Pre-catalyst activation and speciation in topical cross-couplings – why it matters? David R. Husbands a , Theo Tanner a , Adrian C. Whitwood a , Neil S. Hodnett b , Katherine M. Wheelhouse b and Ian J. S. Fairlamb a, * a University of York, UK, b Drug Substance Development – Chemistry, GSK Medicine Development & Supply, UK The Suzuki-Miyaura cross-coupling reaction is one of the most widely used reactions in Chemistry. One of the ubiquitous and highly active Pd pre-catalysts is the Herrmann-Beller palladacycle (1), which has been used extensively as a pre-catalyst for Heck reactions with very low catalyst loadings. 1 Past work on the activation of the Herrmann-Beller palladacycle was performed by Jutand et al. Under the conditions of 80 °C in DMF, it was proposed that pre-catalyst activation occurs via migration of the bridging acetate group to the phosphine ligand, cleaving the palladacycle. 2 On the other hand Blackmond et al. reported a mechanistic study examining the behavior of palladacycles in Heck reactions, including the Herrmann-Beller palladacycle. 3,4 Critically, water was revealed as important for the activation of this pre-catalyst, but the origin of this effect at Pd was not examined.
We have investigated the behavior of the Herrmann-Beller palladacycle under aqueous basic conditions which is of central relevance to cross-coupling chemistry. We have found that a stable [Pd(C^P)(µ 2 -OH)] 2 ( 2 ) palladacycle is readily formed, which is a highly active (pre)catalyst for SMCC reactions under mild conditions. We have identified reaction conditions operating in a single phase using a common base (K 3 PO 4 ) in NMP/H 2 O, enabling reaction monitoring by ReactIR for kinetic analysis. We reveal that P(o-tolyl) 3 is non-innocent at several stages within a SMCC catalytic cycle, and water plays a critical role in pre-catalyst activation. These findings are important for understanding the mode of pre-catalyst activation, the role of water, and how P(o-tolyl) 3 influences effective Pd-catalysis. References 1. A. H. M. de Vries, J. M. C. A. Mulders, J. H. M. Mommers, H. J. W. Henderickx and J. G. de Vries, Org. Lett.,2003, 5, 3285–3288. 2. F. d’Orlyé and A. Jutand, Tetrahedron, 2005, 61, 9670–9678. 3. T. Rosner, A. Pfaltz and D. G. Blackmond, J. Am. Chem. Soc., 2001, 12, 4621–4622. 4. T. Rosner, J. le Bars, A. Pfaltz and D. G. Blackmond, J. Am. Chem. Soc., 2001, 12, 1848–1855.
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