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 sp2 spirocyclization
and sp3 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.