The Direct Ortho-selective C-H Functionalization Of Aromatic Acids

In the past decades,more and more scientists have devoted themselves to developing efficient methodology to synthesize natural products,bioactive molecules and materials.The highly regioselective functionalization of C-H bond has attracted much attention of organic chemists due to its advantages of step economy,atom economy and environmental friendliness.Although the directing group strategy is an effective approach to realize regioselective activation of C-H bonds,the introduction and removal of directing groups increase additional steps and reduce the efficiency of C-H bond activation.In the past decades,carboxyl group has been proved to be a weak coordination center,which can realize the high regioselective functionalization of C-H bonds.As an intrinsic functional group of organic molecules,carboxyl group can realize all kinds of functional reactions of C-H bond by using it,which has direct and efficient characteristics and has unique application value in synthetic chemistry.In this paper,the carboxyl assisted functionalization of C-H bonds was introduced,including indirect trifluoromethylation,ortho alkylation of benzoic acid and thiolation of benzoic acid.This paper consists of four parts,as follows:In the first part:we summarize the regioselective reactions of construct carbon-carbon,which is directed by carboxyl group and summarize the characteristics and significance of these reactions.The second part:it is found that 3-bromo-1,1,1-trifluoroacetone is an efficient indirect trifluoromethylation reagent.The indirect trifluoromethylation of benzoic acid is realized by the weak guidance of carboxyl group and the joint action of iridium complex and phosphine ligand.And it has been extended to a series of modification of drug molecules,such as bexarotene,probenecid,the key precursors of roflumilast.The third part:it is found that the aziridine can be used as an effective alkylation reagent.Under the condition of palladium catalysis,it can realize the ortho direct alkylation of benzoic acid,thus providing a most direct strategy for the formation of the core structure of phenylethylamine directly on the molecule containing benzoic acid skeleton.In the fourth part:thiolation of benzoic acid was studied,and the sulfurization of benzoic acid without protection under rhodium catalysis was realized.