Study On 2-Arylation Reaction Of N-Substituted Benzoimidazole Catalyzed By Cu And Their Pharmacological Activity

Parkinson's disease(PD)is a long-term neurodegenerative disorder that has affected 6.2 million people and resulted in about 117,400 deaths globally(data reported in 2015).There 's no cure for PD,but medications can provide relief from parkinsonian syndrome.L-DOPA(levodopa)has been used in the initial treatment of PD for over 30 years.However,it becomes less effective as the disease progresses and produces a complication characterized by dyskinesia.Therefore,the design and development of better dopamine agonists has become a research focus in antiparkinson drug studies.In 1997,Vimala et al.studied the anti-PD activity of U-95666E,which is a benzimidazole analog.It is found that U-95666E can selectively activate D2 dopamine receptor,while U-95666-hydrochloride increased locomotor activity in habituated rats and induced minimal stereotyped behavior.Producing a series of benzimidazole compounds,and screening their anti-PD activity,can provide information for the discovery of new anti-PD drugs.Previously reported synthetic methods for 2-arylbenzimidazoles include intermolecular cyclization reactions and transition metal-catalyzed direct arylation reactions.In general,intermolecular cyclization reaction is simple,low cost,and fast.As a result,it often results in relatively simple benzimidazole products.It is known that biologically active benzimidazole derivatives are often with complex structures.the transition metal catalyzed direct arylation reaction is more commonly used in the synthesis of 2-arylbenzimidazoles to obtain more complex products.Currently reported direct arylation reactions have a variety of disadvantages,such as cumbersome operation,catalyst,expensive ligand or alkali,limited substrate expansion,etc.Thus,it is particularly important to explore a simple,easy-to-operate,low-cost,widely applicable method for a variety of substrates.Compared to Pd and Ni,the price of Cu is relatively low.In this study,copper was chosen as the catalyst,and bromoarenes as the substrates.The reaction conditions were optimized to increase the yield and expand the substrate range,and the products were subjected to anti-PD activity analysis.This thesis is divided into three parts,the research background,research process,and the physiological activity of transition metal Cu catalyzed 2-arylation reaction of benzoimidazole compounds with aryl bromides.The first part described the significance of 2-arylbenzimidazole compounds,and summarized the synthetic methods of these compounds.The second part described the CuI/PPh3 catalyzed direct arylation reaction of benzimidazoles with aryl bromides.In our optimized method,a broad range of substrates could be adopted to afford diverse products with minor limitations.The third part described the anti-PD activity screening of the synthesized N-substituted 2-arylated benzimidazole derivatives.Among these compounds,2-(6-methoxy-2-naphthyl)-1-methylbenzimidazole showed the highest activity and can be subjected to further structural modification.