A Plausible Mechanism for the Iridium-Catalyzed Hydrogenation of a Bulky N-Aryl Imine in the (S)-Metolachlor Process

The hydrogenation of N-(2-ethyl-6-methylphenyl)-1-methoxypropan-2-imine is the largest-scale asymmetric catalytic process for the industrial production of agrochemical (S)-metolachlor. The challenging hydrogenation across the sterically crowded carbon-nitrogen double bond was achieved using a mixture of [IrCl(COD)](2), (R,S-Fc)-Xyliphos, NBu4I and acetic acid. Acetic acid was critical in achieving excellent productivity and activity. Despite its industrial significance, a mechanism that explains how the sterically hindered bond in the imine is reduced has yet to be proposed. We propose a plausible proton-first, outer-sphere mechanism based on density functional theory calculations that is consistent with the experimentally observed activity and the enantioselectivity of the industrial process. Key findings include transition states involving acetate-assisted dihydrogen splitting, and a hydride transfer from a five-coordinate iridium trihydride directed by a C-H center dot center dot center dot Ir interaction. This article was submitted to a Special Issue in honor of Professor Henri Kagan.