Org. Chem. 1997, 62, 1200. (d) Breit,
B. Angew. Chem., Int. Ed. 1998, 37, 525. (e) Breit, B. Eur. J. Org. Chem.
1998, 1123. (f) Jun, C. H.; Lee, H. J. Am. Chem. Soc. 1999, 121, 880. (g)
Buezo, N. D.; Mancheno, O. G.; Carretero, J. C. Org. Lett. 2000, 2, 1451.
(13) (a) Karabelas, K.; Westerlund, C.; Hallberg, A. J. Org. Chem. 1985,
50, 3896. (b) Karabelas, K.; Hallberg, A. Tetrahedron Lett. 1985, 26, 3131.
(c) Karabelas, K.; Hallberg, A. J. Org. Chem. 1986, 51, 5286. (d) Karabelas,
K.; Hallberg, A. J. Org. Chem. 1988, 53, 4909. (e) Voigt, K.; von
Zezschwitz, P.; Rosauer, K.; Lansky, A.; Adams, A.; Reiser, O.; de Meijere,
A. Eur. J. Org. Chem. 1998, 1521.
(14) Yamashita, H.; Roan, B. L.; Tanaka, M. Chem. Lett. 1990, 2175.
(15) Jeffery, T. Tetrahedron Lett. 1999, 40, 1673.
(16) For a review on the use of TFP in metal-catalyzed reactions, see:
Andersen, N. G.; Keay, B. A. Chem. ReV. 2001, 101, 997.

DiVersity-Oriented Synthesis of Multisubstituted Olefins
J. Am. Chem. Soc., Vol. 123, No. 47, 2001 11579
Table 1. Palladium-Catalyzed One-Pot Double Heck Coupling of
1 with Aryl Iodidesa
and triethylamine, giving the â-substituted vinylsilane 2 in
extremely high yield (eq 1).9 Noteworthy features of this process
are that (1) the formation of styrene (C-Si bond cleavage) was
completely suppressed, (2) the coupling occurred under mild
conditions (50 °C) and at low catalyst loading (as low as 0.1
mol %), (3) virtually complete stereoselectivity (>99% E) was
observed, (4) coupling occurred with a wide array of electron-
ically and structurally diverse aryl, heteroaryl, and alkenyl
iodides, and (5) the regio- and stereoselective coupling occurred
even with the â-substituted vinylsilane 3. Moreover, by taking
advantage of the phase tag property of the 2-PyMe2Si group,8a,17,18
the coupling products 2 were isolated by simple acid-base
extraction without using any chromatographic isolation tech-
nique. Recovery and reuse of the palladium catalyst were also
possible.9
1-2. One-Pot Double Heck Coupling of 2-Pyridyldimethyl-
(vinyl)silane with Aryl Iodides. In our strategy, a mild and
efficient protocol for the double Heck coupling must be
developed (Scheme 2). However, such a process is known to
be extremely sluggish and, therefore, such doubly arylated
products were usually prepared by the stepwise reactions.19-22
At the first outset, we began by establishing the conditions
for the one-pot double Heck coupling of 1 with iodobenzene.
After many experiments, the reaction with 2.4 equiv of
iodobenzene, 3.0 equiv of Et3N, and molecular sieve (MS4A)
in THF at 60 °C afforded the doubly arylated product 4aa in
74% yield (Table 1, entry 1). Without MS4A, we observed a
small amount of silanol and siloxane, which were likely to be
produced by the hydrolysis of 4aa. The realization of previously
difficult one-pot double Heck coupling is likely to be attributed
to the strong directing effect of the pyridyl group on silicon.
With the feasibility of one-pot double Heck coupling estab-
lished, we next examined the one-pot double Heck coupling
with two different aryl iodides. To demonstrate the production
of closely related library compounds, three aryl iodides (iodo-
benzene, 2-iodothiophene, and 3-iodothiophene) were subjected
to the one-pot double Heck coupling of 1 (Table 1). Initially,
Ar1-I (1.0 equiv) was added to the reaction mixture to produce
monoarylated product in situ. After completion of the first
coupling, Ar2-I (1.4 equiv) was added to the mixture and further
heating of the reaction mixture afforded the doubly arylated
product 4. For all combinations examined, the reaction proved
to be mild and high-yielding. Noteworthy features of this process
are that (1) nine possible products (4aa-4cc) which arise from
a All reactions were performed at 60 °C in THF (1.0 mL) with 1
(0.30 mmol), Ar1-I (0.30 mmol), Ar2-I (0.42 mmol), Pd2(dba)3‚CHCl3
(2.5 mol %), TFP (5 mol %), Et3N (0.90 mmol), and MS4A (10 mg).
b Isolated yields based on 1.
the three aryl iodides were stereoselectively prepared,23 (2)
stereoselective synthesis of â,â-diarylvinylsilane is accomplished
in a one-pot process, and (3) both stereoisomers can be easily
prepared by simply changing the order of addition.
