Study On The Intramolecular Cyclization Of N-Alkoxyamide Compounds Under Metal-Free Conditions

Nitrogen-containing heterocyclic compounds are rich in species and diverse in structure,and are widely used in the fields of medicine,pesticides and materials,especially accounting for a large proportion of small molecule drugs that have been approved.Therefore,the synthesis of nitrogen-containing compounds has always been the research focus of organic chemists and pharmaceutical chemists,and the development of green,efficient,and sustainable synthetic strategies has great significance.In this paper,the isoquinolinone skeleton and the cycloheptatriene skeleton containing nitrogen heterocycles constructed under metal-free conditions have rich and diverse biological activities,and are widely found in natural products and drug molecules.In this paper,a strategy for rapid synthesis of isoquinolinone derivatives catalyzed by PIDA,a high-valent iodine reagent,was established.Polycyclic six-,seven-and eightmembered N-heterocycles can be rapidly synthesized from available amides under metal-free conditions within 1 min at room temperature through C–H/N–H functionalization.This reaction has a wide range of substrates and 44 novel compounds were synthesized,the corresponding products can be obtained in a maximum yield of 99%.In addition,a scale-up reaction study was conducted,and the gram-grade reaction yield was excellent,proving that the reaction has the potential for large-scale preparation.At the same time,a general and practical protocol for the construction of isoxazolidine-fused isoquinolin-1（2H）-ones has been described by electrochemical-oxidation-induced intramolecular annulation via amidyl radicals using the same substrate.In an undivided cell,isoquinolinones could be easily generated from various available amides bearing CONHOR groups under metal-free,additive-free and external oxidant-free conditions.It is worth mentioning that this reaction uses cheap and readily available 95%ethanol as a green solvent and can be extended to the gram scale.In addition,we have established a new strategy for the expansion of the intramolecular benzene ring into a seven-membered ring using Ph I（OAc）₂ as a promoter.The traditional ring expansion reaction of benzene ring can be achieved by Rh-carbene produced from Rh（II）catalyst and diazo compound.Herein,we have developed a metal-free intramolecular benzene ring expansion reaction to construct[6,5,7]heterocyclic-fused lactam.The reaction has obvious advantages over the traditional ring expansion method.The reaction conditions are mild and can be carried out at room temperature,and he operation is safe and simple,the reaction is rapid,and the conversion can be achieved within one minute.In addition,1,3-diene can be easily obtained by subsequent heating under this strategy.We have characterized all the synthesized compounds by ¹H NMR,¹³C NMR,and HRMS,and by single crystal X-ray diffraction,compound 2ao in chapter 2 and compound 2i in chapter 4 were analyzed to determine the structure of corresponding product.