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.