Cu-Catalyzed C–N Couplings with Benzilamide Ligands

A linker fragment used in the preparation of an oncology candidate is efficiently synthesized via Cu-catalyzed C–N coupling. The original route required a Cu-catalyzed coupling, followed by an oxidation and protection sequence. After the evaluation of hydroxypicolinamide ligands and other amide ligands as inefficient for a more desirable C–N coupling sequence, screening of new ligands commenced. With a new catalyst derived from Cu salts and dimethoxyphenylbenzilamide (DMPB), the linker fragment can be directly prepared with commodity chemicals, avoiding oxidation. The DMPB ligand for the Cu catalyst is readily prepared from benzilic acid and 2,6-dimethoxyaniline. A brief survey of the scope of this Cu-DMPB system is explored for secondary and primary amines.