Synthesis Of 2-Amino-benzoxazinones And 2-Amino-phenylglyoxylate Esters Based On Ring-Expanding/Ring-Opening Reaction Of Isatin

Isatin is an important class of nitrogen-containing heterocyclic compounds,belonging to the indole family of natural small molecules.Its structural fragments not only exist in many natural products,drug small molecules,and organic functional material molecules,but also are important starting materials for the synthesis of various complex indole alkaloids.Due to its unique chemical structure and abundant reaction sites,its related research has always been an important field of organic synthesis chemistry,mainly involving the types of chemical reactions such as oxidation reactions,spiration reactions,condensation reactions,ring-expanding reactions,and ring-opening reactions.This thesis mainly focuses on the ring-expanding/ring-opening reaction of the five-membered ring fragments of isatin,and the specific contents are as follows:In the first chapter,after summarizing the relevant literatures,the application of isatin and its derivatives in natural products in recent years was introduced.The common reaction types as reaction substrates are briefly summarized,mainly involving ring-expanding and ring-opening reactions of isatin.Subsequently,the applications of highly reactive halodifluoroalkyl reagents and cyclopropene in organic synthesis are introduced.Then,the main research ideas and content of this paper are proposed by designing the reaction of multiple sites of isatin with halogenated difluoroalkyl reagents and cyclopropene,respectively.In the second chapter,2-amino-benzoxazinone,as an important class of nitrogen containing heterocyclic compound and the core structural unit,is widely present in various biologically active molecules.This chapter establishes a new method for the synthesis of 2-amino-benzoxazinone compounds in CH₃CN in one-pot using readily available isatin,sodium chlorodifluoroacetate,and aliphatic amines as starting materials,tert-butyl hydroperoxide（TBHP）as oxidant,and K₃PO₄or Cs₂CO₃as base.The experimental results show that the ring-opening and ring-closing reaction of isatin occurs.The carbon atom at the 2-position of the benzoxazinone ring originated from an unusual quadruple cleavage of sodium chlorodifluoroacetate.Water also participates in the reaction and provides oxygen atom at the 3-position of the benzoxazinone ring.Finally,the target product is obtained through an intermolecular cyclization reaction between the intermediate isatin anhydride and the imine cation.Compared with traditional synthetic methods,this route has mild conditions,a wide range of substrates,and transition metal-free condiitions.In addition,amine substrates can be expanded to commercially available drug molecules such as mexiletine hydrochloride,fluoxetine hydrochloride,and tormoxetine hydrochloride.A total of forty-five compounds are synthesized and characterized by ¹H NMR,¹³C NMR,IR and HRMS.The structure of II-5a is verified by X-ray single crystal diffraction.In the third chapter,the applications and synthetic methods of2-amino-phenylglyoxylate esters in biological activities is introduced.This chapter reports the successful preparation of 2-amino-phenylglyoxylate esters under the catalysis of triphenylphosphine,using isatin,cyclopropene,and alcohol as starting materials in dichloroethane at room temperature.When the substrates are changed from alcohols to aromatic amine or thiols,the corresponding target product can also be obtained.However,phenolic compounds are not suitable for this reaction system due to their weak nucleophilicity compared to alcohols.This method has the characteristics of good substituent compatibility,mild reaction conditions,and high yield.The possible reaction mechanism suggests that triphenylphosphine catalyzes the ring-opening reaction of cyclopropene to form alkene structure,and then undergoes a nucleophilic addition reaction with the nitrogen atom in isatin to open the ring of isatin,forming 2-amino-phenylglyoxylate esters under the attack of alcohol.When Na OH is used as a base in methanol/ethanol,the corresponding 2,3-diaryl-4-ester substituted quinoline derivatives are obtained at 100 ^oC.A total of thirty-five target compounds are synthesized,all of which are characterized by ¹H NMR,¹³C NMR,IR and HRMS.The structure of III-6a has been verified by X-ray single crystal diffraction.