Synthesis Of Oxazoles Via Palladium Catalyzed Tandem Reaction Of Functionalized Aliphatic Nitriles And Diverse Arylation Reagent

Oxazole derivatives are a relatively common type of nitrogencontaining heterocyclic compounds with pharmacological activity.As the structural unit of drug molecules,it has always been a hotspot in the field of synthesis.In recent years,transition metal-catalyzed chemical reactions involving nitriles are one of the effective ways to construct nitrogencontaining heterocyclic compounds.Based on the above literature reports and our research interests,the study of the palladium-catalyzed tandem reaction of functionalized aliphatic nitriles and diverse arylation reagents has been carried out,providing new channels for the assembly of multisubstituted oxazoles in one pot.The main contents are presented as follows:Firstly,the palladium-catalyzed tandem cyclization reaction of functionalized aliphatic nitriles and aryl boronic acid has been developed.This transformation achieves the construction of 2,4-disubstituted and 2,4,5-trisubstituted oxazoles in one pot,and features mild reaction conditions,wide substrate scope,and good functional group tolerance.Introduction the benzoyl group into the nitrile substrate,the isocoumarin compounds can be obtained smoothly,the control experiment reveals the imine is the key intermediate of the cyclized reaction.Secondly,the decarboxylation/tandem cyclization reaction of aryl carboxylic acid with functionalized aliphatic nitrile via palladium catalysis has been developed.Utilizing the ester-substituted nitriles as the substrate,the oxazole skeleton is obtained,and the target product of imidazole can be generated using the amide-substituted nitrile as substrate by modulating the reaction conditions.This protocol is of practical utility,which is easy for gram-scale production,and late-stage derivatization of pharmaceutical momelotinib.Finally,an efficient and straightforward protocol for the assembly of the oxazole skeleton is achieved from readily available simple arenes and functionalized aliphatic nitriles.This transformation involves palladiumcatalyzed C–H activation,carbopalladation and a tandem annulation sequence in one pot.This reaction features mild reaction conditions,excellent reactivity,good functional group tolerance and high atom economy.Deuterium-labeling experiments suggested that C–H bond cleavage of the simple arenes might be the rate-determining step.