We further extended this one-pot double Heck coupling to
R-substituted vinylsilane 5, with the hope for stereoselective
preparation of tetrasubstituted olefins (Table 2). The mono-Heck
coupling of 5 with iodobenzene proceeded well to give 6a in
good yield in the presence of Pd/TFP catalyst. However, in this
case, we observed a small amount of 2-furyl group transferred
product, which is likely derived from TFP via the well-known
(17) For an excellent review on the strategic separations in organic
synthesis, see: Curran, D. P. Angew. Chem., Int. Ed. 1998, 37, 1174.
(18) Borman, S. Chem. Eng. News 2001, 79 (June 4), 49.
(19) Moreno-Man˜as, M.; Pe´rez, M.; Pleixats, R. Tetrahedron Lett. 1996,
37, 7449.
(20) For double Heck arylation of acrylates under high-pressure and high-
temperature conditions, see: Sugihara, T.; Takebayashi, M.; Kaneko, C.
Tetrahedron Lett. 1995, 36, 5547.
(21) Carretero has recently reported that one-pot double Heck arylation
occurred with 1-sulfinylcyclopentanes. However, the second arylation does
not occur at the same carbon where the first arylation takes place. de la
Rosa, J. C.; D´ıaz, N.; Carretero, J. C. Tetrahedron Lett. 2000, 41, 4107.
(22) While preparing this manuscript, a sequential and multiple Heck
arylation of vinyl ethers carrying a coordinating auxiliary has been
reported: Nilsson, P.; Larhed, M.; Hallberg, A. J. Am. Chem. Soc. 2001,
123, 8217.
(23) The stereochemistry of 4 was determined by the NOE experiments.
See Supporting Information for the details.

11580 J. Am. Chem. Soc., Vol. 123, No. 47, 2001
Itami et al.
Table 2. Palladium-Catalyzed One-Pot Double Heck Coupling of
5 with Aryl Iodides
Scheme 3
out with 1 (1.0 equiv), methyl acrylate (1.0 equiv), styrene (1.0
equiv), iodobenzene (1.0 equiv), and triethylamine (1.2 equiv)
in the presence of Pd2(dba)3/TFP catalyst (5 mol % Pd). To
our surprise, the only product detected in the reaction mixture
was 2-pyridyldimethyl(styryl)silane (2a) (89% yield), which
clearly signifies the high reactivity of 1 toward the Heck-type
coupling.
1-4. Mechanistic Considerations of Heck-Type Coupling
of 2-Pyridyldimethyl(vinyl)silanes. It was quite interesting to
observe that 2-pyridyldimethyl(vinyl)silanes possess unusually
high reactivity toward the Heck-type coupling with organic
iodides. This may be rationalized by assuming that the
coordination of the pyridyl group to palladium might render
the carbopalladation event kinetically and/or thermodynamically
favorable (Scheme 3).26
To substantiate the governance of CIPE on the Heck-type
coupling of 1, we conducted the stoichiometric reaction of 1
with palladium(II) complex. First, 1 was treated with trans-
PhPdI(PPh3)2 to see if the pyridyl group is coordinating to
palladium during the carbopalladation process. However, be-
cause of the rapid â-hydride elimination from the intermediate
B, we obtained the coupling product 2a instead of the pyridyl-
coordinated palladium(II) complex. Thus, we next examined
the stoichiometric reaction of 1 with PdCl2(CH3CN)2, and the
palladium(II) complex 8 was isolated in 99% yield (eq 2).27 In
a The reactions were performed at 60 °C in THF (3.0 mL) with 5
(1.0 mmol), Ar1-I (1.05 mmol), Pd2(dba)3‚CHCl3 (2.5 mol %), P(OPh)3
(10 mol %), i-Pr2NEt (1.1 mmol), and MS4A (10 mg). b The reactions
were performed at 60 °C in THF (3.0 mL) with 5 (1.0 mmol), Ar1-I
(1.0 mmol), Ar2-I (1.4 mmol), Pd2(dba)3‚CHCl3 (2.5 mol %), P(OPh)3
(10 mol %), i-Pr2NEt (3.0 mmol), and MS4A (10 mg). c Isolated yields
based on 5.
migration of aryl group on phosphorus to palladium.24 Thus,
we reexamined the reaction conditions for the Heck coupling
of 5 and found that the ligand/base combination of P(OPh)3
and diisopropylethylamine greatly improved the efficiency of
the desired Heck coupling. The mono-Heck coupling of 5 with
iodobenzene or 3-iodothiophene was completed within 1 h to
give 6a and 6c in quantitative yields (entries 1 and 2). It should
be noted that R,â-diarylvinylsilane with two different aryl groups
such as 6c cannot be prepared in a stereoselective fashion by
the conventional alkyne hydrosilylation chemistry.25 Subjection
of 5 to the one-pot double Heck coupling with iodobenzene
afforded the desired tetrasubstituted olefin 7aa in 48% yield
(entry 3). However, monoarylated compound 6a (6%) was also
found in the reaction mixture. Similarly, subjection of 5 to the
one-pot double Heck coupling with 3-iodothiophene and 2-io-
dothiophene produced tetrasubstituted olefin 7cb in 28% yield
with virtually complete stereoselectivity (entry 4). Again,
monoarylated compound 6c, which failed to undergo a second
Heck coupling, was produced in 7% yield. Nevertheless, the
realization of a long-sought stereoselective synthesis of tetra-
substituted olefins attached with four different substituents is
of great importance.
