Palladium-catalyzed Sequential Functionalization Of Ortho-C–H And Ipso-C–O Bonds Of Benzyl Alcohols

In recent years,transition metal-catalyzed functionalization of non-activated C-H bonds assisted by directing groups has been widely used as a simple and efficient method in the synthesis and modification of natural products,drugs and pesticides.As an electron-donating ligand,the directing group can coordinate the metal center and transfer it to the target C-H bond,so as to achieve regio-selective C-H bond functionalization.The directing group not only facilitates the proximity of the metal catalyst to the site-specific C-H bond,but also gives the intermediate complex the necessary stability and reactivity.However,an obvious disadvantage of the functionalization of template-directed C-H bond is that the assembly of the directing group and the removal afterwards.These usually require additional reaction operations,which will increase the reaction steps and reduce the economy of synthesis reaction.Therefore,a transformable directing group in C-H functionalization can not only be removed,but can also introduce a new functional group,thereby greatly improving the synthesis efficiency of this method.In this thesis,the directing group of C-H bond functionalization is also used as an electrophilic reagent for subsequent cross-coupling reaction,which significantly improves the step economy of synthetic applications of directed C-H functionalization.Through using a well-defined bifunctional directing template,palladium catalyzed ortho-C-H alkenylation and arylation of benzylic alcohols were achieved via an end-on nitrile-embedded 12-membered macrocyclic transition state.Thereafter,the directing template is further used as a handle for palladium-catalyzed ipso-C-O cross-coupling to provide functionalized diarylmethanes.This template-directed sequential ortho-C-H/ipso-C-O functionalization methodology allows for an easy approach to synthesis of biologically important ortho-functionalized diarylmethanes from simple benzylic alcohols,which are widely distributed in the natural lignans,coumarins and pharmaceuticals.In order to demonstrate the synthetic utility of the strategy,sequential ortho-C-H olefination and ipso-C-O arylation were also performed on a scale of more than 1 mmol and the corresponding products were obtained with good yields.