Decagram Scale Synthesis and Deployment of a Picolinamide Ligand for a Copper-Catalyzed C–N Cross-Coupling

Abstract The synthesis of a picolinamide ligand is demonstrated on a 70 g scale in a process-friendly solvent, and its application in a copper-catalyzed C–N cross-coupling on a 20 g scale is reported. The ligand can be accessed in one step via an amide coupling using inexpensive, commercially available 6-hydroxypicolinic acid and 6-methylquinolin-5-amine. A simple aqueous workup followed by a pH-swing-induced crystallization affords the ligand without the need for column chromatography. The combination of the scalable access to the ligand and its excellent performance in copper-catalyzed C–N cross-coupling on decagram scale renders this ligand attractive for deployment in process chemistry applications.