Late-stage (radio)fluorination of alkyl phosphonates via electrophilic activation

Constructing organic fluorophosphines, vital drug skeletons, through the direct fluorination of readily available alkyl phosphonates has been impeded due to the intrinsic low electrophilicity of PV and the high bond energy of P═O bond. Here, alkyl phosphonates are electrophilically activated with triflic anhydride and N-heteroaromatic bases, enabling nucleophilic fluorination at room temperature to form fluorophosphines via reactive phosphine intermediates. This approach facilitates the late-stage (radio)fluorination of broad dialkyl and monoalkyl phosphonates. Monoalkyl phosphonates derived from targeted drugs, including cyclophosphamide, vortioxetine, and dihydrocholesterol, are effectively fluorinated, achieving notable yields of 47−71%. Radiofluorination of medically significant 18F-tracers and synthons are completed in radiochemical conversions (radio-TLC) of 51−88% and molar activities up to 251 ± 12 GBq/μmol (initial activity 11.2 GBq) within 10 min at room temperature. Utilizing a phosphonamidic fluoride building block (BFPA), [18F]BFPA-Flurpiridaz and [18F]BFPA-E[c(RGDyK)]2 demonstrate high-contrast target imaging, excellent pharmacokinetics, and negligible defluorination. Constructing organic fluorophosphines via direct fluorination of alkyl phosphonates is challenging. Herein, the authors show that alkyl phosphonates are electrophilically activated with triflic anhydride and N-heteroaromatic bases, enabling nucleophilic fluorination at room temperature to form fluorophosphines via reactive phosphine intermediates.