Investigation On The Synthesis Of Quinoxaline,Benzimidazole And Quinazolinone Derivatives

Cyclic compounds containing heteroatoms such as oxygen,nitrogen and sulfur are called heterocyclic compounds.Nitrogen-containing heterocyclic compounds are widely used in biomedicine,pesticides,organic optoelectronic materials,catalysts and ligands in organic synthesis because of their unique properties,which are a very important part of organic compounds.Heterocycles such as pyrroloquinoxaline,benzimidazole,and quinazolinone are indispensable components of nitrogen-containing heterocycles.In recent years,researchers have continued to report the synthesis and functionalization of these nitrogen-containing heterocycles.With the deepening of research,new synthetic methods have shown a trend of green and controllable condition with high atom economy.However,there are still a considerable number of synthetic methods that have shortcomings,such as the need for multi-step reactions,noble metal catalysts,high temperature,excess oxidants,etc.On the basis of extensive investigation of previous synthesis methods,we focused on green synthesis and functionalization of pyrroloquinoxalines,benzimidazoles and quinoxalinones,and constructed a series of nitrogen-containings molecule libraries.In the introduction part,we introduced the Kornblum Oxidation,explained the mechanism of the reaction in detail,and summarized the research progress of the reaction;summarized the quinoxaline-benzimidazole heterocyclic rearrangement reaction,especially the Mamedov Heterocyclic Rearrangement,and its application and rearrangement mechanism are described in detail;introduced the application of N,N-dimethylformamide as an organic synthesis precursor in compound modification and cyclization reactions;introduced typical research progress on trifluoromethylation reagents and(hetero)aromatic trifluoromethylation.Finally,we introduced the biological activities of pyrroloquinoxalines,benzimidazoles and quinazolinones and their applications.In Chapter 2,we introduced a potassium iodide-promoted one-pot synthesis of 4-phenylpyrrolo/indolo[1,2-a]quinoxalines.The synthetic method used 1-(2-aminophenyl)pyrrole/indole and benzyl bromide as starting materials,potassium iodide as promoter,dimethyl sulfoxide as solvent,and the reaction was carried out at 120℃ without other catalysts and the target product could be obtained.In this method,benzyl bromide first underwent Kornblum-type Oxidation in the presence of potassium iodide and dimethyl sulfoxide to give a benzaldehyde intermediate,followed by Pictet-Spengler type Reaction with benzaldehyde and 1-(2-aminophenyl)pyrrole/indole,that is,after condensation and dehydration of amino group and aldehyde group,intramolecular cyclization and aromatization occured to obtain the target product.We obtained a series of 4-phenylpyrrolo/indolo[1,2-a]quinoxaline compounds by this method.This method has mild conditions,simple operation,good substrate applicability and potential drug synthetic value.In Chapter 3,we introduced a rearrangement reaction of quinoxalinone to benzimidazole.Based on the foundation of the work in Chapter 2,we understood that 1-(2-aminophenyl)pyrrole has the property of dual nucleophilic sites,and render it react with quinoxalinone under acidic conditions in order to obtain quinoxaline benzenediol azepinocyclic product,which unexpectedly yielded 4-(1H-benzo[d]imidazol-2-yl)pyrrolo[1,2-a]quinoxaline,the product of rearrangement of quinoxalinone to benzimidazole.After literature research,it was found that this reaction is similar to the Mamedov-type Heterocyclic Rearrangement reaction.Compared with the conditions that the reaction requires reflux,this method was conducted at room temperature,and the conditions are milder.We use 1-(2-aminophenyl)pyrrole and quinoxalinone as raw materials,acetic acid as solvent,and react at room temperature for 3 days to obtain the target product.This method has good substrate applicability and could obtain a series of 4-(1H-benzo[d]imidazol-2-yl)pyrrolo[1,2-a]quinoxaline in good yields.This strategy has certain significance in synthetic methodology and provides a good complement for the quinoxalinone-benzimidazole heterocyclic rearrangement.In Chapter 4,we introduced N,N-dimethylformamide as a carbon synthon involved in the cyclization of pyrrole/indolo[1,2-a]quinoxaline and quinazolin-4-one.We used 1-(2-aminophenyl)pyrrole/indole and 2-aminobenzamide as starting materials respectively,elemental iodine as accelerator,N,N-dimethylformamide as solvent and reactant.The corresponding pyrrolo/indolo[1,2-a]quinoxalines and quinazolin-4-ones can be obtained in good yields.We focused on exploring the mechanism of N,N-dimethylformamide participating in the reaction,including the reaction process of methyl group and aldehyde group.We explored the source of the carbon involved in cyclization by controlling the variables to allow the methyl group and the aldehyde group to participate in the reaction,respectively.Through a series of control experiments,we determined that both the methyl group and the aldehyde group of N,N-dimethylformamide could participate in cyclization under this reaction condition simultaneously.This discovery provides a new idea for N,N-dimethylformamide as a precursor for organic synthesis.In Chapter 5,we described the cyclotrifluoromethylation of quinazolin-4-ones with trifluoroacetic acid.We used 2-aminobenzamide and 10 equivalents of trifluoroacetic acid as starting materials,1,2-dichloroethane as solvent,and reacted at 140℃ for 4 h to obtain a series of 2-trifluoromethylquinazolin-4-ones in good yields.This protocol has simple conditions and easy operation.Compared with the multiole step method reported by the previous research,this method can complete the trifluoromethylation in one step without any other catalyst or oxidant and avoids complicated post-treatment.The reaction underwent condensation of amino group and carboxylic acid,intramolecular ring formation,and dehydration to obtain the target compound,which provides a new strategy for the trifluoromethylation of heterocycles.