Synthesis Of Polysubstituted Benzene Catalyzed By Metal/Organic Molecules

Benzene and its derivatives are important pharmaceutical intermediates.Multi-substituted benzenes with hydroxy and amide modifications have good biological activities such as anticancer,antiviral,and antiplatelet aggregation,attracting the attention of many researchers.The traditional methods for synthesizing multi-substituted benzenes mainly include electrophilic and nucleophilic substitution on the benzene ring and transition metal-catalyzed cross-coupling reactions.However,these reactions still have certain limitations,such as harsh reaction conditions,poor tolerance to functional groups,production of toxic by-products,and poor atom economy.This article focuses on the synergistic catalytic effects of transition metal catalysts and organic small-molecule catalysts,and develops an efficient,simple,and economical synthesis route for tetrasubstituted benzene and its derivatives.The specific research contents are as follows:(1)Using α,β-unsaturated aldehydes and cyanoacetic acid alkyl esters as substrates,explore the synergistic catalytic effect of transition metal catalysts and organic small-molecule catalysts.(2)Through experimental exploration,silver hexafluoroantimonate and pyrrolidine are used as synergistic catalysts,potassium carbonate is used as a base,and at a temperature of 100°C,a series of tetrasubstituted benzene compounds are efficiently synthesized in one pot with excellent yield in toluene.(3)The investigation of the substrate scope shows that reaction substrates containing electronwithdrawing and electron-donating groups have good tolerance to functional groups.The product structure is determined using 1H NMR,13 C NMR,and HRMS.(4)Based on the reference literature,design control experiments and speculate on the corresponding reaction mechanism.(5)Derivatization of tetrasubstituted benzene products,such as hydrolysis and sulfonamide reaction.In summary,this article develops a new catalytic system of metal catalysts and organic small molecules,and efficiently synthesizes tetrasubstituted benzene compounds through Michael addition,Knoevenagel condensation,and Thorpe-Ziegler cyclization between α,β-unsaturated aldehydes and cyanoacetic acid alkyl esters in one pot.The method has low-cost raw materials,simple operation,high yield,mild reaction conditions,and a wide range of applicable substrates,which not only enriches the content of organic synthesis methodology but also provides a new pathway for the synthesis of tetrasubstituted benzene.