complex 8, the coordination of the pyridyl group to palladium
(26) For chelation-controlled Heck arylation, see: (a) Andersson, C. M.;
Larsson, J.; Hallberg, A. J. Org. Chem. 1990, 55, 5757. (b) Nilsson, K.;
Hallberg, A. J. Org. Chem. 1992, 57, 4015. (c) Bernocchi, E.; Cacchi, S.;
Ciattini, P. G.; Morera, E.; Ortar, G. Tetrahedron Lett. 1992, 33, 3073. (d)
Badone, D.; Guzzi, U. Tetrahedron Lett. 1993, 34, 3603. (e) Larhed, M.;
Andersson, C. M.; Hallberg, A. Tetrahedron 1994, 50, 285. (f) Buezo, N.
D.; Alonso, I.; Carretero, J. C. J. Am. Chem. Soc. 1998, 120, 7129. (g)
Alonso, I.; Carretero, J. C. J. Org. Chem. 2001, 66, 4453.
1-3. Relative Reactivity Evaluation of 2-Pyridyldimethyl-
(vinyl)silane. To evaluate the relative reactivity of 2-py-
ridyldimethyl(vinyl)silane, competitive reaction was carried out
with methyl acrylate and styrene, the most commonly used
reactive substrates in Heck chemistry.2 The reaction was carried
(27) Crystallographic data for 8: C9H13NSiCl2Pd, M ) 340.60, orthor-
hombic, space group Pbca (No. 61), a ) 15.4551(7) Å, b ) 14.8687(5) Å,
c ) 11.1172(4) Å, V ) 2554.7(1) Å3, Z ) 12, Dc ) 2.656 g/cm3, µ )
28.93 cm-1. Intensity data were measured on a Rigaku RAXIS imaging
plate area detector with graphite-monochromated Mo KR radiation (λ )
(24) Ortiz, J. V.; Havlas, Z.; Hoffmann, R. HelV. Chim. Acta 1984,
67, 1.
(25) Marciniec, B. ComprehensiVe Handbook on Hydrosilylation; Per-
gamon: Oxford, 1992.
0.71069 Å). A total of 3313 reflections were collected. R ) 0.031, Rw )
0.021.

DiVersity-Oriented Synthesis of Multisubstituted Olefins
J. Am. Chem. Soc., Vol. 123, No. 47, 2001 11581
2-1. Effect of Catalyst and Additive on the Palladium-
Catalyzed Cross-Coupling Reaction of 3 with Iodobenzene.
As a model substrate, we selected 2-pyridyldimethyl(hexenyl)-
silane (3) because such â-substituted vinylsilanes are good
substrates for addressing the regioselectivity issue.29 As already
stated, the Pd2(dba)3/TFP catalyst system promoted the Heck-
type coupling of 3 with iodobenzene (eq 1). Although various
palladium catalysts were examined, the only product detected
was the Heck-type coupling product. This may be due to the
strong directing effect of the pyridyl group and the poor
transmetalation ability of silicon.30 However, by adding tet-
rabutylammonium fluoride (TBAF) to the Pd2(dba)3/TFP cata-
lyst system, the course of the reaction changed to the Hiyama-
type coupling and the Heck-type coupling was completely
suppressed (eq 3).10 Moreover, we found that phosphine-free
Figure 1. Molecular structure of 8. Thermal ellipsoids are drawn at
the 40% probability level. The hydrogen atoms are omitted for clarity.
was highly indicated by the noticeable changes of the pyridine
ring chemical shift and nonequivalent two methyl groups on
silicon in the 1H NMR spectrum (see Supporting Information).
The molecular structure of 8, determined by X-ray crystal-
lographic analysis, revealed the cis-coordination of pyridyl and
vinyl groups to palladium (Figure 1). Although one of the two
chlorine atoms of 8 should be an organic group in the real
catalytic cycle, complex 8 can be regarded as a type A
intermediate (Scheme 3). Thus, it might be reasonable to
presume that the pyridyl-coordination is also taking place prior
to the carbopalladation at intermediate A and the strong binding
ability of 1 renders the carbopalladation event kinetically
favorable.
In addition to this kinetic preference, stabilization of the
palladium(II) intermediate (B) by complexation with the pyridyl
group might also contribute to accelerate the carbopalladation
process (Scheme 3). Although the isolation of such an inter-
mediate by the carbopalladation across 1 met with no success
because of the rapid â-hydride elimination, type B palladium-
(II) complex 9, which lacks a â-hydrogen, can be prepared by
using Hiraki’s procedure28 or the alternative procedure devel-
oped by ourselves.8i In complex 9, the coordination of the
palladium complexes were more active catalysts, giving the
Hiyama-type coupling product (1-phenylhexene) in extremely
high yields. Among them, PdCl2(PhCN)2 was found to be the
most active catalyst for the Hiyama-type coupling of 3 (eq 3).31
2-2. Mechanistic Considerations of Hiyama-Type Cou-
pling of 2-Pyridyldimethyl(vinyl)silanes. These conspicuous
and seminal results (eq 3) clearly brought to light several critical
questions which have to be addressed: (1) why was the vinyl
group instead of the pyridyl group transferred into the cross-
coupling product (as well as the vinyl group, the pyridyl group
is also known to transfer from silicon),32 (2) what is the fate of
pyridyl group, and (3) what is the mechanism?
