Advancing Base-Metal Catalysis: Development of a Screening Method for Nickel-Catalyzed Suzuki–Miyaura Reactions of Pharmaceutically Relevant Heterocycles

Interest in replacing palladium catalysts with base metals resulted in the development of a 24-reaction screening platform for identifying nickel-catalyzed Suzuki–Miyaura reaction conditions. This method was designed to be directly applicable to process scale-up by employing homogeneous reaction conditions alongside stable and inexpensive nickel­(II) precatalysts and has proven to be broadly suitable for complex heterocyclic substrates relevant to bioactive molecules. These advances were enabled by the key discovery that a methanol additive greatly improves the reaction performance and enables the use of organic-soluble amine bases. The screening platform and scale-up workflow were applied to a representative cross-coupling using the antipsychotic perphenazine and enabled the rapid development of a gram-scale synthesis that highlighted the utility of this method and the advantages of nickel catalysis for metal remediation.