Theoretical Study On The Reaction Mechanism Of Pd/Ag-Catalyzed Synthesis Of Benzimidazolone Derivatives

Benzimidazolones have a benzene ring and a heterocycle containing two C-N bonds,which can be used to prepare a number of important organic compounds.The benzimidazolone derivatives are used as receptor antagonists,receptor agonists,HSP90inhibitors,or synthetic drugs for the treatment of hereditary diseases,gastrointestinal,lung diseases.Due to its outstanding pharmacological activity and broad application prospects in the field of medicine,the theoretical research on the synthesis of benzimidazolone derivatives is of great significance.The detailed mechanism of the Pd/Ag catalyzed synthesis reaction of benzimidazolone derivatives with?hetero?aromatic amines and isocyanates has been studied by Density functional theory computations?DFT?.The main research contents are divided into following three parts:First,the experimental research progress on the synthesis of benzimidazolone derivatives,and the theoretical research progress of Pd/Ag catalyzed reaction are introduced.Second,the relevant theoretical knowledge and calculation methods of the research reaction mechanism are introduced,including ab initio self consistent method,density functional theory,and related computing software.Third,a series of density functional theory calculations,employing M06 method,have been used to unveil the detailed mechanism for the Pd/Ag catalyzed reaction between aromatic amines and isocyanates.The reaction mechanism is mainly divided into three processes of C-N coupling,N-H activation and single electron transfer?SET?,and there are different paths in each process.The C-N coupling process initially begins with the Pd?OAc?₂coordination on the N atom of isocyanate,followed by intermolecular nucleophilic attack with N-methylaniline.The formation of C-N bond needs to overcome the highest energy barrier?27.3 kcal/mol?which is the rate-determining step in this reaction.In the activation step of the N-H bond,two different reaction pathways are proposed:path I and path II.In path II,N1-H activation produces intermediate 7 and transfers H to the O1 atom through an eight-membered ring transition state TS_2-6,which only overcomes the energy barrier of 23.2kcal/mol and is more advantageous than the path I of H migrating to the N2 atom.The calculations indicate that intermediate 7 is an important active species for single electron transfer,and the conversion between the experimental detected intermediate 5 is a reversible equilibrium process.In the process of single electron transfer,the Pd/Ag bimetallic catalytic path and Ag single-metal catalytic path are calculated,and the calculation shows that the intramolecular single electron transfer process catalyzed by Pd/Ag bimetallic is the optimal pathway.In order to explore the role of oxidants,two kinds of intramolecular single electron transfer paths of AgNO₃ as an oxidant are calculated.The results show that the energy barriers of the two paths are too high to occur.In the whole catalytic cycle,Pd?OAc?₂ and Ag₂CO₃greatly reduce the activation energy required for the reaction and promote the smooth progress of the reaction.In addition,the effect of substituents on the reaction is also studied.The energy barrier of the rate-determining step with different substituents is calculated and the results show that the reaction is universal to the substrate of substituents with different electronic effects,which are consistent with the experimental conclusion.