Directed C(sp~2)-H Activation By Transient Directing Group:Synthesis Of O-chlorobenzaldehydes And Their Derivativation

o-Chlorobenzaldehyde and its derivatives play important roles in drug synthesis and the construction of other compounds scaffolds.It serves as a precursor for transition metal catalyzed cross-coupling reactions,or can be derivatized for the synthesis of various heterocyclic compounds which act as the drug molecule intermediates.Therefore,o-chlorobenzaldehyde has a wide range of application prospects.To date,however,the synthesis of o-chlorobenzaldehyde through direct ortho-C?sp²?-H functionalizations of benzaldehyde substrates has not been reported,which was accounted for the aldehyde's weak coordinating ability,the susceptibility toward oxidation,the easy oxidation to carboxyl or destruction in the reaction process.Hence,it is of great importance to develop a new strategy for one-pot synthesis of o-chlorobenzaldehyde.The ortho-C?sp³?-H arylation of benzaldehyde using transient directing groups have been reported.This strategy affords ortho-C?sp³?-H arylation of benzaldehyde in one-pot mode,abandoning the auxiliary pre-installation and subsequent removal of the directing group.It represents a fast and efficient implementation of benzaldehyde ortho-C?sp³?-H bond activation,however,it is limited to benzaldehyde C-H arylation only.Herein,we plan to synthesis o-chlorobenzaldehyde using the transient directing group strategy,and subsequently the derivatization to construct benzeneheterocycles.This work involves the following two parts:In part I,firstly,by employing anthranilic acid as ligand to combine with aldehyde to form transient directing group,N-chlorosuccinimide?NCS?as the source of chlorine and Pd?OAc?₂ as catalyst,we synthesized monofunctionalized o-chlorobenzaldehyde by transient directing group strategy and obtained the corresponding products in moderate to excellent yields;Secondly,by using transient DG,we also can obtain exquisite site-selectivity of o-chlorobenzaldehyde products for substrates bearing functional groups,such as ester,nitrile,amide,acetyl,sulfone and carbamate,in moderate to excellent yields;Thirdly,a series of biaryl compounds were produced using this new transient directing group strategy,and further the post-diversification of celecoxib was realized and a new drug molecule structure was therefore synthesized.Thus,it highlights the potential of this method in drug molecule structure design.In part II,the derivatization of the synthesized o-chlorobenzaldehyde bearing otherwise strong directing functionalities was accomplished and continued with the synthesis of benzothiophene derivatives,indole derivatives,quinazoline derivatives and phenanthrene derivatives.The aryl-substituted benzimidazoles,benzothiazoles,tetrazole and isoxazole pentaheterocyclic rings were also synthesized by aldehyde condensation reaction.The further derivatization of tetrazolium can give the Sartan structure;the further derivatization of isoxazole can lead to the dicloxacillin structure.Wefurtherextendtheapplicationsofo-chlorobenzaldehydethrough derivatizationproviding a new idea for the application of o-chlorobenzaldehyde in the future.