Overcoming Halide Inhibition of Suzuki–Miyaura Couplings with Biaryl Monophosphine-Based Catalysts

• Published in: Organic process research & development 2019-08, Vol.23 (8), p.1631-1637
• Main Authors: Fuentes-Rivera, José J, Zick, Mary E, Düfert, M. Alexander, Milner, Phillip J
• Format: Article
• Language: English
• ISSN: 1083-6160; 1520-586X
• DOI: 10.1021/acs.oprd.9b00255

The Suzuki–Miyaura reaction is one of the most widely employed transformations in synthetic chemistry. Despite extensive investigation, questions remain about the mechanistic nature of the transmetalation step when catalysts based on advanced ligands such as biaryl monophosphines are used, impeding the development of improved catalysts. Here we demonstrate that the often overlooked halide salt (KX) generated as a byproduct of cross-coupling renders the transmetalation step reversible with SPhos-based catalysts, leading to severe reaction inhibition with (hetero)­aryl iodides. Stoichiometric and kinetic studies reveal that halide inhibition likely originates from disfavoring the formation of a highly reactive Pd–OH intermediate. We demonstrate that changing the organic solvent in the biphasic reaction mixture from tetrahydrofuran to toluene is sufficient to minimize this inhibition and enable the general Suzuki–Miyaura coupling of (hetero)­aryl iodides. Our studies suggest that halide inhibition may be a more general problem in cross-coupling reactions, especially those involving reversible transmetalation processes.