Microwave-assisted multicomponent reaction for the synthesis of 3,4-dihydropyrimidin-2(1H)-ones and their corresponding 2(1H)-thiones using lanthanum oxide as a catalyst under solvent-free conditions

1 Introduction

Dihydropyrimidinones (DHPMs) derivatives have exhibited important pharmacological properties such as antiviral, antibacterial, antitumor and antihypertensive activities (Rovnyak et al., 1995). Some have been successfully used as calcium channel blockers, α-1a-antagonists and neuropeptide Y (NPY) antagonists (Atwal et al., 1990). Several alkaloids, which contain the dihydropyrimidine core unit, have been isolated from marine sources. Most notable among these are the batzelladine alkaloids, which were found to be potent HIVgp-120-CD4 inhibitors (Snider et al., 1996). The Biginelli reaction is considered as an important multicomponent reaction for generating compounds with diverse medicinal applications.

The original one-pot synthesis of 3,4-dihydropyrimidin-2(1H)-ones was first reported by Pietro Biginelli in 1893 performing the three component cyclocondensation reaction of ethyl acetoacetate, benzaldehyde and urea under Bronsted acid catalysis. However, this reaction suffers from the harsh conditions, high reaction times and frequently low yields (Biginelli, 1893). Therefore, the discovery of milder and practical routes for the synthesis of dihydropyrimidin-2(1H)-ones by the Biginelli reaction continues to attract the attention of researchers.

In recent years, new methods for the synthesis of 3,4-dihydropyrimidin-2(1H)-ones have been developed by different groups. In order to improve the efficacy of the Biginelli reaction different Lewis catalyst such as SbCl₃ (Cepenec et al., 2007), InBr₃ (Fu et al., 2002), Cu(NH₂SO₃)₂ (Liu and Wang, 2009), H₃PMo₁₂O₄₀ (Heravi et al., 2006), ZrCl₄ (Reddy et al., 2002), CaF₂ (Chitra and Pandiarajan, 2009), LaCl₃·7H₂O (Lu et al., 2001), lanthanide triflate (Ma et al., 2000) and ionic liquid (Peng and Deng, 2001) were reported.

During recent years, the chemistry of lanthanum and their use in organic synthesis have developed rapidly. Furthermore, their low toxicity and availability at a moderate price makes this element attractive for use in organic synthesis. The use of lanthanide(III) compounds as catalysts or promoters in organic synthesis has attracted great interest from many chemists (Molander, 1992). Lanthanide additives (or) complexes can enhance the reactivity and selectivity of many types of reaction, such as reduction (Nishino et al., 2002), carbon–carbon bond forming reactions (Kobayashi, 1999), aldol condensation (Kobayashi et al., 1993), Fridel–Crafts acylations (Kawada et al., 1994) and aza Diels–Alder reactions (Makioka et al., 1995).

Environmental concerns in research and industries to reduce the amount of pollutants produced, including organic solvents whose recovery is mandated by ever more strict laws. Hence, the challenges for a sustainable environment call for the use of clean procedures, which can avoid the use of harmful solvents. The emergence of microwave assisted solid phase synthesis (Varma, 1999) is a step forward in this direction. In this expeditious and solvent free approach the adsorbed reactants over solid supports are exposed to microwave irradiation. The coupling of a microwave heating mode with the use of solid has allowed the synthesis of several organic compounds with higher purity of products and very simplified ease of manipulation and work up (Katritzky and Singh, 2003).

It is of great practical importance to synthesize by Biginelli reaction DHPMs using easily separable solid catalysts having pore size large enough to allow the diffusion of large molecules, requiring short reaction time and particularly without any solvent, so that the synthesis is also environ-friendly producing little or no waste. The present investigation was undertaken for this purpose. Herein, we wish to report a simple and efficient method for the synthesis of 3,4-dihydropyrimidin-2(1H)-ones and their corresponding thiones under solvent-free conditions using lanthanum oxide as a catalyst.

