Nickel-Catalyzed Asymmetric Reductive Heck Reaction And Directed Alkylation Of Phenolic Esters

In recent years,reductive Heck reactions have been developed into a useful tool for the construction of C(sp2)-C(sp3)bond,and is widely used in the synthesis of natural products and biologically active compounds.However,the asymmetric reductive Heck reaction is still in its adolescence,and the substrates are limited to electron-deficient or electron-rich activated alkenes,or norbornene and its derivatives.In the first chapter of this dissertation,a nickel-catalyzed asymmetric intramolecular reductive Heck reaction of unactivated alkenes has been developed,which employs unactivated 1,1disubstituted alkenes incorporating aryl halides as the starting material with zinc powder as the reducing agent and isopropanol as the solvent,delivering various benzene-fused cyclic compounds in high enantioselectivities,including indanes,dihydrobenzofurans,and indolines.In addition,highly enantioenriched indanone,dihydrocoumarin,and dihydroquinolinone were obtained through derivatizations of an indane product.The results of control experiments and deuterium labeling experiments reveal that migration insertion of the olefinic unit into aryl nickel species is the enantiodetermining step and water or alcohol solvents serve as the proton source.On the other hand,ketones are a ubiquitous structure in natural products and pharmaceuticals,and thus the synthesis of ketones is of great significance.As a relatively stable acylating reagent in comparison to activated acyl sources like acyl halides and anhydrides,phenolic esters are insensitive to air and moisture,and convenient to prepare and to store.However,due to the low reactivity of C(acyl)-O bond of phenolic esters,synthesis of ketones using phenolic esters as the acylating agent under reductive conditions has not been realized.To address the issue of low reactivity of C(acyl)-O bond of phenolic esters,the strategy using hydroxyl or sulfonamide as a directing group to facilitate the C-O bond cleavage has been successfully applied in the nickel-catalyzed reductive cross-coupling of phenolic esters with alkyl halides,providing access to various ortho-hydroxyl and tosyl-protected ortho-amino aryl alkyl ketones.Under these reaction conditions,the acyl C-O bond is selectively activated by nickel,and the decarbonylation side reaction is also avoided.In addition,this reaction demonstrates a broad substrate scope regarding the alkyl electrophiles,which include both primary and secondary alkyl bromides.In the third chapter of the dissertation,given the fact that benzyl halides are prone to undergo homo-coupling,quaternary ammonium salts with relatively low reactivity were selected as the electrophile,which enables a nickel-catalyzed reductive arylmethylation of phenolic esters under the direction of hydroxyl or sulfonamide moiety,furnishing a series of ortho-hydroxyl and tosyl-protected ortho-amino aryl benzyl ketones.In summary,asymmetric intramolecular reductive Heck reaction of unactivated olefins and hydroxyl or sulfonamide-directed cross-electrophile alkylation of phenolic esters have been developed under reductive nickel catalysis,offering a new entry to the synthesis of chiral benzene-fused cyclic compounds and ketones,respectively.