Studies on Palladium Catalyzed Selective C-H Bond Functionalization

Author:Mao Yang Jie

Supervisor:xu dan zuo lou shao jie


Degree Year:2019





Last decade has witnessed the rapid development of transition-metal-catalyzed C-H bond functionalization in organic synthesis.Among them,the strategy of using directing groups has attracted tremendous interest due to its high regioselectivity,which enables the ortho/meta/para-selective C-H bond functionalization of substituted arenes and theα/β/γ/δ-selective C-H bond functionalization of substituted alkanes.In general,the directing group assisted C-H functionalization undergoes several elementary steps e,g.,ligand coordination,C-H activation,oxidative addition,and reductive elimination.Thus,some inevitable issues such as the regio-selectivity and chemoselectivity may be occurred.This dissertation mainly focuses on the solutions to these key issues in the transition-metal catalyzed C-H bond functionalization,which enabled ortho-C-H bond arylation,fluorination and para-C-H bond difluoromethylation of substituted arenes as well asβ-C-H bond fluorination of aliphatic alcohols.The main research content of this dissertation includes four parts as follows:The biaryl synthesis via dehydrogenative C-H/C-H arylation using mechanochemistry was developed for the first time.The protocol was compatible with electron-deficient oximes and electron-rich anilides under mild reaction conditions with high functional group tolerance.Given the mechanochemistry conditions,this transformation obviated using excess arene coupling partners with short reaction time and high para-selectivity in comparison with the traditional batch process which used arene as a solvent.A novel Pd-catalyzed remote para-selective C-H difluoromethylation of aromatic carbonyl via a radical process was developed.The high para-selectivity was enabled by the weak interaction between carbonyl and Pd catalyst,which changed the inherent properties of the arene ring.Diverse aryl ketones and benzoates bearing different functional groups were well tolerated in this transformation with high-level para-selectivity.Notably,the late-stage difluoromethylation of complex bioactive molecules has also been established.Moreover,the difluoromethyl group could be easily transformed into other fluorine-containing functional groups.The selectiveβ-C(sp~3)-H fluorination of masked alcohols by using a rational designed exo-directing group was developed.This novel pyruvate-based bidentate directing group was modular accessible and compatible with diverse methyl,methylene,or benzyl C(sp~3)-H bonds.Moreover,the directing group could be readily removed by the cleavage of the N-O bond to furnish fluorinated alcohols,which significantly expanded its application perspective.The detailed mechanism on anion ligand promoted selective C-F bond reductive elimination from aryl-Pd(IV)-F intermediate enables C(sp~2)-H fluorination was described.The well-defined aryl-Pd(II)-NO_x were prepared and proved to be the key reactive intermediates in the C-H bond fluorination of azobenzenes.DFT calculations showcased that the nitrate and nitrite accelerated the C-F bond reductive elimination from the high-valent Pd(IV).Furthermore,guided by the mechanism studies,the nitrate promoted ortho C-H bond fluorination of symmetric and asymmetric azobenzenes could take place smoothly,and diverse o-fluoroanilines were obtained after a simple reduction of fluorinated azobenzenes.