Synthesis And Bioactivity Of CF₃S-containing Ketones,Alkenes,and Arenes

The incorporation of trifluoromethylthio group（CF₃S）into a drug molecule often profoundly alters the transmembrane permeation,metabolic stability and bioavailability of parent compound because of the strong electron-withdrawing nature and high Hansch lipophilicity parameter of the trifluoromethylthio group.Thus,the CF₃S-containing compounds have widespread applications in pharmaceuticals,agrochemicals,and materials science.In recent years,high-efficiency synthesis of CF₃S-containing compounds has become a hot topic in the field of synthetic chemistry and organofluorine chemistry.In this thesis,we successfully synthesized a-CF₃S substituted ketones,vinyl trifluoromethyl thioethers and aryl trifluoromethyl thioethers by screening different trifluoromethylthiolating reagents,various substrates and reaction conditions.These three novel reactions were supposed to proceed via electrophilic,free radical and oxidative trifluoromethylthiolation,respectively.The mechanisms of corresponding reactions were also proposed.In addition,the bioactivities of target compounds were tested.1.We have developed a general and facile approach for synthesis of α-CF₃S substituted ketones using PhNHSCF₃ as an electrophilic CF₃S source with the assistance of acetyl chloride.at room temperature.This novel protocol has several notable features,such as a broad substrate scope,functional compatibility,high regioselectivity and the avoidance of prefunctionalization of starting materials,and the relevant CF₃S-containing compounds can be obtained in moderate to good yields.In addition,the compounds 3k and 3y exhibited strong cytotoxicity to HepG2 cells.The activity of compounds 3k and 3y is nearly three times that of resveratrol.2.We have developed a new and efficient method for the synthesis of vinyl trifluoromethyl thioethers through hydrotrifluoromethylthiolation of terminal alkynes in the presence of AgSCF₃ and K₂S₂O₈.The Markovnikov and anti-Markovnikov hydrotrifluoromethylthiolated products are obtained in moderate to good yields by changing the reaction conditions.A set of deuterated experiments provide strong evidence that the two hydrogens in the anti-Markovnikov product originated from water and DMF,respectively.Furthermore,Preliminary mechanistic analyses suggest the anti-Markovnikov reaction proceed via a radical process.We anticipate that this strategy may provide an alternative approach to prepare vinyl trifluoromethyl thioethers starting from readily available terminal alkynes.3.We have developed a direct oxidative trifluoromethylthiolation of aryl boronic acids under the conditions of 10 mol%CuI,20 mol%bpy and AgSCF₃ without any additional oxidant.A variety of functional groups in aryl boronic acids are compatible with the reaction conditions and the aryl trifluoromethyl sulfides have been obtained in moderate to good yields.Preliminary mechanistic experiments suggest that AgSCF₃ plays dual roles as the source of CF₃S group and also the oxidant,and（bpy）CuSCF₃ acts as the active species.The major advantage of this method lies in avoiding the preparation of electrophilic trifluoromethylthiolating reagents or（bpy）CuSCF₃ in advance.In addition,the bioactivities of twenty-one target compounds were tested and some coupounds displayed good cytotoxity to HepG2 cells.