Tf₂O-Mediated Multistate Reactivity to Access N-Acyl and N-Aryl Azacycles, Late-Stage Modification of Bioactive Scaffold

Abstract

N-acyl and N-aryl azacycles are key structural motifs found in a wide range of bioactive compounds, which makes the development of efficient synthetic methods essential. This work presents an innovative and efficient metal-free approach for the synthesis of N-acyl and N-aryl azacycles, utilizing nitriles/arylamines and cyclic amines activated with triflic anhydride (Tf₂O). The reaction results in the formation of both five and six-membered azacycles, with the added benefit of a one-pot, two-step deconstructive fluorination that allows the synthesis of mono-fluorinated compounds and enamides. This method provides a practical and versatile strategy for generating functionalized azacycles, which are valuable in enhancing bioactivity and stability, particularly for drug development.