2 Experimental

3 Results and discussion

In a model reaction, ethyl acetoacetate (2) (10 mmol), benzaldehyde (1) (10 mmol), urea/thiourea (3) (15 mmol) and La₂O₃ (10 mol%) in micro oven gave the product in 98% yield (Scheme 1). A variety of substituted benzaldehydes and urea/thiourea were used for this reaction. The results are summarized in Table 1.

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Scheme 1

Synthesis of 3,4-dihydropyrimidinones/thiones catalyzed by La₂O₃ under microwave irradiation and solvent-free condition.

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It was found that the reaction could go smoothly and the corresponding DHPMs were obtained in excellent yield (90–98%) when the mixture was irradiated at 320 W for 20–60 s. No product could be obtained when the reaction was carried out at room temperature for a long time even in the presence of 20 mol% La₂O₃. It was also found that the use of 10 mol% La₂O₃ was sufficient to promote the reaction and no additives were required for this conversion under microwave irradiation. There were no improvements in the reaction rates and yields by increasing the amount of catalyst from 10 to 20 mol%. But in the absence of La₂O₃, the reaction did not proceed even at higher irradiation, further increases the irradiation time induced evaporation and charring. Hence, 10 mol% of La₂O₃ was found to be the optimum level and the same concentration of catalyst was used for all reaction. Encouraged by these results, a series of aldehydes were examined under optimized conditions.

In order to show the merit of the present work, the reaction is compared with some reported protocols. We compared the results of the synthesis of 5-ethoxycarbonyl-4-phenyl-6-methyl-3,4-dihydropyrimidin-2(1H)-one (entry 4a in Table 1) in the presence of SbCl₃, InBr₃, Cu(NH₂SO₃)₂, H₃PMo₁₂O₄₀, ZrCl₄, CaF₂, LaCl₃·7H₂O and ionic liquid with respect to the reaction times (Table 2). The yield of the product in the presence of La₂O₃ is comparable with these catalysts. However, reaction in the presence of these catalysts required longer reaction times and the yield was somewhat low.

The catalyst was used in twenty reactions and the results are summarized in Table 1. It is seen that several aromatic aldehydes carrying either electron-releasing or electron-withdrawing substituent’s in the ortho-, meta- and para-positions afford high yields. Another important feature of this procedure is the survival of a variety of functional groups under the reaction conditions. Thiourea has been used instead of urea, gave the corresponding 3,4-dihydropyrimidin-2(1H)-thione which is also of much interest with respect to its biological activity. The substrate bearing a strong electron withdrawing (NO₂) also gave a good yield within 60 s. It was observed that the reaction of aromatic aldehydes with urea is very fast as compared to thiourea. We have not tried this method for aliphatic aldehydes.

The reaction may proceed via acylimine intermediate 5 (Nandurkar et al., 2007), formed by the reaction of the aldehyde and urea/thiourea, which has been catalyzed by lanthanum oxide. Subsequent addition of β-keto ester enolate to the acylimine, followed by cyclization and dehydration, afforded the corresponding dihydropyrimidinones (Scheme 2).

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Scheme 2

Proposed mechanism for the synthesis of 3,4-dihydropyrimidinones/thiones catalyzed by La₂O₃.

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4 Conclusion

In conclusion, we have described the first time use of lanthanum oxide as an efficient catalyst for the synthesis of 3,4-dihydropyrimidin-2(1H)-ones and their corresponding thiones analogs by multi component Biginelli reactions under microwave irradiation and solvent-free reaction conditions. This method offers several advantages including high yields, very short reaction time and a simple experimental workup procedure, which makes it a useful process for the synthesis of DHPMs. It is also consistent with a green chemistry approach and environmentally friendly process since, no solvent is needed. We believe, our procedure will find important applications in the synthesis of dihydropyrimidinones to cater the needs of academia as well as pharmaceutical industries.