The novel and green synthesis of 6-amino-4-phenyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile via the solvent-free biginelli multi-component reaction catalysed by Choline chloride/2ZnCl2

Abstract

The pyrimidine scaffold is one of the common frameworks presenting in many biologically active compounds, especially in commercial drugs such as anti-cancer (5-fluorouracil, gemcitabine, ...), antibiotics (iclaprim, ...), anti-HIV (stavudine, ...), etc. Therefore, pyrimidines have been studied with several synthetic pathways, however, the well-known route via the multi-component Bignelli reaction has been paid more attention. The Biginelli reaction has been recognized for over 100 years and has been developed using a variety of substrates and catalysts to improve the efficiency, selectivity, and diversity of pyrimidines produced. With the trend towards green chemistry in organic synthesis, catalysts with high recovery and reusability have been explored and developed. For these above reasons, a solvent−free multicomponent reaction between benzaldehyde, malononitrile, and thiourea was investigated with several traditional and green catalysts to afford the main product, 6-amino-4-phenyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile. Among the wide range of catalysts studied, the deep eutectic solvent ChCl:2ZnCl2 showed the best efficiency, with a reaction yield of 62%. Some factors of the reaction such as molar ratio, amount of catalyst, the temperature and reaction time were all investigated. The best conditions including the molar ratio of benzaldehyde (2 mmol): malononitrile (2 mmol): thiourea (2 mmol) and the amount of catalyst 0.3 mmol were chosen and performed at 80oC for 2 hours to afford the highest yield of 62%. Furthermore, DES ChCl:2ZnCl2 was able to be recovered and reused two times.