C–H Functionalization Through Nucleophilic and Radical Addition to the Aromatic π-System

Abstract

Electrophilic, nucleophilic or radical addition to the aromatic π-system is an approach to aromatic C–H functionalization that bypasses the difficult C–H metalation step typical of modern C–H activation chemistry. π-Addition strategies can provide enhanced reactivity, complementary selectivity and improved practicality for aromatic C–H functionalization. This dissertation describes two strategies for aromatic C–H functionalization that proceed through an addition to the aromatic π-system, either by a nucleophile or a radical. First, an aromatic C–H hydroxylation protocol in which the arene is activated through η6-coordination to an iridium(III) complex is described. η6-Coordination of the arene increases its electrophilicity and allows for nucleophilic attack on the aromatic π-system, even for electron-rich arenes. The use of oxygen nucleophiles for C–H functionalization with η6-arene complexes is reported for the first time. High positional selectivity of hydroxylation at the site of least electron density is observed. Through investigation of intermediate η5-cyclohexadienyl adducts and arene exchange reactions, incorporation of arene π-activation into a catalytic cycle for C–H functionalization is evaluated. Second, a direct radical aromatic C–H amination reaction with a dramatic improvement in substrate scope compared to prior art is reported. Addition of the ammoniumyl radical, derived from a cationic hydroxylamine derivative, to the aromatic π-system is proposed for the amination reaction, which is fast, practical, scalable, and tolerant of air and moisture. An iron(II) salt accelerates the reaction but is not necessary for full conversion when the reaction is conducted in hexafluoroisopropanol (HFIP). Factors that rationalize the expansion of the substrate scope are presented: hydrogen bonding by the solvent HFIP to anions of cationic species results in their enhanced reactivity.