An Efficient and Clean One-Pot Synthesis of 3,4-Dihydropyrimidine-2-(1H)-ones Catalyzed by SrCl2.6H2O-HCl in Solvent or Solvent-Free Conditions

Abstract

In recent years, 3,4-dihydropyrimidin-2(1H)-one derivatives have gained much interest for their biological and pharmaceutical properties, such as HIV gp-120-CD4 inhibitors, calcium channel blockers, α-adrenergic and neuropeptide Y antagonists, as well as antihypertensive, antitumor, antibacterial and anti-inflammatory agents. The scope of this pharmacophore has been further increased by the identification of monastrol as a novel cell-permeable lead compound for the development of new anticancer drugs bearing the dihydropyrimidinone core. Thus the development of facile and environmentally friendly synthetic methods towards dihydropyrimidinones constitutes an active area of investigation in organic synthesis. The first synthetic method for the preparation of 3,4-dihydropyrimidine-2(1H)-ones (DHPMs) was reported by Biginelli that involves the onepot three component condensation of aldehydes, β-dicarbonyl compounds and urea or thiourea in ethanol under strongly acidic conditions producing DHPMs, albeit in low yields. In the view of the pharmaceutical importance of these compounds, many improved catalytic methods have been developed. Although these methods have their own merits, long reaction times, harsh reaction conditions, unsatisfactory yields and use of large quantity of catalyst or organic solvent limit their practical applications. Therefore improvements with respect to the above have been continuously sought. In this paper, we wish to report an efficient and convenient procedure for the synthesis of DHPMs from the alkyl or aryl aldehydes using SrCl2·6H2O-HCl catalyst system (Scheme 1). SrCl2·6H2O was chosen for its nontoxicity and further it is inexpensive. First we investigated the catalytic effect of the SrCl2·6H2O and found that it greatly catalyzes the reaction when used with small amount of HCl(aq). Here, we presume the added HCl (aq) would act as a co-catalyst, activating the strontium salts. As shown in Table 1, the product yields were low (28-78%) after 18 h, when the reactions were carried out with HCl(aq) alone (as classical Biginelli reaction). The reactions were much slow when HCl(aq) was replaced with SrCl2·6H2O, as we obtained DHPMs after long reaction time (> 20 h). But when we used 50 mol% of the Lewis acid with 1-2 drop of HCl, the yields increased (85-93%) as well as the reaction rates (6 h). We extended this reaction condition to a series of alkyl or aryl aldehydes under reflux condition in ethanol (2 mL per mmol of aldehyde) as solvent. Although the reaction afforded the products in high yields in other solvents like acetonitrile, we chose ethanol for economical and environmental acceptability. The results are summarized in Table 1(Method A). Both aromatic aldehydes bearing either activating or deactivating groups reacted well with βketoesters to yield the corresponding DHPMs in high to excellent yields (Entries 1-23). Acid-sensitive substrates such as cinnamaldehyde also well proceeded to give the DHPMs without any side products (Entry 23). However, aliphatic aldehydes such as butanal as observed previously are quite resistant to our reaction conditions. We next examined the same reaction conditions without a solvent. The results showed that the solvent-free condensation reactions are much faster (20 min), providing the corresponding products in much higher yields than condition A (Table 1, method B). In conclusion, we have found an efficient, inexpensive and straightforward procedure for one-pot synthesis of dihydropyrimidinones using SrCl2·6H2O-HCl catalyst system. Also