Combinatorial Nickel-Catalyzed Fluoroalkylation

The selective introduction of fluorine or fluorinated moieties into organic molecules will dramatically change the physical properties,chemical properties and biological activities of parent coumpounds.Due to its wide applications in medicine,materials and pesticides,there is a growing demand for efficient,safe and green methods to incorporate fluorine atoms or fluorine-containing functional groups into organic molecules.Recently,nickel catalyst has been widely used in fluoroalkylation for its high efficiency and safety,and has became a hotspot in the field of organic fluorine chemistry.This essay described a novel stategy on ligand-combination acceleration,with which the stereo-or electron-properties of the catalyst could be easily tuned using different ligand combinations.Two kinds of coupling reagents could be generally applied with robust tolerance.Based on this strategy,we have realized the monofluoroalkylation of aryl boric acid,direct difluoromethylation of aryl boric acids and monofluoroalkylation of aryl halides.The dissertation includes four parts:Chapter 1:Research progress of monofluoroalkylation and difluoromethylationWe introduced the application of organofluorine compounds in practical production and life.Meanwhile,the methods on monofluoroalkylation and difluoromethylation have been summarized systematically.The transition-metal catalyzed monofluoroalkylation and difluoromethylation have been introduced in detail.Chapter 2:Nickel-Catalyzed Monofluoroalkylation of Aryl Boronic AcidsA combinatorial nickel-catalyzed cross-coupling between aryl boronic acids and unactived 1-fluoro-1-iodoalkanes has been developed,which demonstrated high efficiency,mild conditions,and excellent functional-group compatibility.Mechanistic investigations indicated a Ni(0)/Ni(Ⅱ)catalytic cycle involving a monofluoroalkyl radical were generated in situ.Chapter 3:Nickel-catalyzed direct difluoromethylation of aryl boronic acidsA nickel-catalyzed direct difluoromethylation of aryl boronic acids has been developed for the first time.In this transformation,we used an abundant industrial raw material and low-cost BrCF2H as the difluoromethyl reagents,and showed good efficiency,mild conditions,and good functional-group compatibility.Chapter 4:Nickel-catalyzed monofluoroalkylation of aryl iodides via reductive cross-coupling.A combinatorial nickel-catalyzed monofluoroalkylation of aryl iodides with unactivated fluoroalkyl halides via reductive cross-coupling has been developed.This method has demonstrated high efficiency,mild conditions,and excellent functional group tolerance,thus enables the late-stage monofluoroalkylation of diversified drugs.This combinatorial catalysis strategy will offer a solution for nickel-catalyzed reductive cross-coupling reactions and provides an efficient way to synthesize fluoroalkylated drug-like molecules for drug discovery.