Copper-catalyzed C-H Bond Activation To Construct Novel N-alkenyl Benzimidazole Derivatives

The chemical compounds with N-alkenyl structure were widely discovered in many natural products and pharmaceutical molecules,exhibting excellent biological activities.For example,both(±)-ξ-Clausenamide and(+)-SB-204900 with many pharmacological effects,extracted from the Clausena lansium(Lour.)Skeels,also possessed the N-alkenyl structure.The unique structure of the N-alkenyl compounds,especially enamine derivatives,are broadly used as building blocks for complex compounds and important pharmaceutical intermediates in organic reactions.In polymer chemistry,these compounds can also be utilized as monomers in the polymerization process.N-alkenyl pyrrolidones(NVP),for instance,are applied to synthesize economically important polymers.Enamines contain a double bond and a nitrogen atom,which can coordinate with various transition metals.Therefore,they are many core ligands of metal complexes.Besides,the enamine compounds can be applied to synthesize poly-substituted heterocyclic compounds,which are difficult to be obtained by using traditional strategies.The related research indicated that these compounds have been employed in the separation of metals,the extraction of polar compounds,the purification of cosmetics and the preparation of dyes.In addition,the N-alkenyl imidazoles are also found have excellent antifungal and antiparasitic effects in the pharmaceutical and pesticide fields.It is also the goal of researchers to find a simple and suitable method for the synthesis of new N-alkenyl benzimidazole derivatives with potential biological activity.C-H bond activation is known as the holy grail in the field of organic chemistry,and the selective activation of C-H bonds is also the pursuit of chemical researchers.The transition metal catalyzed C-H bond activation system has a good functional tolerance to the reaction substrate.Most of the reactions reported in the literatures are applicable to halogen,amide,nitro and ester groups,and thus have been popular in organic chemistry.With the in-depth study of transition metal-catalyzed C-H bondsactivation,the catalyst is converted from transition metals such as Ru,Ir,Rh and Pd to relatively inexpensive Cu catalysts,and the reactions can be carried out under milder conditions.In organic synthesis,the synthetic routes of complex compounds require multi-step reaction,which involve complicated purification and separation processes.In the point of green and economic chemistry,to reduce the unnecessary workload,as far as possible to avoid separating intermediates and saving time is necessary.The domino reaction is that the multiple processes are combined into one synthetic operation without any separation of intermediates,and the materials finished a number of reactions processes.Because of its easy operation,without separation of intermediates,good yields and high efficiency,fully demonstrated the superiority compared to traditional methods,thereby the domino reaction has been active in the forefront of organic chemistry research and reported extensively in the synthetic chemistry literature.In this dissertation,we have demonstrated that the C-N bond formation of N-alkenyl benzimidazoles via intermolecular tandem aza-Michael addition occurred from iodination of the C-H bond and dehydrohalogenation as well as the intramolecular formal α,β-dehydrogenation of benzimidazole esters initiated by the iodide anion under copper catalysis.The method has good functional group tolerance to the benzimidazole containing large conjugated rings,methyl,ester,nitro,and halogen,and these functional gruops also can be further modified to obtain more innovative and potentially bioactive azole compounds.However,the 2-substituted of benzimidazoles and the α-orβ-substituted acrylates have steric hindrance effects,which has a great influence on the reaction and the isolated yields of the target products were remarkably reduced.Both intermolecular and intramolecular reactions included tandem processes,in which selective iodination of sp3C-H bond at the α-position of ester under mild conditions was demonstrated for the first time.Tandem reactions involving sp3 C-H activation viaα-iodo ester intermediate under copper catalysis efficiently provided more than 20 novel azole compounds,and free radicals were not involved in this transformation.All the molecular structure of the compounds were confirmed by high resolution mass spectrometry,1H NMR,13 C NMR and Infrared spectroscopy.In addition,the spatial configuration of product 4a was confirmed by X-ray crystallographic analysis.Exploring the reaction mechanism,we have found an significant intermediate(α-iodoester).It was further confirmed that the mechanism is the aza-Michael addition reaction of benzimidazoles and acrylates,then Cu-catalyzed C-H functionalization toobtain α-iodoester intermediates,and finally dehydrohalogenation to get the target product.In the control experiment,we found that Cu catalyst played an important role in the activation of α-H in the ester,but had a little influence on the subsequent reaction,and the base can not be ignored in the dehalogenation.And in our reported method,iodide esters produced under mild conditions can also serve as a key intermediate for many pharmaceutical reactions.Since most of the benzimidazole derivatives have biological activity,therefore,we also tested the antibacterial activity of the N-alkeny benzimidazole derivatives.Compared with the experimental study of our previous group,it was found that the antimicrobial activity of some compounds was significantly enhanced after dehydrogenation,even the MIC value of some compounds was lower than that related drugs.At the same time,we also found that the antimicrobial activity of compound 4i is generally good,with moderate or strong antibacterial activity,which is expected to further develop as an antibacterial drug.We believed that this protocol described here would provide a viable methodology for synthesizing a series of potential biologically active N-alkenyl azole derivatives.Further studies of functionalizing benzimidazoles and other heterocycles are future goals of our group.