Lignosulfonic Acid-Catalyzed Synthesis Of Biginelli Pyrimidinone

Pyrimidines are widely found in living organisms,and their derivatives,such as cytosine,uracil,and thymine,are important components of the genetic nucleic acids.Among them,3,4-dihydropyrimidin-2（1H）-ones（DHPMs）are an important class of pyrimidines,known as Biginelli compounds as an important pharmaceutical intermediate.In recent years,organic compounds with 3,4-dihydropyrimidin-2（1H）-ones as the basic skeleton have a wide range of applications in antihypertensive,anti-microbial,anti-epileptic,anti-viral and anti-allergic applications for the drug discovery and development,therefore,the efficient synthesis of 3,4-dihydropyrimidin-2（1H）-ones has gradually become a hot research topic in the organic synthesis community.3,4-Dihydropyrimidin-2（1H）-ones are mainly synthesized by the traditional Biginelli reaction,but this method has disadvantages such as low yield,complicated operation,and strong acidic catalysts that are corrosive to the equipment.Although many improved methods for the Biginelli reaction have also been reported in the literature,there are still disadvantages such as high reaction temperature,expensive catalysts,and high solvent toxicity,which are contrary to the concept of green organic chemistry.The aim of this thesis was to conduct an efficient green synthesis of 3,4-dihydropyrimidin-2（1H）-ones.In this paper,3,4-dihydropyrimidin-2（1H）-ones were synthesized by a solvent-free method with benzaldehyde,ethyl acetoacetate and thiourea or urea as raw materials using inexpensive lignosulfonic acid as the catalyst.The paper firstly investigated the effect of different substrates on the reaction yields,and the results showed that the reaction proceeded smoothly when either thiourea or urea was used as the substrate,but the reactivity of urea was slightly lower than thiourea.Secondly,the effects of temperature and lignosulfonic acid amount on the reaction were investigated,and the results showed that the optimal temperature of the reaction was 70℃and the optimal reaction time was 24 h.The yield of the target product could reach 77%.Thirdly,the scope and limitations of the method were further investigated,and the effects of electronic effects and steric effects on the present reaction were further explored by synthesizing various 3,4-dihydropyrimidin-2（1H）-ones using benzaldehyde with different substituents.The experimental results showed that:（1）the method has good generality,and the yields were all in the range of 37%～94%;（2）the electron-donating groups showed higher yields than the electron-wanting substituents when the substituents were attached to the aromatic ring.The present paper reports the synthesis of 3,4-dihydropyrimidin-2（1H）-ones by the Biginelli reaction catalyzed by solvent-free lignosulfonic acid at 70℃for 24 h.The lignosulfonic acid catalyzed the"three-component"reaction of substituted benzaldehyde,ethyl acetoacetate and urea or thiourea to obtain a series of 3,4-dihydropyrimidin-2（1H）-one derivatives were obtained,and the structures of the products were characterized by ¹H and ¹³C NMR.The results of this study showed that the method is green and economical,easy to operate,and the catalytic system has good tolerance for functional groups and excellent yields compared with the classical Biginelli reaction conditions,with the highest yields up to 94%.