Published on Web 02/28/2007
Highly Efficient Monophosphine-Based Catalyst for the
Palladium-Catalyzed Suzuki-Miyaura Reaction of Heteroaryl
Halides and Heteroaryl Boronic Acids and Esters
Kelvin Billingsley and Stephen L. Buchwald*
Contribution from the Department of Chemistry, Massachusetts Institute of Technology,
Cambridge, Massachusetts 02139
Received November 29, 2006; E-mail: sbuchwald@mit.edu
Abstract: A highly active and efficient catalyst system derived from a palladium precatalyst and
monophosphine ligands 1 or 2 for the Suzuki-Miyaura cross-coupling reaction of heteroaryl boronic acids
and esters has been developed. This method allows for the preparation of a wide variety of heterobiaryls
in good to excellent yields and displays a high level of activity for the coupling of heteroaryl chlorides as
well as hindered aryl and heteroaryl halides. Specific factors that govern the efficacy of the transformation
for certain heterocyclic motifs were also investigated.
Since its discovery,1 the Suzuki-Miyaura reaction has
become one of the most powerful and synthetically valuable
processes for the construction of carbon-carbon bonds.2 Its
importance in organic synthesis is evident from its application
in a number of areas, ranging from natural product synthesis to
materials chemistry.3 Much recent work has been directed
toward the development of new catalyst systems that efficiently
process challenging substrates such as aryl chlorides4 and
Figure 1. Structures of ligands 1 and 2.
hindered aryl boronic acids while still using relatively mild
halides and aryl boronic acids are successful coupling partners,
reactions involving their heteroaryl analogues are less straight-
forward.8 In addition, problems with these coupling processes
limit the application of the method, especially in the context of
drug development. Therefore, the development of a “universal”
method for the cross-coupling of heteroaryl substrates would
be highly advantageous.9 Herein, we report a general catalyst
system based upon a palladium precatalyst and dialkyl phosphine
ligands 1 and 2 (Figure 1) for the Suzuki-Miyaura reaction of
heteroaryl boronic acids and esters.
reaction conditions and low catalyst loadings.5
The recent realization of more active catalyst systems can
be attributed to an increased focus on ligand design. Phosphine
ligands have become one standard for palladium-catalyzed
carbon-carbon and carbon-nitrogen bond-forming processes,
and our recent report utilizing the highly effective biaryl
monophosphine ligand SPhos (1) continues this trend.5a Suzuki-
Miyaura reactions employing 1 as the supporting ligand have
displayed exceptional reactivity while maintaining a broad
substrate scope, facilitating the coupling of extremely hindered
substrate combinations as well as aryl chlorides. Catalyst
systems based on palladium precatalysts and trialkyl phosphines6
or N-heterocyclic carbenes7 to generate biaryls have also proven
to be highly effective.
Results and Discussion
Thiophene Boronic Acids. Thiophenes are found in a variety
of natural products as well as pharmaceutically interesting
(6) (a) Netherton, M. R.; Dai, C.; Neuschuta, K.; Fu, G. C. J. Am. Chem. Soc.
2001, 123, 10099-10100. (b) Kirchoff, J. H.; Netherton, M. R.; Hills, I.
D.; Fu, G. C. J. Am. Chem. Soc. 2002, 124, 13662-13663.
Despite considerable effort in developing more active catalysts
for the Suzuki-Miyaura reaction over the past two decades,
many limitations remain. For example, whereas simple aryl
(7) (a) Gsto¨ttmayr, C. W. K.; Bo¨hm, V. P. W.; Hertweck, E.; Grosche, M.;
Herrmann, W. A. Angew. Chem., Int. Ed. 2002, 41, 1363-1365. (b)
Altenhoff, G.; Goddard, R.; Lehmann, C. W.; Glorius, F. J. Am. Chem.
Soc. 2004, 126, 15195-15201. (c) Hadei, N.; Kantchev, E. A. B.; O’Brien,
C. J.; Organ, M. G. Org. Lett. 2005, 7, 1991-1994.
(1) Miyaura, N.; Yamada, K.; Suzuki, A. Tetrahedron Lett. 1979, 36, 3437-
3440.
(2) Recent reviews: (a) Bellina, F.; Carpita, A.; Rossi, R. Synthesis 2004, 15,
2419. (b) Miyaura, N. In Metal-Catalyzed Cross-Coupling Reaction;
Diederich, F., de Meijere, A., Eds.; Wiley-VCH: New York, 2004; Chapt.
2.
(8) Tyrell, E.; Brookes, P. Synthesis 2004, 4, 469-483.
(9) For recent reports on Suzuki-Miyaura reactions of heterocyclic substrates,
see (a) Barder, T. E.; Buchwald, S. L. Org. Lett. 2004, 6, 2649-2652. (b)
Kondolff, I.; Doucet, H.; Santelli, M. Synlett 2005, 13, 2057-2061. (c)
Thompson, A. E.; Hughes, G.; Batsanov, A. S.; Bryce, M. R.; Parry, P.
R.; Tarbit, B. J. Org. Chem. 2005, 70, 388-390. (d) Kudo, N.; Pereghini,
M.; Fu, G. C. Angew. Chem., Int. Ed. 2006, 45, 1282-1284. (e) Guram,
A. S.; King, A. O.; Allen, J. G.; Wang, X.; Schenkel, L. B.; Chan, J.;
Bunel, E. E.; Faul, M. M.; Larsen, R. D.; Martinelli, M. J.; Reider, P. J.
Org. Lett. 2006, 8, 1787-1789. (f) A portion of this work has been
communicated: Billingsley, K. L.; Anderson, K. W.; Buchwald, S. L.
Angew. Chem., Int. Ed. 2006, 45, 3484-3488.
(3) For a review on applications of the Suzuki-Miyaura, reaction, see Miyaura,
N. Top. Curr. Chem. 2002, 219, 11-59.
(4) For a review on Pd-catalyzed coupling reactions of aryl chlorides, see Littke,
A. F.; Fu, G. C. Angew. Chem., Int. Ed. 2002, 41, 4176-4211.
(5) (a) Barder, T. E.; Walker, S. D.; Martinelli, J. R.; Buchwald, S. L. J. Am.
Chem. Soc. 2005, 127, 4685-4696. (b) Marion, N.; Navarro, O.; Mei, J.;
Stevens, E. D.; Scott, N. M.; Nolan, S. P. J. Am. Chem. Soc. 2006, 128,
4101-4111.
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J. AM. CHEM. SOC. 2007, 129, 3358-3366
10.1021/ja068577p CCC: $37.00 © 2007 American Chemical Society