Mechanistic study of nucleophilic fluorination for the synthesis of fluorine-18 labeled fluoroform with high molar activity from N-difluoromethyltriazolium triflate

Abstract

The synthesis of fluorine-18 labeled fluoroform with high molar activity has grown in importance for the development of fluorine-18 labeled aryl-CF₃ radiopharmaceuticals that are useful as diagnostic radiotracers for the powerful technique of positron emission tomography (PET). We designed a strategy of synthesizing fluorine-18 labeled fluoroform from N1-difluoromethyl-N3-methyltriazolium triflate (1) via S_N2 fluorination without stable fluorine isotope scrambling. Fluoroform was generated at rt in 10 min by fluorination of the triazolium precursor with TBAF (6 equiv.). We propose three routes (a), (b), and (c) for this fluorination. Quantum chemical calculations have been carried out to elucidate the mechanism of experimentally observed nucleophilic attack of fluoride at difluoromethyl group via route (a), not N3-methyl via route (b). ¹H and ¹⁹F NMR studies using deuterium source have been performed to examine the competition between S_N2 fluorination (route (a)) and the formation of difluorocarbene (route (c)). The observed superiority of S_N2 pathway to formation of difluorocarbene in the reaction of the precursor using CsF in (CD₃CN/(CD₃)₃COD (17.8 : 1)) gives the possibility of preparing the fluorine-18 labeled fluoroform in high molar activity.