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.