Synthesis Of Indole-containing Azaspiro Compounds Via Isatin Derivatives

Aza spirocycles containing indole structures are an important class of oxindolespirocycles,which also exist as core backbones in many natural alkaloids and drugs with a wide range of biological and pharmacological activities.Therefore,the research on the synthesis of aza spirocycles containing indole structures can not only provide an efficient and simple synthesis method for new indole spirocyclic derivatives and expand their applications,but also further provide a research basis for biological activity studies,which is not only of important academic value but also of potential application and social value.Multi-component reactions（MCRs）are an effective method for the rapid and bulk synthesis of organic compounds with complex and diverse structures,and are now widely used in synthetic chemistry and medicinal chemistry.In addition,MCRs are green,fast and efficient,with high atomic economy,high regioselectivity and stereoselectivity.Therefore,multicomponent reactions are very suitable for the synthesis of spirocyclic compounds with diverse substituents and complex structures.In this thesis,three methods for the synthesis of novel indole-containing structures of aza spirocyclic derivatives were constructed using multicomponent reactions,and a total of 60 aza spirocyclic compounds containing indole structures were synthesized,which were divided into the following three parts.The first part investigated the synthesis of a series of spiro[4H-pyridine-3,3’-indolones]analogues using a three-component reaction between an indole derivative,three different active 1,3-dicarbonyl compounds and4-aminocoumarins in the aqueous phase.The optimal reaction conditions were determined by screening the reaction conditions such as solvent,temperature and catalyst to optimize the reaction.Twenty-seven derivatives of spiro[4H-pyridine-3,3’-indolones]analogues（TM-01～TM-27）were reactively synthesized under the optimal reaction conditions and structurally characterized by elemental analysis,¹H NMR,and ¹³C NMR.In addition,we initially explored the reaction mechanism,deduced the possible reaction course,and tested the antibacterial activity of some products,which its inhibitory activity against apple verticillium reached more than 60%.This method has the advantages of easy availability of raw materials,simple reaction operation,safety,high yield and environmental friendliness,and the target compounds exhibit antibacterial activities,which are valuable for further studies.In the second part,we investigated the efficient synthesis of indolespiro[4H-pyrido[3,2-c][5,6-c]bicoumarins]derivatives from an indole derivative,two molecules of 4-aminocoumarin as a three-component reaction.The optimal reaction conditions were determined by screening the solvent,temperature,catalyst and other reaction conditions.Twenty-one indolespiro[4H-pyrido[3,2-c][5,6-c]bicoumarins]analogues（TM-28～TM-48）were synthesized by reaction under the optimal conditions,and the structures were characterized by elemental analysis,¹H NMR,and ¹³C NMR.In addition,we initially explored the reaction mechanism,deduced the possible reaction course,and tested the antibacterial activity of some of the products,and the results showed that its inhibitory activity against apple verticillium reached more than 60%.The synthesis method is characterized by short reaction time and high yield,good generalizability and simple reaction treatment,and the target compounds exhibit antibacterial activity,which are valuable for further studies.In the third part,a series of novel indolespiro[benzofuran-2,2’-pyrrolidine]analogues were successfully constructed by a one-pot method using indole derivatives,6-hydroxyheptanone derivatives and benzylamine as raw materials.The optimal reaction conditions were determined by screening the solvent,temperature and catalyst and other reaction conditions.Twelve indolespiro-pyrrolidino derivatives（TM-49～TM-60）were synthesized under the optimal conditions,and the structures were characterized by elemental analysis,¹H NMR,and ¹³C NMR.In addition,we preliminarily explored the reaction mechanism,deduced the possible reaction course,and tested the anti-TMV activity of some products against tobacco mosaic virus（TMV）.The results showed that the anti-TMV activity of TM-58 was between that of the positive control agents ninhydrin and ribavirin,with good inhibition.The synthesis method,which requires no catalyst,mild reaction conditions and simple reaction processing,and the target compounds exhibited anti-active TMV,which are valuable for further studies.