Quantitative Analysis on Two-Point Ligand Modulation of Iridium Catalysts for Chemodivergent C–H Amidation

The transition-metal-catalyzed nitrenoid transfer reaction is one of the most attractive methods for installing a new C–N bond into diverse reactive units. While numerous selective aminations are known, understanding complex structural effects of the key intermediates on the observed chemo­selectivity is still elusive in most cases. Herein, we report a designing approach to enable selective nitrenoid transfer leading to sp 2 spirocyclization and sp 3 C–H insertion by cooperative two-point modulation of ligands in the CpXIr­(III)­(κ2-chelate) catalyst system. Computational analysis led us to interrogate structural motifs that can be attributed to the desired mechanistic dichotomy. Multivariate linear regression analysis on the perturbation on the η5-cyclopentadienyl ancillary (CpX) and LX coligand, wherein we prepared over than 40 new catalysts for screening, allowed for construction of an intuitive yet robust statistical model that predicts a large set of chemo­selective outcomes, implying that the catalysts’ structural effects play a critical role on the chemo­selective nitrenoid transfer. On the basis of this quantitative analysis, a new catalytic platform is now established for the unique lactam formation, leading to the unprecedented chemo­selective reactivity (up to >20:1) toward a diverse array of competing sites, such as tertiary, secondary, benzylic, allylic C–H bonds, and aromatic π system.