The Construction Of Heterocyclic Structures Via Arylglyoxal-involved Multicomponent Tandem Cyclizations

Heterocyclic compound is an important core framework widely found in various natural products,pesticides,pharmaceuticals and functional materials.In the field of synthetic chemistry and pharmaceutical industry,the synthesis of heterocyclic compounds has become a hot topic in the current research.However,the synthesis of heterocyclic compounds with diversity and complexity from simple starting materials is a very challenging research topic.At present,one of the most promising methods for constructing heterocyclic compounds is based on multicomponent tandem cyclization reactions.Multicomponent reactions are widely used in the fields of organic synthesis and biomedical synthesis because of its high reaction efficiency,great atom economy,simple operation,step economy,convergence,product structure complexity and diversity.The tandem cyclization reaction is based on the formation of multiple chemical bonds in one pot,leading to the formation of a ring or more.It can not only avoid the cumbersome operation of the step-by-step reaction,but also reduce the consumption of solvents and reagents.Thus,tandem cyclization reaction,as a most intuitive and effective method of synthesizing heterocyclic compounds with great economy and environmental friendliness,is widely concerned by organic synthetic chemists.In this thesis,the arylglyoxal-involved multicomponent reaction was used as the synthesis strategy with the tandem cyclization reaction as the medium,and a series of nitrogen,oxygen and sulfur-containing heterocyclic compounds with potential biological activity and pharmacological activity were designed and synthesized by the self-organization and integration of multiple unit reactions.The main contents areas follows:In chapter 1,we first briefly summarize the theory of multicomponent tandem cyclization system,and then review the research progress of multicomponent tandem cyclizations to synthesize heterocyclic compounds in recent years both domestically and abroad,including the study of multicomponent tandem cyclization reactions based on named reactions,transition-metal catalysis,acid/base mediation,small molecule catalysis or other conditions.Subsequently,we discuss the arylglyoxal-involved multicomponent tandem cyclization reactions for synthesizing polycyclic heterocyclic rings or fused ring compounds.At last,we present the research ideas of this thesis.In chapter 2,we described an acid-catalyzed multicomponent tandem double cyclization protocol for the synthesis of 4,9-dihydropyrrolo[2,1-b]quinazolines via the integration of condensation,nucleophilic addition,Michael addition,Henry cyclization and oxidative aromatization using arylglyoxal monohydrates,2-aminobenzylamine,and traps-?-nitrostyrenes as the substrates.This method achieved the construction of four new bonds and two ring moieties directly in one pot.Comparing with the previous literature,this method has the advantages of high efficiency,simple and readily available materials,mild conditions and easy operation.In chapter 3,we described an metal-free multicomponent tandem double cyclization protocol for the synthesis of dihydroindolizino[8,7-b]indoles via the integration of Pictet-Spengler cyclization,Michael addition,Henry cyclization,and oxidation aromatization using arylglyoxal monohydrates,tryptamines,and traps-?-nitrostyrenes as the substrates.We achieved the one-step direct synthesis of alkaloid analogs for the first time by in situ capture of the active intermediate 1-arylcarbonyl-tetrahydro-?-carboline.In chapter 4,on the basis of the above chapter,we chose arylglyoxal monohydrates and tryptamines as substrates to form the active intermediate 1-arylcarbonyl-tetrahydro-?-carboline,which could be captured in situ by cinnamaldehyde,dimethyl acetylenedicarboxylate or malononitrile to furnish a series of diverse substituted dihydroindolizino[8,7-b]indole derivatives.The reaction was based on the diversity-oriented synthetic strategy,which further reveal that compounds containing an?-amino ketone fragment have a wide range of applications in the synthesis of heterocyclic compounds.In chapter 5,on the basis of the rapid development of sp3 C-H bifunctionalization,we chose to use acetophenone as the substrate.The sp3 C-H of the methyl group was designed to be iodinated and oxidized to form arylglyoxal,which could be captured in situ by two 4-hydroxycoumarins to form bifunctional substituted aryl ketone.Then this intermediate underwent transesterification and oxidative aromatization to synthesize pyrano[3,2-c]chromene-2,5-dione derivatives.In contrast to the traditional metal-catalyzed sp3 C-H activation and bifunctional reactions,this method does not require the use of metal catalysts,ligands and other additives,possessing the feature of mild reaction conditions,wide range of substrates,economic and environmental friendly.In chapter 6,on the basis of the research of self-organizing reaction network,we proposed the combination of multicomponent tandem cyclizations and self-sorting reactions to build a novel multicomponent self-sorting domino cyclization reaction.We chose arylglyoxal monohydrates,nitriles,and thioureas as the reaction substrates to develop a solvent-controlled chemoselective synthesis of pyrrolo[1,2-c]imidazole and pyrrolo[1,2-c]thiazole derivatives.In chapter 7,all the works of this thesis are summarized,and the synthesis of heterocyclic compounds by the strategy of multicomponent tandem cyclizations is prospected.