Delineating Physical Organic Parameters in Site-Selective C–H Functionalization of Indoles

Site-selective
C–H functionalization is a great challenge
in homogeneous transition-metal catalysis. Herein, we present a physical
organic approach to delineate the origin of regioselective amidation
of N-acylindoles through Ir­(III) catalysis. Bulkiness
of N-directing groups of indole substrates and electronics
of carboxylate additives were identified as two major factors in controlling
C2 and C7 selectivity, and their microscopic mechanisms were studied
with DFT-based transition state analysis. Computational insights led
us to interrogate a linear free energy relationship, and parametrization
of molecular determinants enabled the establishment of an intuitive
yet robust statistical model that correlates an extensive number of
validation data points in high accuracy. This mechanistic investigation
eventually allowed the development of a new C2 amidation and alkenylation
protocol of indoles, which affords the exclusive functionalization
at the C2 position with up to >70:1 selectivity.