Computational Study On Reaction Mechanism Of The Quinazoline Derivatives Synthesis

The molecule structure of the quinazoline consists of a benzene ring and a heterocycle,which is an important unit in a lot of drug.Quinazoline represents a key structural motif in a large number of compounds used as ?-adrenergic receptor antagonists,anticonvulsants,antibacterial,psychosedative,antihypertensive,hypotensive compounds,or inhibitors of puromycin-sensitive aminopeptidase for pharmaceutical synthesis.The quinazoline derivatives have very broad prospects for development in the field of medicine.Therefore,the study on synthesis of related derivatives has become increasingly the focus of attention for many chemists.In this paper,we have carried out the density functional method M06 to unravel the reaction mechanism of metal salt catalytic synthesis of quinazoline derivatives studied in detail.The cesium salt and copper salt are used as catalyst,respectively.The main contents are as follows:In the first part,we mainly introduced the research progress on the synthesis of quinazoline derivatives,the selected research background,and significance.The second part briefly introduces the theoretical knowledge of the calculation methods used in the study of reaction mechanism,including ab initio self consistent method,density functional theory,transition state theory,and the computational software.In the third part,a series of density functional theory?DFT?calculations have been carried out to unravel the mechanism for Cs₂CO₃-catalyzed reaction between carbon dioxide with 2-aminobenzonitrile.Two kinds of reaction mechanisms involving either the 2-aminobenzonitrile coordinating to Cs₂CO₃ or CO₂ as the first step are examined.The preferred mechanism mainly includes carboxylative coupling and intramolecular rearrangement,each of which consists of different steps.The calculations show that the intermediate 5b is a key active specie,which is formed by carboxylative coupling,facilitating the later intramolecular rearrangement to give the final product.The rate-determining step of the catalytic cycle is concerted protonation and nucleophilic cyclization?4 ? 5b?characterized by a six-membered-ring transition state.As the pivotal catalyst,the multiple roles of Cs₂CO₃ have been elucidated.Additionally,further analysis is conducted on the reaction conditions?temperature and pressure?that could control the efficiency of Yogeshs' chemical fixation of carbon dioxide.The fourth part describes the detailed reaction mechanism of 2-bromophenyl and benzamide catalyzed by CuI.The cascade reactions were performed under air sequential Ullmann-type coupling and aerobic oxidation without addition of any ligand or additive under air.The Ullman coupling reaction process mainly contains replacement reaction,oxidative addition,reductive elimination,constructing C-N bond,and giving intermediate 22.In the whole Ullman coupling reaction of the catalytic cycle,the oxidation addition process?21 ? 15 ? TS?15/3b?? 3b?need overcome the highest energy barrier?29.5 kcal/mol?.Therefore,this step is the rate-determining step in Ullman coupling reaction.Subsequently,from the intermediate 22,the K₂CO₃-assisted cascade reactions,such as proton cyclization and aromatization,occurs to creat the target product 2-substituted quinazoline derivative.In this part,the aromatization process?29 ? TS?29/Product?? Product?need overcome the highest activation energy?41 kcal/mol?.Accordingly,we believe that this step is the rate-determining step of deproton cyclization and aromatization reaction.In the whole catalytic cycle,the catalyst CuI and alkali K₂CO₃ significantly reduce the activation energy required for the reaction and promote the smooth progress of the reaction.