Careful examination of the reaction mixture revealed that the
pyridyl group was quantitatively converted into pyridine. This
led us to investigate the reaction mechanism in more detail.
First, 2-pyridyldimethyl(styryl)silane (2a) was allowed to react
with 1.0 equiv of PdCl2(CH3CN)2 in the presence of TBAF (1.2
equiv) and (E,E)-1,4-diphenyl-1,3-butadiene was isolated in 72%
yield. This result unambiguously supports the occurrence of the
transmetalation pathway.33
Next, we monitored the reaction of 2a and TBAF in THF-d8
1
by H NMR and found that 2a is converted into styryldimeth-
ylsilanol and pyridine within 30 min at 30 °C.34 A small amount
of water (ca. 5%) present in the commercially available THF
solution of TBAF seemed to be the reactant in this case. Indeed,
pyridyl group to palladium was highly indicated by the
noticeable changes of the pyridine ring chemical shift in the
1H NMR spectrum. The molecular structure of 9, determined
by X-ray crystallographic analysis, revealed the coordination
of the pyridyl group to palladium.8i Thus, it might be reasonable
to presume that the pyridyl-coordination is also taking place
after the carbopalladation at intermediate B, which may be the
thermodynamical driving force of the carbopalladation process.
2. Palladium-Catalyzed Hiyama-Type Coupling of 2-Py-
ridyldimethyl(vinyl)silanes with Organic Halides. Having
established the Heck-type coupling reaction of 2-pyridyldim-
ethyl(vinyl)silanes, we next turned our attention to the pal-
ladium-catalyzed Hiyama-type coupling reaction of 2-pyridyldim-
ethyl(vinyl)silanes with organic halides.4l-n
(29) Hatanaka, Y.; Goda, K.; Hiyama, T. J. Organomet. Chem. 1994,
465, 97.
(30) For the palladium-catalyzed cross-coupling reaction utilizing fluo-
rosilicates, see: (a) Yoshida, J.; Tamao, K.; Takahashi, M.; Kumada, M.
Tetrahedron Lett. 1978, 2161. (b) Yoshida, J.; Tamao, K.; Yamamoto, H.;
Kakui, T.; Uchida, T.; Kumada, M. Organometallics 1982, 1, 542.
(31) The cine substitution product (2-phenylhexene) was formed in 1%
yield.
(32) The transfer of substituted pyridyl group from Si to Pd in the
presence of KF has been reported. Hagiwara, E.; Kusumoto, T.; Hiyama,
T. 76th National Meeting of the Chemical Society of Japan, Yokohama,
1999.
(33) Weber, W. P.; Felix, R. A.; Willard, A. K.; Koenig, K. E.
Tetrahedron Lett. 1971, 4701.
(34) Protodesilylation of styryldimethylsilanol was found to take place
upon letting the mixture stand for several hours to afford styrene
quantitatively.
(28) Fuchita, Y.; Nakashima, M.; Hiraki, K.; Kawatani, M.; Ohnuma,
K. J. Chem. Soc., Dalton Trans. 1988, 785.

11582 J. Am. Chem. Soc., Vol. 123, No. 47, 2001
Itami et al.
Scheme 4
known to be good estrogen receptor ligands (both agonist and
antagonist),40 and are also found in natural products such as
resveratrol, which recently have been shown to have cancer
chemopreventive activity.41 Moreover, recent screening of
hydroxystilbene library revealed that such compounds selectively
inhibit the B cell antigen receptor kinase cascade42 or possess
a novel antibacterial activity against MRSA bacterial strains.43
Heteroaromatic compounds containing thiophene have attracted
widespread interest because their linear and nonlinear optical
properties are superior to those of the corresponding aryl
analogues.44 The rapid and diversity-oriented synthesis of such
compounds (10d-f) is of great importance for understanding
the structure-property relationships. Photochemically and bio-
logically interesting styrylpyridines such as 10g can also be
prepared in a diversity-oriented manner.45 This Heck/Hiyama
coupling sequence is not limited to the synthesis of diaryl-
ethenes. By applying R-substituted vinylsilane 5 as a platform,
triarylethenes (11a and 11b) can also be prepared in a regio-
and stereoselective fashion.
silanol was not formed with anhydrous tris(diethylamino)-
sulfonium difluorotrimethylsilicate (TASF) instead. This
2-Py-Si bond cleavage is reminiscent of that attained by the
KF-promoted methanolysis of 2-pyridylsilanes.35
Very recently, Mori36 and Denmark37 have reported that
silanols can be cross-coupled with organic halides in the
presence of palladium catalyst and we assume that our cross
coupling using 2-pyridylsilanes is mechanistically similar to
theirs (Scheme 4). Indeed, the cross-coupling reaction of
styryldimethylsilanol with iodobenzene did occur under our
reaction conditions giving trans-stilbene in 98% yield. After
all, it seems plausible to deduce that the perfect switch of the
reaction pathway (Heck-type coupling vs Hiyama-type coupling)
stems from the selective removal of the Heck-coupling-directing
pyridyl group and the introduction of an electronegative group
that activates silicon as a leaving group (Scheme 4).
