Synthesis Of Isoquinolinones And Isoindolinones Based On Molecular Editing

Molecular editing techniques include peripheral editing and skeletal editing,and C-H bond functionalization,a hot research topic in molecular peripheral editing strategies,has evolved from an abstract concept to a practical synthetic tool.It provides an efficient and cost-effective synthetic route for late-stage functionalization of important molecules.Single-atom"insertion"and"deletion"skeletal editing techniques are still in the early stages of development,and it is still challenging to achieve a wide range of applications for skeleton transformation.Currently,the substrates used in skeletal editing are mainly cyclic ketones,pyridines,imidazoles and pyrroles,and the range of substrates is somewhat limited.Therefore,the breadth of substrates in skeletal editing technology needs to be further investigated.Isoquinolinones and isoindolinone derivatives have a wide range of biological activities and are important compound backbones in new drug development.Due to the unique physicochemical properties of fluorine atoms,the introduction of fluorine atoms into organic compounds usually significantly enhances their biological activities.At present,the synthesis of fluoroisoquinolones has been studied with some limitations.Based on the previous research of the group,this thesis develops a Cp*Rh（III）-catalyzed C-H bond activation method for the synthesis of difluorinated substituted isoquinolinone derivatives;based on this,an efficient method for the synthesis of five element ring of isoindolinone derivatives from six element ring of isoquinolinone derivatives by a skeletal editing single carbon atom deletion strategy is intensively investigated.This thesis mainly includes the following two parts.Part Ⅰ:it is the efficient construction of fluorinated isoquinolinones by C-H bond activation reaction,which is catalyzed by Cp*Rh（III）for the C-H bond activation and cyclization/addition reaction of N-methanobenzamide analogues containing fluorine coupling reagents.The reaction was carried out using inexpensive and readily available fluorovinyl sulfonate and benzamide analogues as raw materials.And the optimal reaction conditions were finally obtained by screening the reaction solvent,catalyst type,dosage,temperature and additives:5 mol%[Cp*Rh Cl₂]₂,2.0 equivalents of sodium acetate,water as solvent,and 80^oC for 10 hours.A series of fluoroisoquinolone derivatives were prepared under the optimum conditions.Part Ⅱ:it is the skeletal editing technique to construct isoindolinones.The method is to obtain isoindolinone derivatives by single-atom carbon deletion under mild reaction conditions using isoquinolinones constructed by rhodium-catalyzed peripheral editing technique as substrates.After screening the reaction solvent,the type and amount of oxidant and the temperature,different types of isoindolinones were prepared in moderate to high yields using inexpensive m-chloroperoxybenzoic acid（m-CPBA）as the oxidant.In the future,this method will provide a new direction for the development of skeletal editing techniques.This method can provide a new direction for the development of skeletal editing and an important synthetic pathway for the synthesis of biologically active isoindolinone derivatives.