Reaction Study On The Synthesis Of Gem-Difluorocyclopropane Amides And Seven-Membered Nitrogen Heterocyclic Compounds From Gem-Difluorocyclopropenes

The introduction of fluorine atoms into drug molecules can increase their lipophilicity,metabolic stability and drug activity.Therefore,the design and modification of fluorine-containing compounds have important research significance in the development of drug molecules.There are many methods for introducing fluorine atoms,among which the method of introducing fluorine atoms through gemdifluorocyclopropene is one of the key research directions,which can be used to prepare functionalized gem-difluorocyclopropane and fluorine-containing seven-membered nitrogen heterocyclic compounds.However,there are still some deficiencies in the research on the synthesis methods of these two types of compounds: in the research on the synthesis of functionalized gem-difluorocyclopropane from gemdifluorocyclopropenes,it is difficult to synthesize amine substituted gemdifluorocyclopropane;it is difficult to synthesize seven-membered nitrogen heterocyclic compounds from gem-difluorocyclopropenes.This paper mainly describes the research in the above two aspects through three chapters:The first chapter briefly describes the synthesis methods and reaction research progress of gem-difluorocyclopropenes,and introduces several synthetic methods and existing problems in the literature of gem-difluorocyclopropane compounds and sevenmembered nitrogen-containing heterocyclic compounds,and proposes our reaction design ideas.In the second chapter,the research work on the synthesis of amine-substituted gem-difluorocyclopropane compounds was carried out,and a series of aminesubstituted gem-difluorocyclopropanes were synthesized through gemdifluorocyclopropene and N-methoxybenzamide under the action of alkali,provides a new method for the synthesis of amine-substituted gem-difluorocyclopropane compounds.The optimal reaction conditions,substrate applicability range,application experiments,and application in drug molecules were explored.In the third chapter,on the basis of the [4+3] cycloaddition reaction of Nmethoxybenzamide and gem-difluorocyclopropene catalyzed by rhodium(Ⅲ)to synthesize fluorine-containing seven-membered nitrogen heterocyclic compounds,and further research was carried out on the synthesis of fluorine-containing sevenmembered nitrogen heterocyclic compounds by [4+3] cycloaddition reaction between N-methoxymethacrylamide and gemdifluorocyclopropene catalyzed by rhodium(Ⅲ).The optimal reaction conditions,substrate applicability range,and application in drug molecules were explored,and the possible reaction mechanism was proposed.In summary,this thesis mainly uses gem-difluorocyclopropene and Nmethoxyamide compounds as raw materials to synthesize amine-substituted gemdifluorocyclopropane and fluorine-containing seven-membered nitrogen heterocyclic compounds.The realization of these two works provides a simple and efficient method for the synthesis of diastereoselective amine-substituted gem-difluorocyclopropanes and fluorine-containing seven-membered nitrogen heterocyclic compounds,which has important research significance and application prospects in the design of drug molecules and application.