Study On Synthesis Of Difluoromethoxy And Trifluoromethylthio Nitrogen Heterocyclic Compounds Based On Tandem Reaction Of Organic Small Molecules

Fluorine compounds are important part of natural products and modern medicine and pesticides.How to introduce fluorine-containing groups into small organic molecules to excavate their potential application value has been a hot topic pursued by several generations of chemical scientific researchers.From the initial use of fluorine-containing inorganic salts to construct C-F bonds,to the development and application of modern new fluorine reagents,various novel and effective methods to construct C-F bonds have been reported successively.Among them,the tandem reaction using small organic molecules is particularly outstanding in the synthesis of F-containing compounds such as-F,-SCF₃,-OCF₂H.Tandem reaction is characterized as greatly reducing the reaction steps,reducing the amount of reagents,and the simple operation,which can directly modify some functional groups of the compound.Fluorine-containing benzothiazole and pyridine derivatives have a wide range of applications in medicine and pesticides.For example,ortho-fluorinated2-arylbenzothiazole derivatives play a role in biological regulation of gastric cancer cells,Flumark,a F-containing pyridinederivative,is an antibacterial drug,which can be used for treatment infections in the bronchi,urinary tract,and lungs.Haloxyfopmethyl,a pesticide molecule containing a fluoropyridine unit,can inhibit the synthesis of some specific grass fatty acids,and is an effective selective herbicide for soybean,cotton,peanut and other crops.Therefore,it is of great significance to synthesize fluorine-containing benzothiazole and pyridine derivatives.Based on the previous research on the ortho-functionalization of benzothiazole and tandem cyclization of 1,3-enyne compounds,this thesis mainly studies the introduction of fluorinated groups on two substrates through tandem reactions.The first chapter of this thesis mainly introduces the research progress of difluoromethylation reaction and direct trifluoromethylthiolation reaction based on various fluoro reagents.In second chapter,we describes the synthesis of ortho-difluoromethoxylated2-arylbenzothiazole via three components tandem cyclization reaction of o-hydroxybenzaldehyde,and using introduces the use of ICF₂COOEt as the difluoromethyl source,and thiophenol as sulfur source,ortho-difluoromethoxy-2-arylbenzothiazole derivative can be obtained in high yield.The reactive functional group has good compatibility,and the electron-withdrawing substituent is better than the electron-donating effect.For the mechanism of the reaction,we speculate on two ways,one is the oxidative condensation nucleophilic substitution mechanism,the other is the difluorocarbene mechanism.Preliminary evaluation results of bioactivity of ortho-difluoromethoxylated 2-arylbenzothiazoles indicate that some compounds exhibit good inhibitory effects on human ovarian cancer cells?SKOV3?by methyl thiazolyl tetrazolium?MTT?assay.In the third chapter,we report a novel method for the synthesis of trifluoromethyl substituted pyridines via tandem cyclization of 1,3-alkyne azide compounds,using AgSCF₃ as the trifluoromethylsulfide source,K₂S₂O₈ as the oxidant,and CuF₂ as the catalyst,in the presence of S-phos ligand.A series of CF₃S-containing pyridine compounds were synthesized in moderate to good yields.The reaction functional group has a wide range and the product yield is medium to good.The experimental results of mechanism verification prove that the reaction may go through a process of electrophilic substitution of free radical addition.