Copper-Catalyzed Difluoroalkylation Of Alkenes

As a bioisostere of oxygen atom,carbonyl,and methylene,difluoromethyene(CF₂)has been extensively applicated in the design of pharmaceutical and biologically active molecules.Related study indicates that incorporation of difluoromethyene into organic molecules can significantly improve their lipophilicity and metabolic stability.Thus,the difluoromethylene group(CF₂)is a valuable structural motif and the exploration of practical synthetic methodologies for the introduction of CF₂ in organic molecules is in high demand.In the past decade,the transition metal-catalyzed difluoroalkylation has become a reseach hotspot in organofluorine chemistry.In this dissertation,we reviewed the latest advances in difluoroalkylation and developed a Cu/PMDETA catalytic system.The low-cost copper salt was chosen as the catalyst;pentamethyldiethylenetriamine(PMDETA)was applied as ligand and base;commercially available ethyl bromodifluoroacetate(Br CF₂CO₂Et)was used as CF₂ radical source.The difluoroalkylation of a variety of alkenes has been investigated.Firstly,a general and facile synthetic method for C(sp²)-H difluoromethylation and perfluoroalkylation of alkenes and(hetero)arenes with commercially available fluoroalkyl halides has been developed with the copper-amine catalyst system.This method is characterized by high yields,mild reaction conditions,low-cost catalyst,broad substrate scope,and excellent functional group compatibility,therefore providing a convenient synthetic strategy towards various difluoromethyl-and perfluoroalkyl-substituted alkenes and(hetero)arenes.The mechanism of the reaction was preliminarily investigated and a plausible mechanism was suggested.Then,we developed a radical cascade annulation of amine-containing olefins and ethyl bromodifluoroacetate catalyzed by Cu I.Through the aminodifluoroalkylation of the unactivated alkenes and the rapid intramolecular nucleophilic substitution between amine and ester,three new bonds,including a C(sp³)-CF₂ and two C-N bonds,are forged simultaneously.A series of2,2-difluorinated pyrrolizidine and indolizidine derivatives have been conveniently synthesized in one-pot fashion.In addition,this reaction provided a convenient synthetic strategy toward difluoroalkylated indolin derivatives.Through the preliminarily investigation of the mechanism,two plausible pathways were proposed.Finally,a novel and efficient protocol for difluoroalkyl radical-promoted remote alkenyl migration was presented.The vicinal difluoroalkylalkenylation of unactivated alkenes had been successfully achieved through this radical cascade with excellent chemo-,regio-,and stereoselectivity.(E)-N-allyl-N-2-phenylethenesulfonamide derivatives containing two double bonds were designed as the starting materials.The difluoroalkyl radical selectively attacked the terminal alkene because of the less steric hinderance.The intramolecular 1,4-alkenyl migration was achieved through cascade 5-exocyclization/desulfonylation,and a nitrogen radical was generated simultaneously.The deuterium experiment indicated that the nitrogen radical can undergo hydrogen atom abstraction from the solvent to give difluoroalkylated amines.The reactions afford unprecedented3,3-difluoro-5-styrylpiperidin-2-one derivatives or?-styryl-?-difluoroalkyl amines bearing a quaternary stereocenter in high efficiency under mild conditions.This is the first report of difunctionalization of unactivated alkenes through desulfonylation-initiated distal alkenyl migration.