2-4. Sequential Double-Heck/Hiyama Coupling Reactions.
(38) For reviews on the use of stilbenoid compounds in photophysics
and photochemistry, see: (a) Meier, H. Angew. Chem., Int. Ed. Engl. 1992,
31, 1399. (b) Papper, V.; Likhtenshtein, G. I. J. Photochem. Photobiol., A
2001, 140, 39. For recent applications of stilbenoid compounds in various
fields, see: (c) Lewis, F. D.; Wu, T.; Zhang, Y.; Letsinger, R. L.; Greenfield,
S. R.; Wasielewski, M. R. Science 1997, 277, 673. (d) Albota, M.; Beljonne,
D.; Bre´das, J. L.; Ehrlich, J. E.; Fu, J. Y.; Heikal, A. A.; Hess, S. E.; Kogej,
T.; Levin, M. D.; Marder, S. R.; McCord-Maughon, D.; Perry, J. W.; Ro¨ckel,
H.; Rumi, M.; Subramaniam, G.; Webb, W. W.; Wu, X. L.; Xu, C. Science
1998, 281, 1653. (e) Simeonov, A.; Matsushita, M.; Juban, E. A.; Thompson,
E. H. Z.; Hoffman, T. Z.; Beuscher, A. E., IV; Taylor, M. J.; Wirsching,
P.; Rettig, W.; McCusker, J. K.; Stevens, R. C.; Millar, D. P.; Schultz, P.
G.; Lerner, R. A.; Janda, K. D. Science 2000, 290, 307.
(39) Eckert, J. F.; Nicoud, J. F.; Nierengarten, J. F.; Liu, S. G.;
Echegoyen, L.; Barigelletti, F.; Armaroli, N.; Ouali, L.; Krasnikov, V.;
Hadziioannou, G. J. Am. Chem. Soc. 2000, 122, 7467.
(40) For an excellent structure-activity relationship study, see: Fang,
H.; Tong, W.; Shi, L. M.; Blair, R.; Perkins, R.; Branham, W.; Hass, B. S.;
Xie, Q.; Dial, S. L.; Moland, C. L.; Sheehan, D. M. Chem. Res. Toxicol.
2001, 14, 280.
2-3. Sequential Heck/Hiyama Coupling Reactions. Under
the standard set of reaction conditions (5 mol % of PdCl2-
(PhCN)2 and 1.5 equiv of TBAF in THF at 60 °C), various
electronically and structurally diverse aryl and alkenyl halides
were found to cross-couple with the pyridyl-substituted vinyl-
silanes in good to excellent yields (eq 4).10 Not only aryl iodide
but also aryl bromide was applicable.
(41) (a) Jang, M.; Cai, L.; Udeani, G. O.; Slowing, K. V.; Thomas, C.
F.; Beecher, C. W. W.; Fong, H. H. S.; Farnsworth, N. R.; Kinghorn, A.
D.; Mehta, R. G.; Moon, R. C.; Pezzuto, J. M. Science 1997, 275, 218. See
also: (b) Soleas, G. J.; Diamandis, E. P.; Goldberg, D. M. Clin. Biochem.
1997, 30, 91. (c) Orsini, F.; Pelizzoni, F.; Verotta, L.; Aburjai, T.; Rogers,
C. B. J. Nat. Prod. 1997, 60, 1082. (d) Jang, D. S.; Kang, B. S.; Ryu, S.
Y.; Chang, I. M.; Min, K. R.; Kim, Y. Biochem. Pharmacol. 1999, 57,
705. (e) Babich, H.; Reisbaum, A. G.; Zuckerbraun, H. L. Toxicol. Lett.
2000, 114, 143. (f) Cha´vez, D.; Chai, H. B.; Chagwedera, T. E.; Gao, Q.;
Farnsworth, N. R.; Cordell, G. A.; Pezzuto, J. M.; Kinghorn, A. D.
Tetrahedron Lett. 2001, 42, 3685. (g) Wright, J. S.; Johnson, E. R.; DiLabio,
G. A. J. Am. Chem. Soc. 2001, 123, 1173.
We next examined the sequential Heck/Hiyama coupling
reactions utilizing 2-pyridyldimethyl(vinyl)silanes (1 and 5) as
a platform for multisubstituted olefin synthesis (Table 3). First,
Heck-type coupling of 2-pyridyldimethyl(vinyl)silane was con-
ducted with Ar1-I under Pd2(dba)3/TFP catalyst. After the
isolation of the initial coupling product, Hiyama-type coupling
was conducted with Ar2-I under the PdCl2(PhCN)2/TBAF
system.
