Synthesis Of Tetra-substitution Urea Derivatives By Palladium-catalyzed Decarbonylative C-N Coupling Reaction

Urea derivatives are a class of substances with unique biological activities,especially in anticancer,antitumor,active target molecules and inhibitors,and are widely used in fields such as medicinal chemistry;meanwhile,they also have strong hydrogen bonding ability,widely used in molecular recognition and organo-catalysis.Urea compounds are synthesized mainly by the nucleophilic addition of an amine to isocyanate.Utilization of transition metal catalysis can effectively synthesize urea derivatives,and at the same time,multiple functional groups can be introduced into the product.This synthetic method has attracted widespread attention from researchers.In this paper,urea derivatives were synthesized by the palladium-catalyzed intermolecular decarbonylation coupling reaction.Using arylcarbamoyl chloride as the substrate,the optimized experimental conditions obtained by the single variable method were:Pd(PPh3)4(5 mol%)was used as a catalyst,KHCO3(2.0 equiv)was used as a base,1,4-dioxane(1 mL)was used as a solvent,and the reaction was performed at 100? for 48 h.On this basis,the generality and limitations of the method are then studied,and finally 26 urea compounds with different substituents were synthesized,and the yield was good.The results show that when different types of functional groups are introduced into the substrate,urea derivatives with multiple functional groups can be prepared.This paper also discusses the reaction mechanism of the above-mentioned synthesized tetra-substituted urea derivatives.Under the catalysis of Pd(PPh3)4,this reaction undergoes an oxidative addition reaction between arylcarbamoyl chloride and zero-valent palladium(Pd0 changed Pd?),and the intermediate produced by the reaction undergoes decarbonylation C-N coupling After decarbonylation,it undergoes a nucleophilic addition reaction with another molecule of arylcarbamoyl chloride to achieve the synthesis of tetra-substituted urea derivatives.Finally,divalent palladium continues to participate in the catalytic cycle under the action of base,PPh3 and carbon monoxide make Pd?into Pd0,and finally realize the whole reaction cycle.In summary,this paper provides a method for preparing tetrasubstituted urea derivatives with simple operation and atom,step-economy.