Investigation On The Synthesis Of Quinoxaline,Isoquinolin-1(2H)-one And Imidazole Derivatives With Drug Activities

Polycyclic compounds containing one or more heteroatoms(N,O or S)are usually called heterocyclic compounds.They are indispensable parts of organic compounds with special biological activities.Among this,nitrogen-containing heterocyclic compounds are widely used in biology,drug,pesticide and material fields because of their special structures and high modifiability,and they are closely related to survival and life of human beings.Although nitrogen-containing heterocyclic compounds widely exist in nature products,organic synthetic chemists are interested in synthesizing them because of difficulties in exacting and low content.Therefore,it is always hotspot and difficulty to synthesize and modify nitrogen-containing heterocyclic compounds.Quinoxaline,isoquinolin-1(2H)-one and benzimidazole derivatives are important parts of nitrogen-containing heterocyclic compounds with excellent drug activities and played important roles in the treatment of human diseases.After studying for the synthesis of these compounds in recent years,we discovered that existing methods have some shortcomings,such as high reaction temperatures,expensive catalysts and multi-step reactions,which cannot meet the needs of these kinds of compounds.We have made deep study on bidentate-auxiliary-directed and palladium catalyzed C-H bond activation,I2-DMSO co-oxidation system,Ullmann reaction to construct C-N bond and CBr4 involved in construction of C-N bond.Based on these,we developed some new methods to synthesize quinoxaline,isoquinolin-1(2H)-one and benzimidazole derivatives and realized the e effective construction and modification of these compounds.In the introduction part,we gave a detailed introduction about application of the co-oxidation of I2-DMSO in the formation of C-C bond to synthesize organic compounds,the use of DMSO in participating in the reaction as a synthon besides solvent and oxidant.In addition,the reaction of the C-H bond activation catalyzed by palladium and directed by bidentate ligand and Ullmann reaction to construct heterocyclic compounds were also explained.We described the mechanisms and types of the reactions and listed some typical reactionsIn the second chapter,we reported an efficient synthesis of quinoxaline derivatives catalyzed by I2-DMSO.We described the biological activities and applications of quinoxalines.The reaction,using o-diaminobenzenes and ?-hydroxy ketone derivatives as reactants,I2 as additive and DMSO as solvent and oxidant,went through the process of oxidation,dehydration and ring-closing reaction,and gave the desired products in one pot with satisfying yields.The a-hydroxy ketones were oxidized by co-oxidant of I2 and DMSO,and I-generated in this process was oxidized to I2 by DMSO to the next step.I2 promoted the dehydration of a-carbonyl ketones and o-diaminobenzenes.This method provides an efficient and green way for the construction of quinoxaline derivatives.In the third chapter,we described the excellent biological and drug activities and developed an efficient synthesis of pyrrolo[1,2-a]quinoxalines promoted by Bronsted acid.The reaction was performed with 2-(1H-pyrrol-l-yl)aniline and ?-diketones as starting materials and TsOH as additive.The one-pot domino process included dehydration condensation,intramolecular nucleophilic addition and cleavage of C-C bonds.Both ?-diketones and ?-keto esters were well tolerated in this reaction and gave the desired products.The reaction can be conducted at room temperature when the ?-diketones bearing aliphatic groups.Besides,the by-product in this reaction can be recycled.In the fourth part,dimethyl sulfoxide involved one-pot synthesis of quinoxaline derivatives was introduced.2-(1H-pyrrol-1-yl)aniline was used as starting material in this method promoted by AcOH at 130 ?.The reaction condition was mild and the carbon source of the reaction,DMSO,was cheap and easy to be obtained.pyrrolo[1,2-a]quinoxalines,indolo[1,2-a]quinoxalines,imidazo[1,5-a]quinoxalines,and benzo[4,5]imidazo[1,2-c]quinazolines can be obtained in this method.It provides a new method in constructing varieties of nitrogen-containing heterocyclic compounds,which may be used in organic and medicinal chemistry synthesis.The next chapter presented a cascade method to synthesize isoquinolin-1(2H)-ones catalyzed by palladium via C-H bond activation.Isoquinolin-1(2H)-ones are effective structures of many clinical drug molecules,so it is necessary to synthesize this structure with efficient and direct ways.The reaction was performed with N-(quinolin-8-yl)benzamides and ?-bromo ketones,realized the couping of sp2 C and sp3 C through sp2 C-H activation.Then intramolecular nucleophilic addition occurred to give the cyclization products isoquinolin-1(2H)-ones.The C-C bond activation guided by bidentate ligands has attracted many interests in recent years.We applied this strategy to construct isoquinolin-1(2H)-one derivatives,providing a new method for the construction of nitrogen-containing heterocyclic compounds.In the sixth chapter,we described an efficient method to synthesize 1,2-disubstituted benzimidazoles catalyzed by copper.Disubstituted benzimidazole derivatives were effective skeletons of many commercial drugs.Scientists have been focused on the synthesis of these compounds,however traditional methods suffered from high reaction temperatures,multi-step reactions and other problems.Catalyzed by copper,more than 30 1,2-disubstituted benzimidazole derivatives were obtained in one pot with substituted 2-haloanilines and benzamides,going through a cascade process of Ullmann reaction and intramolecular nucleophilic addition.This strategy has potential applications in the synthesis of medical and biological compounds.The main content of the seventh chapter was the synthesis of N-(1H-benzo[d]imidazol-2-y1)benzamide derivatives.This skeleton was proved to have efficient drug activities;however the synthesis of this compound was rarely reported,so it was necessary to develop a simple and green method for these compounds.The method we presented was achieved by readily available 1H-benzo[d]imidazol-2-amine and ?-keto esters,promoted by CBr4 at 80 ? through constructing two new C-N bonds.Easily accessible reactants,simply operations and high atom economy made this strategy a useful method in organic and pharmaceutical chemistry.