Late-Stage Desulfurative Fluorination Methodology Development

Fluorine-containing small molecules play a significant role in medicinal chemistry, material science, and PET imaging. However, there is a scarcity of mild and versatile strategies for incorporating fluorine. Typically, due to this challenge, fluorine-containing motifs are introduced at an early stage, impeding the progress in developing new pharmaceuticals, materials, and radiotracers. To address these issues, a methodology was developed to enable late-stage desulfurative fluorination, allowing the synthesis of difluoroethers from thionoesters, difluorobenzodioxoles from catechols, difluoromethyl ethers from alcohols, and difluoromethylated heterocycles from unfunctionalized heterocycles. Desulfurative fluorination was achieved using AgF, a mild fluoride source capable of selectively fluorinating a wide range of small molecules adorned with diverse functional groups. The versatility of this methodology was demonstrated by successfully applying it to the 18F-labeling of thionoesters and 1,3-dithioles using carrier-added [18F]AgF.Furthermore, a systematic approach for the preparation of quaternary ammonium trifluoromethoxide and pentafluoroethoxide salts was developed, revealing a correlation between the experimentally derived Nparameter (Mayr’s nucleophilicity parameters) and the conversion of specific tertiary amines. These alkoxides were then reacted with primary alkyl iodides in the presence of a silver(I) salt, leading to the formation of trifluoromethyl and pentafluoroethyl ethers.