Research On Novel Fluoromethylated And Fluoromethylthiolated Reactions

Fluorine-containing compounds have important application value in the fields of synthesis,medicine and pesticides.The introduction of fluorine-containing groups into molecules can effectively reduce the electron cloud density,thereby improving the metabolic stability and fat solubility of the molecules,and it has great application prospects in the field of medicinal chemistry.Therefore,the development of new fluoroalkylation reagents,the exploration of new construction methods of fluoroalkyl groups and the new applications of traditional fluoroalkylation reagents have become popular research directions in the field of organic fluorine chemistry in recent years.This dissertation mainly studies the difluoromethylthiolation and monofluoromethylation reactions.We developed a one-pot,three-component method to construct difluoromethylthio group and deuterated difluoromethylthio group.In addition,the new application of fluoroalkylsulfonyl chlorides and monofluoromethyl iodide has also been studied.Firstly,the one-pot three-component difluoromethylthiolation reaction of electron-rich aromatic heterocycles is studied.This method uses odorless and tasteless thiourea as the sulfur source,diethyl bromodifluoromethylphosphonate as the difluorocarbene source,and water as the hydrogen source.Under optimal conditions,the strategy enabled the introduction of SCF₂H moieties into indoles,pyrroles,and activated arenes and formed a number of diflfluoromethyl thioethers with moderate to excellent yields.The transition-metal-free protocol,readily available reagents,and mild reaction conditions are the main advantages of this method.Secondly,after properly adjusting the reaction conditions,the method can be extended to the difluoromethylthiolation of alkyl electrophiles such as alkyl bromides,benzyl chlorides,and alkyl iodides.The control experiments show that the source of hydrogen ion in this reaction was mainly from H₂O(?70%)and the hydroxyl group of CH₃OH(?30%).By replacing the‘‘H''source with commercial available‘‘D''sources CD₃OD and D₂O,the one-pot deuterated difluoromethylthiolation reaction of alkyl electrophiles can be realized in good yields with high levels of D incorporation(93%–97%D).This reaction system can be scaled up.The Bn SCF₂D synthesized by this reaction can be used as a raw material to synthesize deuterated difluoromethylthio reagents Phth SCF₂D and Ph SO₂SCF₂D.The high levels of D incorporation will not change significantly during the reaction process.Thirdly,the unprecedented use of fluoroalkylsulfonyl chlorides for direct bifunctional chloro-fluoroalkylthiolation of alkenes and alkynes is studied.The reaction uses PPh₃ as reducing agent and DMF as solvent to realize the chloro-trifluoromethylthiolation of alkenes and alkynes with CF₃SO₂Cl in good yields.The reactions of styrenes gave regioselective Markovnikov adducts,while nonstyrene-type alkenes mainly gave anti-Markovnikov adducts.The highly effiffifficient and concise nature of the reaction process and good atom economy,along with the mild conditions employed,are the major advantages of this new method.Mechanism studies have shown that CF₃SO₃H produced by the hydrolysis of CF₃SO₂Cl can be used as a catalyst for the reaction to promote electrophilic addition.High regioselectivity for Markovnikov products from styrenes resulted from the favorable electronic conjugation of a phenyl ring with a bridged episulfonium ion in the addition of Cl^-to intermediate.The reaction system can be extended to the reaction of CF₂HSO₂Cl with alkenes and alkynes to obtain the corresponding chloro-difluoromethylthiolated products.Finally,the carbon-oxygen chemoselectivity of monofluoromethylation of?-ketoesters is studied.Using fluoromethyl iodide as the monofluoromethylation reagent,lithium tert-butoxide as the base,and diglyme as the solvent,a broad scope of?-ketoesters were converted into the corresponding carbon-selective monofluoromethylated products in good yields with high chemoselectivities.The effect of the lithium ions has a great influence on the results.The DFT calculations show that due to its affinity with oxygen sites,the free energy of intermediates formed by fluoromethyl iodide attacking carbon atoms is lower than that formed by attacking oxygen atoms,resulting in the high chemoselectivity on carbon atoms.