<scp>TEMPO</scp> ‐Catalyzed Electrochemical Oxidative Rearrangement for the Synthesis of [1,2,4]‐Triazolone‐Fused Purine Nucleosides and Related Heterocycles

Comprehensive Summary Polycyclic nucleosides have broad applications in medicinal chemistry and fluorescence‐based bioimaging. Therefore, developing efficient synthetic strategies for the rapid construction of novel polycyclic nucleoside frameworks is of significant importance. Herein, we report a novel and practical TEMPO‐mediated electrochemical oxidative cyclization/rearrangement, which provides efficient and versatile access to otherwise inaccessible sterically hindered or enantiopure N ‐alkyl [1,2,4]‐triazolone‐fused purine nucleosides and related heterocycles with moderate to excellent yields. By combining electrochemical anodic oxidation with aminoxyl catalysis, this protocol enables tandem N–H dehydrogenation, intramolecular cyclization, and 1,2‐carbon migration at low potential under mild, metal‐ and oxidant‐free conditions. The synthetic value of this methodology is demonstrated by its broad substrate scope (80 examples, yields up to 99%), excellent functional group tolerance, readily available starting materials (including various N ‐heteroarenes and primary, secondary, and tertiary alkyl carboxylic acids), and the ability for late‐stage functionalization of pharmaceutical compounds and natural products. The protocol has been further applied to the gram‐scale preparation of chiral triazolopurinone, maintaining complete stereochemical retention. Detailed mechanistic studies, including radical trapping and crossover experiments, cyclic voltammetry studies, and density functional theory (DFT) calculations, provide evidence supporting a concerted mechanism for C–N bond formation and C–C bond migration. This scalable and sustainable electrochemical rearrangement offers a powerful complementary strategy for the efficient synthesis of structurally diverse 1,2,4‐triazolone‐fused heterocycles, which may have broad applications in synthetic, biological, and pharmaceutical chemistry.