Study On Synthesis And Mechanism Of Fluoroalkyl(Thio) Ethers Based On CF₃SO₂Na

Fluorine-containing compounds are an important part of the chemical industry.In biochemistry,the creation of fluorine-containing drugs is an important research direction.Numerous studies have shown that the improvement of the drug structure using trifluoromethyl as the fluorine source increases the chemical stability,metabolic stability and electronegativity of the candidate drug,improves the lipophilicity and bioavailability of the drug,and enhances the binding selectivity of drugs.In the research of fluorine-containing groups,compared with C-CF₃,the construction of fluoroalkyl(sulfide)ethers,especially S-CF₃ and O-CF₃ compounds,is attracting more and more attention.Based on the excellent performance of sodium trifluoromethanesulfinate(a cheap and readily available industrial product,a stable white solid)in the application of trifluoromethylthio group,this article explores the electrophilic trifluoromethylthiolation reaction of this reagent with various unactivated aromatic compounds and the dehydroxylation nucleophilic trifluoromethylthiolation reaction of various alcohol compounds.In addition,inspired by the fact that CF₃SO₂Na can generate trifluoromethylthio anion(CF₃S^-)and decompose in situ to produce highly active thiocarbonyl fluoride(F₂C=S)intermediates,the alkyl fluorothioester compound synthesized from thiocarbonyl fluoride was developed for the first time as the fluorination precursor for the synthesis of trifluoromethoxyalkyl compound,and further expansion was made in the process.Firstly,the electrophilic trifluoromethylthiolation reaction based on sodium trifluoromethanesulfinate under the superacid system was studied.Abandoning the phosphine reducing agent of the previous electrophilic reaction,the self-disproportionation redox reaction of trifluoromethyl sulfoxide fragments produced by sodium trifluoromethanesulfinate is realized by using the oxygen abstraction ability of trifluoromethanesulfonic anhydride and the super acid system created.At the same time,using Tf O^-to activate the C-H bond in aromatic ring,various trifluoromethylthio aromatic compounds have been successfully synthesized.And the yirls of the target product obtain can reach 82%.On this basis,the trifluoromethylthiolation reaction of estradiol and other biologically active macromolecules has been successfully realized.Combining experimental results and mechanism verification,it proved the existence of two disproportionation reactions of trifluoromethyl sulfoxide compound and the key intermediate CF₃S(O)-OTf.Secondly,based on the experimental results of in-situ generation of trifluoromethylthio anion by sodium trifluoromethanesulfinate under reducing conditions,Secondly,based on the experimental results of in-situ generation of trifluoromethylthio anion by sodium trifluoromethanesulfinate under reducing conditions,this reagent was used for the first time to realize the nucleophilic dehydroxytrifluoromethylthiolation reaction of a variety of alcohol compounds.Under the action of transition metal,sodium trifluoromethanesulfinate is reduced to generate trifluoromethylthio anion,which then decomposes to produce highly active thiocarbonyl fluoride,and reacts with hydroxyl group to form easy leaving group OC(=S)F.This group is subsequently nucleophilic attacked to generate alkyl trifluoromethylthio compounds.This reaction is not only suitable for active benzyl alcohols,but common alkyl alcohols can also achieve this reaction.The mechanism experiment verified the possibility of the fluorothioester intermediate as the key reactive intermediate of the reaction.Finally,the experiment of fluorothioester compounds as precursors of trifluoromethoxylation reaction is reported for the first time.Initially,sodium trifluoromethylsulfinate was tried as the fluorine source of fluorothioesters,but it could not be converted efficiently.Subsequently,a variety of fluorinated thioesters were prepared from trifluoromethylthiosilver.On this basis,the efficient synthesis of alkyl trifluoromethyloxy compounds was achieved by oxidative desulfurization and fluorination under mild conditions using commercially available cheap reagents.Then,a variety of alkyl Trifluoromethoxy compounds were directly synthesized from common alkyl alcohols by one pot two-step method,and the trifluoromethoxylation of a variety of bioactive macromolecules was expanded.In addition,the intermediate yield of bromodifluoromethoxy alkyl compounds was synthesized for the first time by controlling the reaction conditions.Using the physicochemical properties of the group itself,it is the first time to realize a variety of late functional modifications to the bromodifluoromethoxy group.Through DFT calculation,the feasibility of the two reaction systems was verified,and a new idea of the existence of difluoromethoxy cation(OCF₂⁺)in the process of desulfurization and fluorination was put forward.