TEMPO-Catalyzed Electrochemical Oxidative Rearrangement for the Synthesis of [1,2,4]-Triazolone-Fused Purine Nucleosides and Related Heterocycles

Abstract

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.

Keywords

Electrochemistry / Purine nucleosides / Anodic oxidation / Heterocycles / Rearrangement / TEMPO / Electrosynthesis / Cyclization

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