Copper-Catalyzed Asymmetric Alkynylation Of Ortho-Aryl Substituted Cyclic Oxime Ester Via Radical Ring Opening:Sythesis Of Alkynyl Substituted Chiral Nitrile Derivatives

Alkylnitriles are considered as key structural motifs due to their widely existence in numerous natural products and pharmaceutical compounds.Furthermore,alkylnitriles are of vital importance in modern organic chemistry because of their versatility as intermediates for transformation into other functional groups,such as amides,esters,carboxylic acids,amidines and aldehydes.Therefore,preparation of alkylnitriles has attracted tremendous attention from the synthetic community.Traditional methods for alkylnitrile synthesis include cyanation of alkyl halides,dehydrogenation of amines,addition of hydrogen cyanide to alkenes and dehydration of amides or aldoximes.Recently,radical-initiated C（sp³）–H bond oxidative functionalization of alkyl nitriles has emerged as a powerful platform to access structurally diverse alkylnitriles,in which the alkyl radical is adjacent to cyano group.Nevertheless,introducing cyanoalkyl groups into target molecules via distal cyano-substituted alkyl radicals is rarely reported and still in high demand.Under the condition of transition metal catalysis or light,cyclic oxime ester compounds can generate imine radicals through the single electron transfer（SET）process.Then,due to the presence of ring tension,the C–C bond breaks and produces chain free radicals.Finally,the cyclic oxime ester compounds combine with nucleophile to form C–C bond or C–Y bond（Y=O,S,Se,Te,N₃ or B）.Considering that the free radicals generated by alkyl cyclic oxime ester after cracking could not form stable chiral centers,in this paper,the ring opening reaction of ortho-aromatic cyclic oxime ester was used to form benzyl radical intermediates,and the coupling reaction with phenylacetylene compounds was realized under the catalysis of copper.At the same time,due to the high stability of benzyl radicals in the reaction process,the target product with single orientation can be obtained by the chiral ligands under suitable conditions,and the chiral C（sp³）–C（sp）bond can be successfully constructed.Inspired by the chiral ligand structures in the literature,we synthesized the chiral amino acid phosphine ligand by ourselves.In this paper,aryl acetylene compounds were used as reaction substrates and reacted with o-aryl-substituted cyclobutyl oxime ester compounds under the action of copper catalyst,so as to realize the molecular coupling between end-acetylene and benzyl radical intermediates,which provides a new and efficient method for the synthesis of acetylene substituted chiral alkylnitrile compounds.The research content of this paper is mainly divided into the following two parts:The first part:The synthesis method of alkyl nitriles and the ring-opening reaction of cyclic oxime ester are briefly introduced.The second part:The research background of this topic,the optimization of experimental conditions and the application range of substrates were introduced.The reaction provides an efficient way to synthesize chiral endocyyne without the addition of toxic cyanide,and has a high degree of regional selectivity,good stereoselectivity,and a wide range of functional group compatibility.