Study On The Difunctionalization Of Gem-Difluorocyclo-Propene For The Synthesis Of Fluorine-Containing Three-Membered Ring/Seven-Membered Ring Compound

The introduction of fluorine atoms into organic molecules will change their physical,chemical and biological properties,such as metabolic stability,lipophilicity and p Ka value.Fluorine-containing organic molecules have a wide range of applications in agricultural chemistry,materials,medicine and pharmaceutical chemistry.This thesis mainly adopts two different bifunctionalization reaction strategies for gem-difluorocyclopropene,including the addition of phosphinate to gem-difluorocyclopropene,the transition metal-catalyzed oxidative positioning group ortho C-H bond After activation,the ring-opening and defluorination reaction after the insertion of difluorocyclopropene.This paper mainly includes three chapters,the main content is as follows:Chapter 1:A comprehensive description of the importance of fluorinated three-membered ring and seven-membered ring organic molecules in the fields of medicine,agriculture and materials.There are two reaction strategies to construct fluorinated(hetero)aromatic ring:fluorination reaction and defluorination reaction.In recent years,the removal of part of fluorine atoms by reaction with polyfluoroolefins has become a new strategy for the synthesis of fluorinated(hetero)aromatic rings.Gemini difluorocyclopropene has multiple reaction sites,which can regioselectively and stereoselectively undergo nucleophilic substitution reaction at position 1,electrophilic addition reaction at position 3,electrophilic substitution reaction at position 3,and positions 2,3 In this paper,starting from gem-difluorocyclopropene,a simple and efficient method for synthesizing fluorinated three-membered ring,especially seven-membered ring,has been developed.This will provide important information for the development of organic synthesis and medicinal chemistry.Reference value.Chapter 2:Gedifluorocyclopropane is a key skeleton structure in many natural products or drug molecules.The methods for synthesizing cyclopropane structure reported previously mainly include Simmons-Smith cyclopropanation of allyl alcohol and metal-catalyzed carbene The insertion reaction and conjugate addition to the terminal olefins are then activated in series to cyclize the olefins to cyclopropane;in this chapter,we use geminal difluorocyclopropene and diphenylphosphine oxide/phosphate in N,N-dimethyl ethyl Under the conditions of amide solvent,air atmosphere and temperature of 25℃,only cesium carbonate base is needed to successfully synthesize gem-difluorocyclopropane hypophosphorous acid(ester)derivatives with moderate to good yields;then we optimize the reaction conditions,Substrate expansion,derivatization,and then the structural modification of the drug-active estrone steroidal macromolecule for application experiments,all of which can obtain the target compound with good yield.Chapter 3:Since the olefin part of gem-difluoride is electron-deficient,it is conducive to the difunctionalization of olefins.It is common to construct five-membered or six-membered(hetero)aromatic rings,but it is more difficult to construct seven-membered rings.In this chapter,through the activation of the ortho C-H bond of the benzene ring of the oxidative positioning group N-methoxybenzamide catalyzed by the transition metal,the insertion reaction of the difluorocyclopropene firstly forms the five with kinetic properties.Six-membered ring intermediate,the ring-opening and defluorination reaction of difluorocyclopropane can efficiently obtain seven-membered fluorinated heteroaromatic compounds in one step.Many seven-membered rings are difficult to metabolize in drug molecules.The molecular structure of estrone macromolecules,apadaline,probenecid and other drugs,the target compound obtained by reacting with difluorocyclopropene can enhance the biological activity and metabolism of the drug molecule,and replace the substrate with N-methoxysulfide Substituted benzamide,the reaction can still proceed smoothly.Therefore,this will provide a new method for the construction of a series of fluorinated(hetero)aromatic compounds with diverse structures,good regioselectivity,and easy derivatization.In This paper mainly uses two types of difunctionalization reactions of gem-difluorocyclopropene,including the hydrophosphinating reaction of gem-difluorocyclopropene and the reaction of N-methoxybenzamide with gem-difluorocyclopropene under rhodium-catalyzed conditions.Insertion and ring-opening and defluorination reaction to construct fluorinated seven-membered aromatic heterocyclic compounds.The realization of these works not only provides a universal,simple and efficient synthetic method for the construction of fluorinated(hetero)aromatic rings,but also can be expanded.The reaction types of polyfluoroalkenes and the rich types of fluorinated(hetero)aromatic rings have important academic research significance and industrial application prospects.