Study On The Copper-catalyzed Introduction Of Cyano Groups Into Compounds Using Acetonitrile And Trichloroacetonitrile As Raw Materials

Cyano group is widely found in pharmaceuticals,since 2012,there are more than ten kinds of small molecule chemical drugs with cyano group approved by FDA,including Bosutinib for leukemia and Lenatinib for breast cancer.Cyano（CN）is also a common functional group with versatile transformations,which can be converted into carboxylic acid,amide and amine.Therefore,efficient synthesis of nitriles and their derivatives with potential drug activities is of great significance.In this thesis,we designed methods for construction nitrile derivatives with potential drug activity by copper catalyzed 1,2-addition and free radical cascade reactions using acetonitrile and trichloroacetonitrile as nucleophile and free radical precursor,respectively.This thesis is divided into two parts,as following:Part one:Cu₂O-catalyzed selective 1,2-addition of acetonitrile toα,β-unsaturated aldehydesIn this thesis,Cu₂O-catalyzed cyanomethylation ofα,β-unsaturated aldehydes with acetonitrile as a nucleophile was realized.The reaction proceeded in a highly selective 1,2-fashion.By optimation of the reaction conditions,δ,γ-unsaturated-β-hydroxylnitriles were synthesized in high yields.This reaction underwent under mild conditions and was benefited with broad substrate scope and easily handle,providing a new way for introduction of cyano intoα,β-unsaturated aldehydes.Part two:Copper（I）-catalyzed generation of dichlorocyanomethyl radical and its cascade reactions for preparation of dichlorocyanomethyl-functionalized oxindoles.In this thesis,a copper（I）-catalyzed method to synthesize dichlorocyanomethyl-functionalized oxindoles with dichlorocyanomethyl radical was developed,which is generated from trichloroacetonitrile via single-electron transfer reaction.From the mechanism perspective,the transformation is realized via single-electron transfer/radical addition/intramolecular radical cyclization/deprotonation.This method realized the radical addition reaction of the electrophilic dichlorocyanomethyl radical to electron-deficient C=C bonds of N-arylacrylamides and synthesized a series of dichlorocyanomethyl-functionalized oxindoles.Moreover,the reaction can be scaled up to gram level.