The present diversity-oriented synthesis of stilbene analogues
may be exploited for the discovery of new lead compounds in
this chemistry.38 For example, compound 10b is the key
intermediate in the synthesis of oligophenylenevinylene-based
photovoltaic devices.39 The rapid synthesis of hydroxystilbenes
such as 10c is extremely intriguing since hydroxystilbenes are
(42) Bishop, A. C.; Moore, D.; Scanlan, T. S.; Shokat, K. M. Tetrahedron
1997, 53, 11995.
(43) Nicolaou, K. C.; Roecker, A. J.; Barluenga, S.; Pfefferkorn, J. A.;
Cao, G. Q. ChemBioChem 2001, 2, 460.
(44) For the interesting properties of styrylthiophenes, see: (a) Gajdek,
P.; Becker, R. S.; Elisei, F.; Mazzucato, U.; Spalletti, A. J. Photochem.
Photobiol., A 1996, 100, 57. (b) Song, X.; Perlstein, J.; Whitten, D. G. J.
Phys. Chem. A 1998, 102, 5440. (c) Geiger, H. C.; Perlstein, J.; Lachicotte,
R. J.; Wyrozebski, K.; Whitten, D. G. Langmuir 1999, 15, 5606. (d) Ho,
T. I.; Wu, J. Y.; Wang, S. L. Angew. Chem., Int. Ed. 1999, 38, 2558. (e)
Wu, J. Y.; Ho, J. H.; Shih, S. M.; Hsieh, T. L.; Ho, T. I. Org. Lett. 1999,
1, 1039. (f) Lee, I. S.; Seo, H.; Chung, Y. K. Organometallics 1999, 18,
1091. (g) Breitung, E. M.; Shu, C. F.; McMahon, R. J. J. Am. Chem. Soc.
2000, 122, 1154. (h) Wang, S. L.; Ho, T. I. J. Photochem. Photobiol., A
2000, 135, 119. (i) Song, K.; Wu, L. Z.; Yang, C. H.; Tung, C. H.
Tetrahedron Lett. 2000, 41, 1951. (j) Rademacher, P.; Marzinzik, A. L.;
Kowski, K.; Weiss, M. E. Eur. J. Org. Chem. 2001, 121 and references
therein.
(45) (a) Guay, D.; Gauthier, J. Y.; Dufresne, C.; Jones, T. R.; McAuliffe,
M.; McFarlane, C.; Metters, K. M.; Prasit, P.; Rochette, C.; Roy, P.; Sawyer,
N.; Zamboni, R. Bioorg. Med. Chem. Lett. 1998, 8, 453. (b) Lewis, F. D.;
Kalgutkar, R. S.; Yang, J. S. J. Am. Chem. Soc. 2001, 123, 3878. (c) Yamaki,
S.; Nakagawa, M.; Morino, S.; Ichimura, K. Macromol. Chem. Phys. 2001,
202, 325. (d) Yamaki, S.; Nakagawa, M.; Morino, S.; Ichimura, K.
Macromol. Chem. Phys. 2001, 202, 354 and references therein.
(35) Itami, K.; Mitsudo, K.; Yoshida, J. J. Org. Chem. 1999, 64, 8709.
(36) (a) Hirabayashi, K.; Kawashima, J.; Nishihara, Y.; Mori, A.; Hiyama,
T. Org. Lett. 1999, 1, 299. (b) Hirabayashi, K.; Mori, A.; Kawashima, J.;
Suguro, M.; Nishihara, Y.; Hiyama, T. J. Org. Chem. 2000, 65, 5342. (c)
Mintcheva, N.; Nishihara, Y.; Tanabe, M.; Hirabayashi, K.; Mori, A.;
Osakada, K. Organometallics 2001, 20, 1243.
(37) (a) Denmark, S. E.; Wehrli, D. Org. Lett. 2000, 2, 565. (b) Denmark,
S. E.; Wehrli, D.; Choi, J. Y. Org. Lett. 2000, 2, 2491. (c) Denmark, S. E.;
Neuville, L. Org. Lett. 2000, 2, 3221. (d) Denmark, S. E.; Sweis, R. F. J.
Am. Chem. Soc. 2001, 123, 6439.

DiVersity-Oriented Synthesis of Multisubstituted Olefins
Table 3. Sequential Heck/Hiyama Coupling Reactionsa
J. Am. Chem. Soc., Vol. 123, No. 47, 2001 11583
Table 4. Sequential Double-Heck/Hiyama-Type Coupling
Reactionsa
a See Table 1 for the conditions of double Heck coupling. The
Hiyama-type coupling reactions were performed with vinylsilane (1.5
equiv), Ar2-I (1.0 equiv), TBAF (1.5 equiv), and PdCl2(PhCN)2 (5 mol
%) in THF at 60 °C. b See Table 1 for the yield of double Heck
coupling.
and Ar2-I) were cross-coupled with 1 in a one-pot process to
give â,â-diarylvinylsilane 4. The Hiyama-type coupling of 4
was conducted with Ar3-I under the PdCl2(PhCN)2/TBAF
system to produce triarylethenes 11 in high yields. For example,
treatment of 4aa with 4-iodoacetophenone in the presence of
Pd/TBAF catalyst afforded the triarylethene 11c in 75% yield.
