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

Abstract

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. The monofluoromethyl (CH2F) motif is valuable as it can mimic CH3 and CH2OH motifs frequently found in bioactive molecules, but the synthesis of N-CH2F amides is challenging. Now the synthesis of numerous N-CH2F amides has been achieved via successive acylation and fluorination of imines, enriching pathways for N-methylation of biomolecules.