Synthesis Of 4-fluoropyridine And Spiro Five-membered Ring And Difluorocyclopropane Compounds From Difluorocyclopropene

The introduction of fluorine atoms into organic molecules often significantly alters their biological activity,therefore,many fluorine-containing organic compounds have a wide range of applications in the fields of pharmaceuticals,pesticides,materials and pharmaceutical intermediates,so that the synthesis and application of fluorinecontaining organic compounds have become a hot spot in the current research of organic synthetic chemistry.Difluorocyclopropene is a kind of fluorine-containing olefin compound with novel structure and unique properties that has been popular in recent years,it can be applied to the construction of a variety of fluorine-containing compounds,including the synthesis of fluoropyridine and five-membered ring and difluorocyclopropanes.This dissertation focuses on the construction of the skeleton of fluoropyridine and five-membered ring and difluorocyclopropane compounds,and provides new ideas for the research and development of fluorine-containing drugs.The research content of this dissertation mainly includes three chapters,as follows:1.The first chapter briefly introduces the synthesis and application of difluorocyclopropenes,and comprehensively describes the important applications and synthetic methods of 4-fluoropyridine and five-membered ring difluorocyclopropane compounds.2.The second chapter introduces a new method for the synthesis of 4-fluoropyridines.The imine substituted by the electron withdrawing group at the αposition first undergoes a [3+2] cycloaddition reaction with a difluorocyclopropene under the action of a base,and the ring-opening defluorination obtains an intermediate,which is then oxidized by the solvent DMSO to obtain the 4-fluoropyridine derivatives further enrich the synthesis methods of 4-fluoropyridine.The optimal reaction conditions,substrate adaptability range and application in drug molecules were mainly explored,and the possible reaction mechanism was proposed.3.The third chapter introduces a novel synthetic method of spiro five-membered ring and difluorocyclopropanes.Under the activation of trifluoromethyl group,isatin derivatives undergo [3+2] cycloaddition reaction with difluorocyclopropene to construct five-membered ring and three-membered ring structure,and then rearranged under the catalysis of base,form a spiro ring structure.The optimal reaction conditions and substrate adaptability range of the reaction were explored,and the spiro ring structure was characterized.Finally,a reasonable reaction mechanism was proposed.In summary,this paper proposes two types of cycloaddition reactions using geminal difluorocyclopropenes as raw materials,the synthesis of 4-fluoropyridine derivatives with imines substituted with electron withdrawing groups at the α position,and the reaction with isatin derivatives to synthesize spiro five-membered ring and difluorocyclopropanes.These works provide a simple,efficient and novel synthetic method for the construction of 4-fluoropyridines and spiro five-membered ring difluorocyclopropanes,which enriches the types of fluorine-containing compounds and has important academic significance and research value.