Stereoisomeric 4ab and 4ba were cross-coupled with 3-iodo-
benzaldehyde to give the stereoisomeric triarylethenes 11d and
11e in high yields. Similarly, stereoisomeric 4ac and 4ca were
cross-coupled with 4-iodobenzoic acid ethyl ester to give the
stereoisomeric triarylethenes 11f and 11g in quantitative yields.
To the best of our knowledge, this is the first general procedure
for the stereoselective production of triarylethenes bearing three
different aryl groups.46,47 Strategic synthesis of regio- and
stereoisomers (11a/11c, 11d/11e, and 11b/11f/11g) is of great
importance since triarylethenes, as exemplified by the breast
cancer drug tamoxifen, are known to be ligands for the estrogen
a The Heck-type coupling reactions were performed with vinylsilane
(1.0 equiv), Ar1-I (1.1 equiv), Et3N (1.2 equiv), Pd2(dba)3‚CHCl3 (0.5
mol %), and TFP (2 mol %) in THF at 50 °C. The Hiyama-type
coupling reactions were performed with vinylsilane (1.5 equiv), Ar2-I
(1.0 equiv), TBAF (1.5 equiv), and PdCl2(PhCN)2 (5 mol %) in THF
at 60 °C. b Reference 9. c See Table 2 for the conditions of Heck-type
coupling of 5.
(46) For the synthesis of triarylethenes through the palladium-catalyzed
sequential Stille-type arylation of â,â-dibromostyrenes, see: Shen, W.;
Wang, L. J. Org. Chem. 1999, 64, 8873.
The sequential double-Heck/Hiyama coupling reactions were
also examined (Table 4). As in Table 1, two aryl iodides (Ar1-I

11584 J. Am. Chem. Soc., Vol. 123, No. 47, 2001
Itami et al.
Table 6. One-Pot Sequential Heck/Hiyama Coupling Reactionsa
Table 5. Synthesis of Di- and Triarylethenes by Protodesilylationa
a All reactions were performed at 60 °C for 1 h with vinylsilane
(0.30 mmol) and TBAF (0.30 mmol) in THF.
a All reactions were performed with the vinylsilane (0.30 mmol),
R2-I (0.27 mmol), R3-I (0.20 mmol), Et3N (0.32 mmol), TBAF (0.46
mmol), Pd(OAc)2 (10 mol %), and TFP (10 mol %) in THF (0.9 mL)
at 60 °C. b Yields based on R3-I.
receptors, which play an important regulatory role in the
reproductive, skeletal, and cardiovascular systems and are
validated therapeutic targets for diseases such as breast cancer
and osteoporosis.48 The diversity-oriented synthesis of such
triarylethenes is particularly interesting for new drug discovery.
Moreover, it should also be mentioned that thiophene-containing
triarylethenes demonstrated herein have recently emerged as a
promising structural motif in organic electroluminescence
materials.49
met with no success. Since the stereoselective synthesis of
tetraarylethene, bearing four different aryl groups, is one of the
hardest synthetic challenges in current organic synthesis, the
development of more active catalyst and/or active alkenylmetal
species must be needed in this approach. Instead, we obtained
the protodesilylation products. This TBAF-mediated protode-
silylation does not require the palladium catalyst. In light that
this protodesilylation may be a useful alternative for the
stereoselective synthesis of di- and trisubstituted olefins, we
conducted several protodesilylations of 2-pyridyldimethyl-
(vinyl)silanes (Table 5).
The protodesilylation of 7aa and 7cb afforded triarylethenes
12a and 12b in quantitative yields (entries 1 and 2). This double-
Heck-coupling/protodesilylation sequence from 5 is a useful
alternative to the Heck-coupling/Hiyama-coupling sequence
from 5 for the stereoselective synthesis of triarylethenes. The
protodesilylation of 4ab and 4cb gave 1,1-diarylethenes 12c
and 12d in 98% and 91% yield, respectively (entries 3 and 4).
By using the conventional Heck arylation of styrene derivatives,
such 1,1-diarylethenes are only produced as minor products.
The protodesilylation of 6a and 6c gave 1,2-cis-diarylethenes
12e and 12f in 100% and 92% yield, respectively (entries 5
and 6). This Heck-coupling/protodesilylation sequence from 5
is a good complement to the Heck/Hiyama coupling sequence
from 1 with regard to the stereochemistry of 1,2-diarylethenes.
