Biphasic Aqueous Reaction Conditions for Process-Friendly Palladium-Catalyzed C–N Cross-Coupling of Aryl Amines

We herein describe a method for palladium-catalyzed C–N cross-coupling of aryl amines and aryl halides in a biphasic reaction medium composed of 2-methyltetrahydrofuran (MeTHF) and water. By effective solubilization of the inorganic base used, common challenges associated with the scalability of Buchwald–Hartwig aminations using inorganic bases were circumvented. The mildly basic nature of the reaction conditions was highlighted by the facile coupling of a base-sensitive substrate, which could be converted to the corresponding product with a high level of crude purity. The method is operationally simple and displays an improved safety and sustainability profile compared with many alternative strategies for large-scale Buchwald–Hartwig amination. Relying on a commonly available dialkylbiarylphosphine ligand, this approach was applied to three clinically relevant C–N cross-coupling reactions on the hecto- to kilogram scale.