Copper-Catalyzed Hydroxylation of Aryl Halides Using Hydroxypicolinamide Ligands

Abstract

Hydroxylation of haloarenes is a fundamental transformation in synthetic organic chemistry. Hydroxypicolinamide ligands enable the efficient Cu-catalyzed hydroxylation of heteroaryl halides with a wide functional group tolerance. The Cu-MPBS system, originally designed for C−N coupling, enables the Cu-catalyzed hydroxylation of aryl bromides. A related derivative, Cu-HMPS, provides exceptional reactivity and purity for hydroxylation of aryl bromides, aryl iodides, and activated aryl chlorides. Orthoactivated substrates have shown exceptionally high reactivity and selectivity for Cu-catalyzed hydroxylation. More difficult aryl chlorides, substrates that require a higher activation temperature (120 °C), may be hydroxylated by the Cu-DMPS system that has superior intrinsic ligand stability. Reaction conditions may be tuned to target substrates through ligand, solvent, and base selection. Safe and robust processing conditions have been designed utilizing aqueous KOH, K 2 CO 3 , or K 3 PO 4 in sulfolane or sulfolane and alcohol blends.