Cu-promoted Tandem C-H Activation/intramolecular Cyclization Reaction Assisted By Bidentate Directing Group

The construction of carbon-carbon bonds and carbon-heteroatom bonds via transition metal catalyzed C-H activation is a hot topic in modern organic synthesis methodology,simultaneously,plays an an indispensable role in synthesizing a series of biological and pharmacological active molecules.The reaction of noble metals such as palladium,ruthenium,rhodium has been greatly enriched and developed in the past decade.The cheap transtion metal catalyzed or mediated reaction,however,has gradually movedontothecentreoforganicsythesisbecauseofits environment-friendlyandmoreeconomicalcharacteristics.The involvement of bidentate ligand as a directing group in C-H activated functionalizationscanstabilizetheorganometallicmacrocycle intermediate,making it a hot research topic in morden organic synthesis methodology.Based on the above background,this paper mainly presents the research of highly efficient Cu-promoted synthesis of isoindole-1-ones by using benzamides and nitroalkanes as substrates assisted by bidentate directinggroup.ThistransformationisbasedontandemC-H activation/intramolecular cyclization process.In the optimization of the reaction,the effects of the variables such as alkali,additive,solvent,temperature and Cu salt on the reaction were discussed.The optimal reaction condition was determined by a series of screening,and the target product was obtained at a high yield(78%).With the optimized reaction condition in hand,we next set out to explore the scope and limitations of this reaction.It was found that the methyl,methoxy,halogen,and trifluoromethyl substituted benzoic acid derivatives were well tolerated under the reaction with nitromethane,It is noteworthy that all these 3-hydroxyimino-isoindolin-1-one products were obtained as an E/Z mixture.The ~1H-~1H NOSEY experiment showed that the E configurationwasthemainconfigurationinthemixture.Besides nitromethane,we also extended our coupling to other nitroalkanes.such as nitroethane,1-nitropropane,1-nitro butane,nitro-isopentane.We were pleased to see all these substrates worked well with various benzamides to givethedesiredproducts.When1-nitropropane,1-nitrobutane,nitro-isopentane were used as the reaction substrates.All these products exist as an E/Z mixture and the ratios range from 1:1 to 1.5:1.According to the related literature and experimental results,the reaction mechanism is proposed.Benzamides first reacts with Cu(II)salt and subsequently undergoes C-H activation assisted by 8-amino quinoline as bidentate ligand.For the reaction with nitromethane,an intramolecular cyclization takes place and the final product is obtained through dehydration As for the reaction with nitroethane and other higher alkyl substituted nitroalkanes,the reaction undergoes a Nef type process to give the ketone intermediate which subsequently cyclizes intramolecularly to give the final product...