Remote site-selective arene C–H functionalization enabled by N-heterocyclic carbene organocatalysis

Abstract

Catalytic site-selective functionalization of distal C–H bonds represents a formidable challenge in organic synthesis. Particularly, the precise functionalization of distal aromatic C(sp2)–H bonds remains largely unexplored. Here we present a highly para-selective acylation strategy to target ultraremote aryl C(sp2)–H bonds, eight chemical bonds away from an activated functionality, through radical N-heterocyclic carbene organocatalysis. This method is developed on the basis of a unique single-electron pathway involving the site-selective activation of aryl C–H bonds by a nitrogen-centred radical generated in situ. Importantly, this organocatalytic approach shows potential for the functionalization of drugs, amino acids and peptides, thus highlighting its importance for medicinal chemistry. Our investigation encompassed meticulous mechanistic studies, including control experiments and density functional theory calculations, to unravel the intricacies behind the observed site selectivity and shed light on the mechanism of radical N-heterocyclic carbene organocatalysis. The precise functionalization of distant aromatic C(sp2)–H bonds remains largely unexplored. Here the authors report a para-selective acylation strategy to target remote aryl C(sp2)–H bonds away from an activated functionality through radical N-heterocyclic carbene organocatalysis.