Nickel-catalyzed C-alkylation Of Carbonyl Compounds Via Borrowing Hydrogen Method And Asymmetric Arylation Of Imines

This thesis contains the following three parts of research work:?.Nickel-catalyzed alkylation of amides and estersC-alkylation of amides has a wide range of aplycation in the fields of medicine,pesticide and fine chemical synthesis.The traditional method of using alkyl halides as alkylating reagents is cumbersome to operate,pollutes and has many by-products.Among them,alcohol is used as alkylating reagent to synthesize amide through borrowing hydrogen strategy has attracted more attention due to its high atom utilization and environmental friendliness.Before 2016,most of the alkylation of amides were achieved with noble metal catalysis.After 2016,the use of cheap metal catalysis has become the mainstream trend.But most of the reaction conditions are relatively harsh and the catalyst need mutiple steps synthesis,which limited their wide applycations.In chapter 1,we achieved the C-alkylation of amides and esters with primary alcohols by using nickel acetate Ni(OAc)₂ and monophosphine ligand P(t-Bu)₃.Various alkylation products have been synthesized with high yields,and the substrates scope is wide.Primary,secondary and tertiary amides can be successfully alkylated.In particular,the selective C-alkylation of primary amides is realized for the first time.The model reaction can be scaled up to more than 100 mmol,which is very suitable for industrial scale applications?.Nickel-catalyzed alkylation of thioamideThioamide has been intensive studied because of its various biological activities and synthetic uses.Many methods have been developed to synthesize thioamides,but the most commonly used method is the vulcanization of carbonyl compounds.However,when using Lawesson reagent,elemental sulfur,phosphorus pentasulfide and other vulcanizing reagents,the strong odour and messives pollution of the reactions limit their application.The simple alkylation of sulfurized amide based on borrowing hydrogen strategy is an environmental friendly,atom economic method to synthesize complex thioamides.To our knowledge,there are no report on this reaction.In chapter 2,we used nickel acetate Ni(OAc)₂ and monophosphine ligand P(t-Bu)₃ in situ as a catalyst to successfully realize the C-alkylation of thioamide.Using common aromatic primary alcohols as alkylation reagent,various thio-tertiary amides can be alkylated smoothly,with an average yield of more than 90%.A series of deuterium-label experiment confirmed that this reaction go through a hydrogen borrowing reaction process with Ni-H as an intermediate.?.Nickel-catalyzed asymmetric arylation of iminesAsymmetric arylation of imines is an important method to construct chiral alkylamine compounds with pharmaceutical value.In the past reported imine arylation,the arylation reagents are expensive boronic acids or boronic acid esters,which are complicated to synthesize.The protecting group on N is very critical,like p-toluenesulfonyl is commonly used,the catalyst are mostly based on precious metals,such as rhodium and palladium.In chapter 3,we have developed a catalyst generated in situ by Ni Br₂(DME)and pyridine-oxazoline ligands,and achieved the enantioselective addition reaction of alkyl halides to N-heteroaryl aldimines catalyzed by cheap metal nickel for the first time.Various substituted bromobenzenes can be used as arylation reagents to prepare a series of optically pure chiral diarylmethylamine compounds with excellent yield and enantioselectivity.