Facile Synthesis of β,β-(Radio)difluoroamines via Amino(radio)fluorination of α-Fluoroalkenes

Given their prevalent presence in bioactive molecules, the synthesis of radiolabeled gem-difluoromethylene ([18F]–CF2−) motifs is of practical relevance for radiotracer development. However, conventional strategies to construct [18F]–CF2– motifs are limited, primarily relying on either 18F-fluorination of bespoke precursors or multistep 18F-difluoromethylation using radiosynthesized difluoromethylating reagents. Herein, a conceptually distinct alkene difunctionalization strategy is adopted in 18F-gem-difluoromethylene synthesis, enabling an iron-catalyzed three-component amino(radio)fluorination of α-fluoroalkenes to furnish unprotected β,β-difluoroamines and their 18F-labeled analogues. This transformation proceeds efficiently under low heat and air-insensitive conditions and accommodates a broad range of substrates, including complex drug-like molecules, without requiring prefunctionalized precursors. Mechanistic studies reveal a radical-polar crossover pathway involving an electrophilic N-centered radical addition and a subsequent nucleophilic ring-opening of an aziridinium intermediate to forge the C–F bond. This work effectively broadens the toolkit for the construction of complex 18/19F-gem-difluoromethyl compounds.