Scheme 1. Orthogonal and Sequential Integration of
Mizoroki-Heck Reaction and Cross-Coupling Reaction of
Vinylmetals in the Synthesis of Multisubstituted Olefins
arylation [cross-coupling reaction (CCR)]5 with aryl halides
under the catalytic influence of palladium complexes, an
orthogonal and sequential integration of these arylation
manifolds would produce a multisubstituted olefin structure
very rapidly (Scheme 1). However, because of the apparent
difficulty in controlling (switching) those two reaction
pathways reflecting the similarity in arylating conditions for
MHR and CCR, such a sequential integration has not been
utilized in the construction of extended π-systems. We
recently reported that the use of dimethyl(2-pyridyl)vinyl-
silane as such a vinylmetal (M ) Si) enables the synthesis
of multisubstituted olefins through the sequential integration
of MHR and Hiyama-type silicon-based CCR.6-8 Though
this can be regarded as a proof-of-principle of our strategy,
this silicon-based method suffered severely from limited
reaction scope. In addition, the one-pot integration of these
π-component-assembling reactions was not possible with the
silicon-based method. Toward this end, we embarked on the
sequential integration of MHR and CCR of vinylboron
compounds (M ) B) for the rapid construction of multisub-
stituted olefin-type extended π-systems.
Figure 1. One-pot double Mizoroki-Heck reaction of 1 with ArX.
optimization experiments of our own, we found that the
catalyst/base combination of Pd[P(t-Bu)3]2/i-Pr2NH is par-
ticularly effective for MHR of vinylboronate pinacol ester
(1).10 More importantly, we found that a “hard-to-achieve”
double-MHR11 also proceeds smoothly when 2.2 equiv of
aryl halides are employed, furnishing â,â-diarylated vinyl-
boronate pinacol esters 2. Thus, under the influence of Pd-
[P(t-Bu)3]2 catalyst (5 mol %) and i-Pr2NH (4.0 equiv), the
double-MHR of 1 proceeded in good yields with electroni-
cally and structurally diverse aryl halides (2.2 equiv) at 80
°C in toluene (Figure 1).12 Not only aryl iodides but also
aryl bromides can be used in this reaction.
The initial focal point of our study was to determine the
optimal conditions to switch the reaction pathway of vinyl-
boron compounds to the C-H arylation manifold (MHR)
from the otherwise favorable C-B arylation manifold
(Suzuki-Miyaura-type CCR). In pioneering work on these
transformations, Whiting has previously disclosed the real-
ization of MHR of vinylboronate esters.9 After extensive
The resultant â,â-diarylated vinylboronate pinacol esters
2 were found to undergo Suzuki-Miyaura-type CCR under
the influence of Pd[P(t-Bu)3]2 catalyst and NaOH/H2O.13
Capitalizing on the ability of Pd[P(t-Bu)3]2 to promote both
(10) Pd/P(t-Bu)3 catalyst for Mizoroki-Heck reaction: (a) Littke, A. F.;
Fu, G. C. J. Am. Chem. Soc. 2001, 123, 6989. Also see: (b) Itami, K.;
Mineno, M.; Muraoka, N.; Yoshida, J. J. Am. Chem. Soc. 2004, 126, 11778.
(11) Multiple Mizoroki-Heck reaction: (a) Bra¨se, S.; de Meijere, A. In
Handbook of Organopalladium Chemistry for Organic Synthesis; Negishi,
E., Ed.; Wiley-Interscience: New York, 2002; p 1179. (b) Nilsson, P.;
Larhed, M.; Hallberg, A. J. Am. Chem. Soc. 2003, 125, 3430. (c) Reference
8. (d) Reference 10b.
(12) The use of i-Pr2NH is effective in producing double-MHR products
(2). For example, when Et3N (2.4 equiv) was used in the reaction of 1 and
4-iodoanisole (2.2 equiv) under the influence of Pd[P(t-Bu)3]2 catalyst (5
mol %) in toluene at 90 °C, mono-MHR product (monoarylated vinylbo-
ronate pinacol ester) was produced in 34% yield together with 2ee (50%).
The Suzuki-Miyaura coupling products (styrene derivatives) are usually
not observed when Pd[P(t-Bu)3]2 catalyst are used in combination with
amines. As for the low-yielding examples in Figure 1, the mono-MHR
products were formed in reasonable yields.
(4) Beletskaya, I. P.; Cheprakov, A. V. Chem. ReV. 2000, 100, 3009.
(5) (a) Metal-Catalyzed Cross-Coupling Reactions; Diederich, F., Stang,
P. J., Eds.; Wiley-VCH: Weinheim, 1998. (b) Cross-Coupling Reactions;
Miyaura, N., Ed.; Springer: New York, 2002.
(6) Itami, K.; Mitsudo, K.; Kamei, T.; Koike, T.; Nokami, T.; Yoshida,
J. J. Am. Chem. Soc. 2000, 122, 12013.
(7) Itami, K.; Nokami, T.; Yoshida, J. J. Am. Chem. Soc. 2001, 123,
5600.
(8) Itami, K.; Nokami, T.; Ishimura, Y.; Mitsudo, K.; Kamei, T.; Yoshida,
J. J. Am. Chem. Soc. 2001, 123, 11577.
(9) (a) Hunt, A. R.; Stewart, S. K.; Whiting, A. Tetrahedron Lett. 1993,
34, 3599. (b) Stewart, S. K.; Whiting, A. J. Organomet. Chem. 1994, 482,
293. (c) Stewart, S. K.; Whiting, A. Tetrahedron Lett. 1995, 36, 3925. (d)
He´naff, N.; Whiting, A. Tetrahedron 2000, 56, 5193. (e) Thirsk, C.; Whiting,
A. J. Chem. Soc., Perkin Trans. 1 2002, 999. (f) Lightfoot, A. P.; Maw,
G.; Thirsk, C.; Twiddle, S. J. R.; Whiting, A. Tetrahedron Lett. 2003, 44,
7645.
(13) Pd/P(t-Bu)3 catalyst for Suzuki-Miyaura coupling: (a) Littke, A.
F.; Dai, C.; Fu, G. C. J. Am. Chem. Soc. 2000, 122, 4020. Also see: (b)
Itami, K.; Kamei, T.; Yoshida, J. J. Am. Chem. Soc. 2003, 125, 14670.
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Org. Lett., Vol. 6, No. 22, 2004