Chemoselective palladium catalyzed cross-coupling reactions allow for the development of more efficient and versatile routes in drug discovery. Phosphine ligands, commonly used in palladium-catalyzed cross-couplings, play a crucial role in determining chemoselectivity. In many cases, modifying the phosphine ligand can influence palladium’s coordination number during oxidative addition, thereby governing chemoselectivity. While the identity of the phosphine ligand impacts chemoselectivity in a variety of substrates, scattered examples in the literature suggest that the cross-coupling partner can also influence the observed chemoselectivity. Notably, Brown and coworkers previously reported that, although the chemoselectivity of some cross-couplings (e.g., Kumada) can switch depending on ligand, Suzuki couplings always favor reaction at bromide. For non-Suzuki couplings, monodentate ligands favor reaction at bromide (presumably via reaction at 12e^– PdL), whereas bidentate ligands promote reaction at triflate (presumably via reaction at 14e^– PdL₂). However, both types of ligands favor reaction at bromide for Suzuki couplings. This observation suggests that the nucleophile impacts the selectivity of oxidative addition, which is inconsistent with the generally accepted mechanism for oxidative addition in these cross-couplings. Motivated by this discrepancy, we conducted a comprehensive investigation into the ‘Suzuki anomaly’ to understand why Suzuki couplings of bromoaryl triflates consistently result in the same selectivity regardless of ligand choice, whereas the selectivity in other cross couplings of these substrates can be ligand controlled. We found that the unusual selectivity observed with bidentate ligands under Suzuki conditions arises from the formation of bisphosphine mono-oxides in situ. The presence of these bisphosphine mono-oxides influences the effective coordination number of the active palladium catalyst during oxidative addition, thereby dictating the chemoselectivity in bromoaryl triflates as well as brominated 2-chloropyridine derivatives. In the course of this work, we also discovered a class of ligands that enable the first examples of ligand-controlled triflate-selective Suzuki cross-coupling of bromoaryl triflates. These findings shed light on the mechanistic intricacies of the active bisphosphine species that govern the chemoselectivity of oxidative addition at Pd(0).

Sharon Neufeldt

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