4. One-Pot Sequential Heck/Hiyama Coupling Reactions.
In light of the ability of 2-pyridyldimethyl(vinyl)silane to cross-
couple with organic halide in two mechanistically different
modes (Heck-type coupling and Hiyama-type coupling), we next
embarked on the one-pot sequential cross-coupling reaction, in
3. Protodesilylation of 2-Pyridyldimethyl(vinyl)silanes with
TBAF. We also examined the synthesis of tetraarylethenes
through the Hiyama-type cross-coupling reaction of triaryl-
substituted vinylsilanes 7 with aryl iodides. However, all
attempts to transfer these sterically condensed alkenyl groups
(47) The palladium-catalyzed reaction of aryl iodides with diarylacety-
lenes in the presence of formic acid and triethylamine produces tri-
arylethenes. However, when an unsymmetrical diarylacetylene was used
as a substrate, the mixtures of regioisomers were obtained. Cacchi, S.; Felici,
M.; Pietroni, B. Tetrahedron Lett. 1984, 25, 3137.
(48) (a) Gao, H.; Katzenellenbogen, J. A.; Garg, R.; Hansch, C. Chem.
ReV. 1999, 99, 723. (b) Simoni, D.; Roberti, M.; Invidiata, F. P.; Rondanin,
R.; Baruchello, R.; Malagutti, C.; Mazzali, A.; Rossi, M.; Grimaudo, S.;
Dusonchet, L.; Meli, M.; Raimondi, M. V.; D’Alessandro, N.; Tolomeo,
M. Bioorg. Med. Chem. Lett. 2000, 10, 2669. (c) Meegan, M. J.; Hudhes,
R. B.; Lloyd, D. G.; Williams, D. C.; Zisterer, D. M. J. Med. Chem. 2001,
44, 1072. (d) Rubin, V. N.; Ruenitz, P. C.; Boudinot, F. D.; Boyd, J. L.
Bioorg. Med. Chem. 2001, 9, 1579. (e) Weatherman, R. V.; Clegg, N. J.;
Scanlan, T. S. Chem. Biol. 2001, 8, 417 and references therein.
(49) (a) Azuma, H.; Hosokawa, C.; Kusumoto, T. Japanese Kokai Tokkyo
Koho JP2000053677, 2000; Chem. Abstr. 2000, 132, 173451. (b) Okutsu,
A.; Onikubo, S.; Tamano, M.; Enokida, T. Japanese Kokai Tokkyo Koho
JP10152677, 1998; Chem. Abstr. 1998, 129, 47262. (c) Kreuder, W.; Lupo,
D.; Salbeck, J.; Schenk, H.; Stehlin, T.; Hoerhold, H. H.; Lux, A.; Teuschel,
A.; Wieduwilt, M. PCT International Application WO9610617, 1996; Chem.
Abstr. 1996, 125, 99554.

DiVersity-Oriented Synthesis of Multisubstituted Olefins
J. Am. Chem. Soc., Vol. 123, No. 47, 2001 11585
Scheme 5
which the Heck-type cross-coupling occurs first and the Hiyama-
type cross-coupling takes place thereafter (Table 6). In our
preliminary screening of the reaction conditions, we established
that Pd(OAc)2, instead of Pd2(dba)3‚CHCl3 or PdCl2(PhCN)2,
is a superior palladium source for this one-pot process.10 The
vinylsilane 1 was initially cross-coupled with iodobenzene
(R2-I) in the presence of Pd(OAc)2/TFP catalyst. After the initial
reaction was completed, 4-iodoacetophenone (R3-I) and TBAF
were added to the mixture. The sequential cross-coupling
product 10a was obtained in 69% yield. Similarly, 1 underwent
one-pot sequential Heck/Hiyama coupling with other different
aryl iodides giving 1,2-trans-diarylethenes 10b and 10e in
excellent yields. The â-substituted vinylsilane 3 was also found
to undergo one-pot sequential Heck/Hiyama coupling to afford
trisubstituted olefin. The advantage of this strategy is apparent
as both regioisomers (13 and 14) were prepared in regio- and
stereoselective fashion by simply changing the order of addition.
Hiyama-type coupling, and the one-pot sequential Heck/Hiyama
coupling are now viable in this strategy. Especially, the
integrated cross-coupling reaction described herein provides an
extremely facile entry into a diverse range of stereo-well-defined
multisubstituted olefins. A noteworthy feature of these processes
is that any stereo- and regioisomers can, in principle, be prepared
by simply changing the order of Ar-X addition. The strategy
described herein is sufficiently diversity-oriented and would
enable the production and screening of a large number of
molecules (multisubstituted olefins) against the targets of
interest.
Acknowledgment. This research was supported by a Grant-
in-Aid for Scientific Research from the Ministry of Education,
Science, Sports, and Culture, Japan. T.N. and K.M. thank the
Japan Society for the Promotion of Science for Young Scientists.
Supporting Information Available: Experimental proce-
dures, characterization of all new compounds, NOE data for 4,
6c, 13, and 14, and crystallographic data for 8 (PDF). This
material is available free of charge via the Internet at
http://pubs.acs.org.
Conclusion
In conclusion, we have established that the 2-pyridyldimethyl-
(vinyl)silane serves as an extremely versatile platform for the
stereoselective synthesis of multisubstituted olefins (Scheme 5).
The Heck-type coupling, the one-pot double Heck coupling, the
JA016790+