Published on Web 03/08/2005
Catalysts for Suzuki-Miyaura Coupling Processes: Scope
and Studies of the Effect of Ligand Structure
Timothy E. Barder, Shawn D. Walker, Joseph R. Martinelli, and
Stephen L. Buchwald*
Contribution from the Department of Chemistry, Massachusetts Institute of Technology,
Cambridge, Massachusetts 02139
Received December 14, 2004; E-mail: sbuchwal@mit.edu
Abstract: Suzuki-Miyaura coupling reactions of aryl and heteroaryl halides with aryl-, heteroaryl- and
vinylboronic acids proceed in very good to excellent yield with the use of 2-(2′,6′-dimethoxybiphenyl)-
dicyclohexylphosphine, SPhos (1). This ligand confers unprecedented activity for these processes, allowing
reactions to be performed at low catalyst levels, to prepare extremely hindered biaryls and to be carried
out, in general, for reactions of aryl chlorides at room temperature. Additionally, structural studies of various
1‚Pd complexes are presented along with computational data that help elucidate the efficacy that 1 imparts
on Suzuki-Miyaura coupling processes. Moreover, a comparison of the reactions with 1 and with 2-(2′,4′,6′-
triisopropylbiphenyl)diphenylphosphine (2) is presented that is informative in determining the relative
importance of ligand bulk and electron-donating ability in the high activity of catalysts derived from ligands
of this type. Further, when the aryl bromide becomes too hindered, an interesting C-H bond functionalization-
cross-coupling sequence intervenes to provide product in high yield.
In 1979, the seminal paper of Miyaura, Yamada, and Suzuki1
laid the groundwork for what now is arguably the most
important and useful transformation for construction of carbon-
carbon bonds in modern day organic chemistry. Although the
original paper reported coupling reactions of alkenyl boronates
with alkenyl bromides, throughout the past 25 years contribu-
tions from myriad research groups2 have led to vast improve-
ments on what now is known as the Suzuki-Miyaura cross-
coupling reaction. Advances have been made in the way of
reaction scope, including the use of aryl chlorides3 as substrates
and the ability to conduct couplings at very low catalyst
loadings4 and at room temperature.5 Moreover, it is now possible
to couple hindered substrates,6 and even asymmetric variations
have been reported.7 Improvements in Suzuki-Miyaura coup-
ling reactions have relied a great deal on the increased reactivity
and stability of the metal catalysts by use of increasing
efficacious supporting ligands. The most common ligands used
today are phosphine-based, although a variety of others, in-
cluding N-heterocyclic carbenes (NHC), have been employed.5f,h,i,8
Also of great importance are the procedures that utilize so-called
“ligandless” conditions.9 The ability to satisfy the diverse
requirements of different Suzuki-Miyaura couplings with a
single ligand, however, remains unrealized. Herein, we present
a full report of a catalyst system that enables the coupling of
heteroaryl-, both electron-rich and -poor aryl-, and vinylboronic
acids with very hindered aryl halides and a variety of heteroaryl
halides at exceptionally low catalyst loadings.10 Additionally,
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10.1021/ja042491j CCC: $30.25 © 2005 American Chemical Society
J. AM. CHEM. SOC. 2005, 127, 4685-4696
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