Transitionmetal Mediated Difluoroalkyaltion Reactions

Due to the unique properties of fluorine atom（s）,fluorinated compounds have paramount applications in pharmaceuticals,agrochemicals,and materials science.Among the organofluorinatede compounds,difluoroalkylated compounds have attracted increasing attention.Over the past decades,significant progresses have been made towards introducing difluoroalkyl groups into organic molecules.However,efficient methods remain limited.To overcome these limitations and meet the increasing demands of life and materials sciences,new methods that can expand the diversity of the difluoroalkylated structures with high site-selectivity is highly desired.In this dissertation,we mainly focus on developing efficient systems to construct Ar CF₂-X bond and Csp³-CF₂R bond and their applications in enantioselective synthesis of difluoroalkylated compounds.1.Silver-Catalyzed Decarboxylative Chlorination and Bromination of Aryldifluoromethylated Carboxylic AcidsIn this chapter,we have developed an efficient method to access chloro/bromodifluoromethylated arenes through decarboxylative halogenation of aryldifluoromethylated carboxylic acids.The mild reaction conditions allow the tolerance of a wide range of important functional groups.Importantly,this method can be applied to introduce chlorodifluoromethyl group into complex bioactive compounds The resulting fluorinated products can serve as the versatile building blocks for diversified transformations,providing potential applications in medicinal chemistry.2.（Fluoro）alkylation of Alkenes Promoted by Photolysis of AlkylzirconocenesIn this chapter,a general and catalyst-free method for the fluoroalkylation of alkenes promoted by photolysis of alkylzirconocenes has been developed.The reaction exhibits high functional group tolerance and broad substrate scope.A wide range of silyl-and alkyl-alkenes as well as fluoroalkyl halides,including difluoroalkyl,trifluoromethyl,perfluoroalkyl,and monofluoroalkyl bromides and iodides,were suitable substrates.In particular,the adaptability of the readily available unactivated difluoroalkyl halides and aliphatic alkenes to the reaction paves a new way for the construction of alkyl-CF₂-alkyl bond.The reaction can also be applied to nonfluorinated alkyl halides,thus demonstrating the generality of this protocol further.Furthermore,the use of simple alkylzirconocene,instead of generating different alkylzirconocenes between HZr Cp₂Cl and a series of alkenes,significantly expands the substrate scope,including a variety of complex molecules that are sensitive to HZr Cp₂Cl.The synthetic utility of this protocol has also been demonstrated by the transformations of the difluoroalkylated compounds,providing good opportunities in medicinal chemistry.Preliminary mechanistic studies reveal that a SET pathway induced by a Zr（Ⅲ）species is involved in the reaction,in which the Zr（Ⅲ）species is generated by the photolysis of alkylzirconocenes with blue light.3.Copper-Catalyzed Highly Enantioselective gem-Difluoroallylation of Alkenyl BoronatesThe first example of Cu-catalyzed highly enantioselective hydrodifluoroalkylation of alkenyl boronates with gem-difluoro-containing electrophiles has been developed.The steric effect of the chiral ligand,directing group and the aliphatic chain length of alkenyl boronates are the key factors for the reaction enantioselectivity.The reaction exhibited high efficiency,good enantioselectivity,and high functional group tolerance,paving a new way for the asymmetric synthesis of difluoroalkylated compounds.The resulting chiral difluoroalkylated boronates compounds can serve as useful building blocks for diversified synthesis of chiral difluoroalkylated compounds that are of interest in medicinal chemistry.