Study On The Oxidative Coupling Reaction Of N-heterocycles With Aldehydes Mediated By Tert-butyl Hydroperoxide/Trifluoroacetic Acid

Objective In recent years, the study found that N-heterocyclic compounds at the C1 position is benzylation or benzoylation and widely exist in bioactive natural products and synthetic drugs, and these natural products and synthetic drugs has antitussive, antipsychotic, antispasmodic, anxiolytic, anti bacteria, anti fungal, and anti-cancer biological activity. Therefore, to find a simple and efficient method for the synthesis of these compounds has become the focus of attention of many researchers. In this paper, we can find a new kind of oxidation system, namely TBHP/TFA oxidation system, which is the direct activation of C-H bond to carry out the direct synthesis of the compound.Methods First, at the beginning of the study, we refer to the literature, to have the preliminary understanding to the development of more mature several oxidative coupling system in recent years; and then makes a summary of the oxidation system of the N-heterocyclic compounds. On the basis of this, we put forward the design ideas of the subject. First, we select the relatively simple structure of isoquinoline and benzaldehyde reaction as a template to study, in order to obtain the optimum reaction conditions, respectively of oxidizing agents, acids and solvents and oxidant, acid dosage, reaction temperature were optimized.After obtaining optimal reaction conditions, we extend the types of substrates, structure. First aldehyde substrate extend, respectively, with different electrical group substituted benzaldehyde and several aliphatic aldehydes, isoquinoline react with these types of substrates on the reaction system has good compatibility, the results can get the products we expected and higher yield; then we have extended the N-heterocyclic compounds,these N-heterocyclic compounds also has good compatibility with the CDC reaction system we have established. The experiment showed that we establish this system has good applicability and achieve higher atom utilization efficiency and shorter synthetic route. In the final stage of the experiment, we studied the mechanism of this reaction.Results We obtain the best reaction conditions: the oxidant is TBHP(0.75 mmol, 3 equivalent), the solvent is DCE(1.0 mL), the additive proton acid is TFA(0.25 mmol, 1 equivalent), the reaction temperature is 110. These N-heterocyclic compounds and aldehydes have good compatibility with the CDC reaction system we have established.Conclusions The system we have established has good applicability, and can achieve higher atomic efficiency and shorter synthetic route, and the system does not need metal participation, which is of great significance in the field of organic synthesis.