Development of Shelf-Stable Reagents for Electrophilic Trifluoromethylthiolation Reaction

Pharmaceutical and agrochemical companies are interested in fluorinated compounds as a promising source of drug candidates. About 25% of marketed pharmaceuticals and 40% of agrochemicals contain fluorine atom(s) in their chemical structures. Therefore, the development of efficient synthetic methodology for organofluorine compounds is an important task for synthetic chemists in the field of medicinal chemistry. Among a variety of fluorinated compounds, we discuss herein trifluoromethylthio (SCF3) compounds. The SCF3 group is one of the most lipophilic functional groups in organic chemistry. The electron-withdrawing effect of the SCF3 group is similar to that of the popular trifluoromethyl (CF3) group. Hence, the replacement of the CF3 moiety in market drugs and drug candidates by a SCF3 group is a potential strategy to control bioavailability and cell-membrane permeability of original compounds. In recent decades, a large number of reports for the synthesis of SCF3 compounds have been appeared. Among them, direct trifluoromethylthiolation reaction using shelf-stable reagents is obviously attractive since this functionalization can be performed at a late stage of the multistep synthesis of target molecules. Currently, several shelf-stable reagents for electrophilic trifluoromethylthiolation have been developed. We herein introduce our recent contributions for the development of efficient, shelf-stable reagents for electrophilic trifluoromethylthiolation reaction. Design, synthesis and reactivity of two novel shelf-stable reagents, trifluoromethanesulfonyl hypervalent iodonium ylide and its diazo-derivative are discussed.