Palladium-Catalyzed Mono-Selective C(sp~3)-H Bond Functionalization Of Aliphatic Carboxylic Acids

In organic synthesis chemistry,the one-step synthesis of important carboxylic acid derivatives from simple and readily available carboxylic acids is very attractive,because carboxylic acid is ubiquitous in many important molecular structures such as drugs,natural products,spices,functional materials,and so on.It is a very important synthetic intermediate in the field of organic synthesis.The use of carboxylic acid groups for site-selective C(sp~3)-H bond functionalization has always been the focus of chemists.The traditional directing group assistant strategy is to design and install the directing group before the reaction and remove the directing group after the reaction.However,this strategy has the inherent limitation of using the same amount of exogenous directing groups,and these exogenous directing groups will eventually enter the product,making the synthesis process of the target product tedious and complicated.Although the use of instantaneous directing group strategy overcomes some limitations,the most effective method is not to use any exogenous directing groups and to functionalize the site-selective C(sp~3)-H bond of aliphatic carboxylic acids.In addition,the practical synthesis of high value-added aliphatic carboxylic acid molecules remains a major goal and challenge for transition metal-catalyzed C(sp~3)-H bond functionalization.In this paper,the arylation scheme of mono-selective C(sp~3)-H bond of pivalic acid catalyzed by palladium(Ⅱ)is reported,which is used to quickly construct the important functionalized 3-aryl-2,2-diethylpropion acid,especially those ortho-substituted aryl compounds,which are tedious and uneconomical to be prepared by traditional multi-step synthesis methods.The strategy developed in this paper greatly simplifies the preparation of a series of trimethyl-lock(TML)type triggers(gem-dimethyl carboxylic acid).These triggers can be used for selective chemical release and activated under specific conditions,such as redox and(enzymatic)hydrolysis trigger mechanisms.Finally,the flexible transformation and derivatization of these activable gem-dimethyl carboxylic acid triggers are also demonstrated.