Palladium-catalyzed Ortho-bromination And Derivatization Of Benzaldehydes Using Transient Directing Group

Transition-Metal-Catalyzed C-H activation using the transient directing group which is a kind of auxiliary molecules has becomes useful tool in synthetic chemistry.With the strategy of transient directing group,the highly valuable functionally tolerant reagent can be reversibly linked to the substrate and serve as a directing group.Upon C-H activation and subsequent functionalization,this reagent would dissociate from the product and transiently link to another substrate molecule.This method of transient directing group could be more efficient and selective to achieve C-H bond functionalization.This dissertation mainly focused on the studies of ortho-C(sp~2)-H bromination of benzaldehydes with the weakly coordinating transient directing group directed C-H activation,which include:1.Palladium-catalyzedortho-brominationofbenzaldehydesusing transient directing group.Compounds containing brominated aromatic structures are widely found in drugs and bioactivity molecules.2-Bromobenzaldehydes also are useful synthetic intermediates used for the synthesis of drug molecules.A palladium-catalyzed ortho-bromination of benzaldehydes leading to 2-bromobenzaldehydes has been accomplished.In the presence of catalytic palladium,benzaldehydes and N-bromosuccinimidesmoothlyundergothetransientDG-mediatedC-H functionalization.2-amino-4-nitrobenzoic acid demonstrated as an effective bidentate transient directing group and it formed in situ via imine linkage can directing C-H activation.Furthermore,palladium-catalyzed bromination using bidentate amino acid-type transient DG can override and tolerate the directing effects of a wide range functional groups present within the aldehyde substrates,such as ester,carbmate,amide,nitrile and sulfone.C-H bromination also could be performed on celecoxib analogues using transient DGs.We supposed that ortho-bromination of benzaldehydes involving the transient directing group formed in situ via imine linkage might be the turnover-limiting step,which is capable of C-H activation.2.Derivatization of substituted 2-bromobenzaldehydes.Combinations of the bromine site and the carboxaldehyde sites of2-bromobenzaldehydes in cascade reactions have been successfully used for the synthesis of diverse benzoheterocyclic compounds or drug with the key motif.A series of benzothiophenes,benzopyransrenes,indenones,isoquinolines,indole-like derivatives can be synthesized by derivatization of 2-bromobenzaldehydes,Many heterocyclic compounds have the key structure of drug or bioactive molecules,which may have potential application value.We developed a series of derivatization reactions with 2-bromobenzaldehydes as the substrate,the utility of this approach is demonstrated through multiple applications,including late-stage diversification of a drug analogue,which has broad application prospects for drug synthesis and new drug development.