Nickel as a Competitive Drop-In Alternative to Palladium in Thermal C–O Cross-Couplings of Aliphatic Alcohols with Heteroaryl Halides: A High-Throughput Experimentation Study

Abstract

Palladium-catalyzed thermal C–O cross-coupling reactions represent first-choice methodologies for alkyl (hetero)aryl ether formation in both academia and industry, especially when commencing from otherwise challenging (hetero)aryl chloride or bromide electrophiles and aliphatic alcohol coupling partners. While highly effective thermal nickel-catalyzed processes of this type have emerged owing to advances in ancillary ligand design, their use as competitive drop-in alternatives to palladium in such applications in the context of high-throughput experimentation (HTE) has not been demonstrated. In targeting the formation of alkyl heteroaryl ethers of biological relevance, we disclose herein a comparative HTE screening study focused on thermal palladium- or nickel-catalyzed C–O cross-couplings of primary, secondary, or tertiary aliphatic alcohols with heteroaryl chlorides or bromides. We demonstrate that appropriate DalPhos-ligated nickel precatalysts can offer catalytic performance in such transformations that is competitive with (e.g., for primary and secondary alcohols) or superior to (e.g., for tertiary alcohols) that achieved by use of otherwise best-in-class palladium catalysts (e.g., featuring biarylmonophosphine, JosiPhos, or other ligation).