Directed ortho‐C(sp2)─H Functionalization of N/O‐Containing Heterocycles: Catalytic and Mechanistic Insights

Abstract

C─H activation has revolutionized synthetic organic chemistry by enabling site‐selective functionalization of unactivated C─H bonds, offering superior atom and step economy compared to conventional existing methodologies. This review highlights the recent advances in directing group (DG)‐assisted, transition metal‐catalyzed ortho‐C(sp²)–H functionalization of pharmacologically relevant N/O‐containing heterocycles that include benzoxazinones, quinoxalin‐2(1H)‐ones, and 2‐arylquinazolin‐4(3H)‐ones. The key transformations include Pd‐/Ru‐/Rh‐catalyzed ortho‐acyloxylation, halogenation, amidation, alkenylation, alkylation, and annulation using diverse coupling partners such as sulfonyl azides, N‐halosuccinimides (NXS), dioxo acids, alkenes, and azo‐compounds. Emerging sustainable approaches, including microwave‐assisted synthesis, electrochemical C─H activation, heterogeneous catalysis, and photoredox‐mediated transformations, are also discussed. Mechanistic insights reveal common pathways involving cyclometallation, oxidative addition/reductive elimination (Pd(II)/Pd(IV), Rh(III)), and migratory insertion, with DGs playing a crucial role in the regioselectivity. Overall, this review provides a comprehensive overview of recent progress in transition metal‐catalyzed C─H functionalization in a regioselective manner, emphasizing synthetic utility, mechanistic understanding, and applications in drug discovery and advanced organic synthesis.