Studies On Multicomponent Reaction Triggered By Heterodimerization Of Isocyanides

Heterocyclic compounds are the most common organic compounds.As an important branch of heterocyclic compounds,nitrogen-containing heterocyclic compounds have diverse structures and important biological activities,and are widely used in many fields such as organic synthesis,medicinal and material chemistry.Therefore,the development of efficient and new methods of nitrogen-containing heterocyclic compounds has attracted much attention.Isocyanides are a very important class of organic synthons,which has unique chemical properties and rich reactivity.Isocyanide-based multicomponent reactions（IMCRs）can efficiently and rapidly construct complex and diverse products from simple and easily available raw materials,and have been widely used in the synthesis of natural products,drug molecules and nitrogen-containing heterocyclic compounds with biological activities.In recent years,the cross-heterocyclic reaction of two different isocyanides has become an important method to construct nitrogen-containing heterocycles and attracted increasing attention.Generally,the vast majority of these reactions are focused on self-reactions or two component reactions of isocyanides,which limits the practicality of generating molecular diversity.However,multicomponent reactions based on dimerization of isocyanides have been far less explored probably due to the difficulties in controlling the chemoselectivity of reactions.Therefore,the development of multicomponent reactions involving the dimerization of isocyanides will further enrich isocyanide-based multicomponent reactions,which has important scientific and application value.This thesis is devoted to the development of new multicomponent reactions triggered by heterodimerization of isocyanides,and the development of concise and efficient new synthetic strategies for many important nitrogen-containing heterocyclic compounds such as indole-substituted quinolones and pyridines,poly-substituted/fused ring quinoxalines.The thesis is mainly divided into four chapters:The first chapter introduces the structure and properties of isocyanides,summarizes the multi-component reactions and cross-heterocyclic reactions in which isocyanides participates,and puts forward the basis of this thesis.The second chapter,the first highly chemoselective heterotrimerization reaction between o-alkenyl aryl/conjugated dienyl isonitrile and aryl isonitrile was developed,which provided a new synthesis method with high efficiency and high atomic economy for indole-substituted quinoline and pyridine derivatives.The reaction may undergoe the"head-to-head"cross-coupling of two different isocyanides to form a nonsymmetrical 1,4-diazabutatriene intermediate,and then[4+1]cyclization tandem reaction with another isocyanide.This tandem reaction not only realized the chemoselective trimerization of three different isocyanides for the first time,but also formed four C-C bonds and two heterocyclic rings in one step,and also had the advantages of wide substrate adap Tableility,no need of catalyst and 100%atomic economy.In the third chapter,multicomponet reactions of ortho-diisocyanoarenes,isocyanides and water/alcohol were developed under catalyst-free conditions.In the reaction,water/alcohol was used as both reactant and reaction solvent,which provided an efficient and green new synthesis method for a series of quinoxalin-2-carboxamides and quinoxaline-2-carbimidates with diverse structures.In addition,the mechanistic studies showed that the chemoselective heterodimerization of two isocyanides produced a novel quinoxaline-based zwitterionic intermediate,and this kind of intermediate was first found in the isocyanide-based multicomponent reactions.The intermediate can be hydrolyzed to obtain a series of amidoquinoxaline derivatives;Alcoholysis reaction with alcohol produces a series of iminoquinoline derivatives.In addition,the reaction can be scaled up in gram scale and successfully applied to the simple synthesis of several bioactive molecules,which proves the practical application potential of this method.In the fourth chapter,three-component reactions of ortho-diisocyanoarenes,isocyanides with TMSCN/TMSN₃/electron-deficient olefins or phenyl acetate were developed without metal catalysis,which provided a simple and efficient new strategy for the diversified synthesis of 2,3-disubstituted quinoxalines and condensed ring quinoxalines.The remarkable characteristics of this new tandem reaction include a wide range of substrates,high atomic economy,no catalyst,simple and accessible raw materials and simple operation.The multicomponent reaction initiated by heterodimerization of ortho-diisocyanoarenes and isocyanides will provide an efficient and universal new synthesis method for quinoxaline derivatives with diversified structures and substituents.