Preparation, separation and storage of N-monofluoromethyl amides and carbamates

N-monofluoromethyl (N-CH₂F) amides, combining amide and monofluoromethyl motifs, represent a practical modification of the amide bond that can mimic N-CH₃ amides. Despite the potential value in transforming peptides and peptidomimetics with N-CH₂F, the very existence of this structure has been controversial. Here we report the preparation of N-CH₂F amides and carbamates via simple and robust chemical methods. The syntheses of N-CH₂F amides were achieved via successive acylation and fluorination of imines and directly used in the modification of drugs, peptides and heteroaryl amides without racemization or epimerization. The use of triethylamine is the key to the separation of N-CH₂F amides. The stability of nine structurally diverse N-CH₂F amides was tested in eight different media, showing that most compounds remained 60-100% intact for 24 h.