Synthesis Of Trifluoromethyprazole-Fused Coumarin And Heterocyclic Alkene Derivatives

Coumarin and its derivatives are heterocyclic compounds with a wide range of biological activities,which are often used as the pharmacophore and core skeleton of clinical drugs.Therefore,it is of profound significance to modify the structure of coumarin and its derivatives.Trifluoromethylpyrazole is the core pharmacophore of drug molecules and biologically active molecules.It can significantly improve drug efficacy or produce new drug properties.It has been extensively used in the fields of chemistry,medicine,pesticide and material.In this dissertation,using 2,2,2-trifluoroadiazoethane（CF₃CHN₂）as a fluoridating reagent,a series of trifluoromethylpyrazoled coumarin derivatives with biological activites were synthesized,and the procedure was applied to aza-and oxa-benzonorbornadienes provide theoretical and experiment basis for the synthesis of coumarin drugs and other pharmacological active trifluoromethylpyrazolated heterocyclic compounds.The research’s main contents and results were as follows:1.Synthesis of related experimental materialsTrifluoroethylamine hydrochloride and sodium nitrite were used as the raw materials which were cheap and available,and7 kinds of CF₃CHN₂storage solutions were synthesized in a gentle,safe,and efficient manner.Then,based on salicylaldehyde,6 kinds of bioactive coumarin derivatives were synthesized with the yields of 60%-89%.Finally,to investigate the application of the reaction,11 heterocyclic alkene derivatives were synthesized with yields of 39%-59%.2.Design and synthesis of trifluoromethylpyrazoled coumarin derivativesIn this experiment,coumarin and CF₃CHN₂were utilized to synthesize trifluoromethylpyrazolated coumarin,but most of the current synthesis methods of trifluoromethylpyrazolated derivatives required transition metal catalysis or harsh reaction conditions.Therefore,a low cost,green and simple route was used to screen the reaction conditions such as base,CF₃CHN₂storage solvent,temperature,and external solvent.The results showed that under the condition of 80^oC,using DBU as catalyst and 1,4-dioxane as enternal solvent,the cycloaddition reaction of coumarin and CF₃CHN₂tert-butyl methyl ether solution can be realized efficiently.Then,9 trifluoromethylpyrazolated coumarins were respectively separated and purified by silica gel column chromatography.The yield was38%-71%.The cyclosddition strategy could realize the last-stage functionization of related natural products.3.Discussion of reaction mechanismBase on the experimental results,this intermolecular triazene-coumarin cycloaddition reaction mechanism was proposed.CF₃CHN₂ is used as the N-electrophile to form a triazene intermediate with DBU,then this intermediate undergo a[3+2]cycloaddition with coumarin to generate the trifluoromethylated product together with reliberating the DBU for further catalytic cycle.4.Applications of related heterocyclic alkenesThe optimized reaction conditions were used in this thesis,8 oxa-benzonorbornadienes and3 aza-benzonorbornadienes were synthesized with trifluoromethylpyrazolated and successfully constructing a series of trifluoromethylated pyrazolines and pyrazoles,with the yields of32%-96%,provide an efficient synthesis strategy for the subsequent synthesis of such derivatives.The intermolecular triazene-coumarin cycloaddition reaction was carried out in this thesis,and successfully synthesized a series of biologically active trifluoromethylpyrazolated coumarins.The protocol was featured with mild reactions,environmental friendliness and operational safety,which provided a new idea for the synthesis of coumarin and analogues.