ZrCl₄-catalyzed Nucleophilic Dearomatization Of Hydroxypyrimidines

Dihydropyrimidones have a wide spectrum of biological activities and play an important role in the field of medicine.At present,the dihydropyrimidine ketone compounds synthesis mainly depends on the multicomponent Biginelli reaction,though the method has been relatively mature,able to effectively synthesize dihydro pyrimidine ketone compounds,but subject to the conditions of reaction substrate type,usually only on chiral carbon connection aryl and alkyl,to some extent,limits the diversity of structure.In view of its role in drug development,it is of great practical significance to develop new and efficient synthetic methods for the preparation of novel dihydropyrimidone compounds.Aromatic compounds exist widely in nature,are cheap and easy to obtain,and are ideal synthetic raw materials.In recent years,great progress has been made in the efficient introduction of substituents to various aromatic rings through dearomatization reactions.Pyrimidine is a six-member azoaromatics compound with strong aromatic stability.Dearomatization of pyrimidine is very difficult.So far,there have been few successful reports.When hydroxyl groups are attached to a pyrimidine,a ketone-like tautomer is present,reducing aromaticity and making dearomatization possible.Based on this idea,this paper uses zirconium tetrachloride as Lewis acid catalyst and phosphite ester as nucleophile reagent to successfully realize the nucleophilic dearomatization of hydroxypyrimidine,and develops a novel and effective method to synthesize the structure of dihydropyrimidone.The following research results were obtained.（1）Seven single-aromatic-substituted hydroxy pyrimidines were synthesized from 2,4-dichloro-5-methylpyrimidine by Suzuki coupling and hydrolysis.And six diaryl-substituted hydroxypyrimidine substrates were synthesized by Suzuki coupling,oxidation and hydrolysis using 5-Bromo-4-chloro-2-（methylthio）pyrimidine as the starting material.All the above compounds were characterized by ¹H NMR,and the new compounds were characterized by¹³C NMR and HRMS.（2）With 5-methyl-4-phenylpyrimidin-2-ol pyrimidine as model substrate and dimethyl phosphite as nucleophilic reagent,the optimal reaction condition was established:Zr Cl₄ as catalyst,THF as solvent and stirring at room temperature for 24 hours.Under the optimum conditions,dihydropyrimidone with phosphorus attached to the chiral center was prepared with 98%separation yield of model compound.And the reaction was performed in gram scale,which performed well.（3）Under the optimum reaction conditions,the reaction has good substrate applicability.Both monoaryl substituted hydroxypyrimidines and diaryl substituted hydroxypyrimidines can react efficiently to obtain DHPMs in excellent yields（81～99%）.The effect of the type of phosphite on the reaction was also investigated.The steric hindrance had a great effect on the nucleophilicity of phosphorus.