Tf2O-mediated multistate reactivity to access N-acyl and N-aryl azacycles: late-stage modification of bioactive scaffolds

Abstract

N-Acyl and N-aryl azacycles are widely recognized pharmacophores, recurring in heterocyclic frameworks that drive biological activity and drug-like properties. Herein, we report an operationally simple, efficient, Tf₂O-driven activation of THF and cyclic amines to afford reactive triflate intermediates that assemble with nitriles or arylamines, followed by cyclization–elimination to furnish N-acyl and N-aryl azacycles. This methodology enables the construction of both five- and six-membered heterocyclic frameworks and accommodates deconstructive fluorination to afford mono-fluorinated derivatives, enamides, and late-stage functionalization of bioactive scaffolds.