Electrochemical Divergent Synthesis of Azetidines via Strain Release of 1‑Azabicyclo[1.1.0]butanes

ABSTRACT Due to the favorable pharmaceutical properties of the azetidine ring, it can serve as a bioisostere to replace saturated heterocycles such as piperazines, piperidines, and pyrrolidines in drug discovery. The diverse methods for azetidine synthesis are still limited and challenging. Herein, we design a new class of 1‐azabicyclo[1.1.0]butanes (ABBs) and report the first electrochemical protocol for the synthesis of chemo‐selective trifluoromethanesulfonylated and trifluoromethylated azetidine derivatives via direct anodic oxidation. The key features of this strategy involve: (i) electrochemical anodic oxidation of ABB to form a N ‐centered radical cation, (ii) a rare [2,3]‐sigmatropic shift of sulfone, (iii) selective oxidation of Langlois’ reagent (NaSO 2 CF 3 ), and (iv) the kinetic study of the developed methodology. The strategy exhibits broad substrate scope and scalability, making it practical. Installation of generated azetidines into marketed drug motifs, including ibuprofen, naproxen, and olaparib derivative, demonstrates the method's utility. Mechanistic investigations, supported by control experiments, cyclic voltammetry, and electrochemical impedance spectroscopy (EIS), provided key insights into the reaction pathway. This electrochemical approach advances the strain‐release chemistry of ABBs and offers a promising platform for future developments.