Iridium(III)-catalyzed site-selective indole C-H functionalization through enone functionality: design, mechanism and applications

Abstract

Transition-metal-catalyzed C-H activation has been a powerful platform for straightforward molecular functionalization, yet the mechanistic intricacies often remain elusive. Here, we report an iridium(III)-catalyzed strategy for direct C4-H amination of indoles, followed by acid-promoted ring closure, to afford 3,4-fused azepinoindoles in the shortest synthetic sequence reported to date. The α,β-unsaturated enone operates bifunctionally, serving as a directed metalation group for site-selective C-H activation and as an electrophile for annulation. Computational mechanistic investigations revealed that the counteranion-assisted early transition state governing C-H activation serves as the siteselectivity-determining step, where a persistent agostic interaction further facilitates C-H bond cleavage. Biological studies reveal that certain synthesized heteroarenes potently inhibit ceramide-1phosphate production in BV-2 microglial cells, highlighting a concise entry to privileged scaffolds with potential therapeutic relevance.