DiploPhos: A Hemilabile Bisphosphine for Sterically Hindered Ni-Catalyzed Suzuki-Miyaura Couplings

Pharmaceutically relevant Suzuki-Miyaura cross-couplings (SMCs) often require designer phosphine ligands and palladium loadings above 1 mol% to couple Lewis basic, sterically congested substrates. Recent work has demonstrated that nickel is an attractive alternative to palladium for facile SMCs, but further ligand development is required for Ni catalysis to rival Pd for more challenging couplings. We applied prior work on monophosphine ligand design for Ni to develop a bisphosphine, DiploPhos, that outperforms state-of-the-art ligands for Ni to achieve sterically hindered Ni SMCs with ≥3 ortho -substituents. Catalyst speciation studies revealed the hemilabile nature of DiploPhos, which improves reactivity relative to stronger chelating ligands but also leads to the formation of less-active DiploPhos-bridged aggregates. Lewis basic functionality (present on substrates or additives) was found to promote the disaggregation of these species and led to increased SMC yields. This observation is contrary to most other systems in which Lewis basic substrates inhibit Ni-catalyzed SMC reactions. Ligand exchange studies demonstrated that despite its hemilability, DiploPhos is more resistant to displacement by heterocycles than similar bisphosphines. Together, these properties led to best-in-class reactivity for sterically hindered, Lewis base-rich Ni SMCs.