On the Mechanism of Iridium-Catalyzed Asymmetric Hydrogenation of Imines and Alkenes: A Theoretical Study

Abstract

Phosphine-oxazoline (PHOX)-based iridium complexes have emerged as useful tools for enantioselective hydrogenation of unfunctionalized alkenes and imines. The mechanistic details of the asymmetric hydrogenation process, however, are poorly understood. Several different mechanisms have been put forward for hydrogenation of unfunctionalized alkenes, but it remains unclear which of these provide an accurate description of the hydrogenation reaction. The mechanistic aspects of Ir-(PHOX)-mediated hydrogenation of imines are little explored, and no detailed mechanism has been formulated to date. Here we provide a comprehensive quantum mechanical study of Ir-(PHOX)-mediated hydrogenation of both alkene and imine substrates. Our results support previous findings by Brandt et al., clearly favoring an Ir(III)/Ir(V) reaction cycle for Ir-(PHOX)-mediated hydrogenation of unfunctionalized alkenes. An important aspect of this reaction mechanism is the orientation of the metal-coordinated alkene substrate, which determines the stereochemistry of the resulting product. Our analysis further shows that none of the proposed alkene hydrogenation mechanisms are applicable for imines. For Ir-(PHOX)-mediated imine hydrogenation, we suggest a fundamentally different catalytic cycle involving dissociation of the imine substrate. The suggested mechanism correctly reproduces the stereoselectivity of imine reduction, but indicates that the enantioselectivity should be more sensitive to the reaction conditions and less controllable than the enantioselectivity of alkene hydrogenations.