Development of an Environment-Friendly and Solvent-Free Synthetic Route for the Synthesis of 3,4-Dihydropyrimidin-2-(1H)-Ones/Thiones Using La(NO3)3.6H2O as an Efficient Catalyst

We present a facile and environmentally friendly procedure for the synthesis of corresponding 3,4-dihydropyrimidin-2(1H)-ones/thiones derivatives. The synthesis was achieved using a one-pot three-component Biginelli reaction among βketo esters (methyl or ethyl acetoacetate), aromatic aldehyde (benzaldehyde derivatives), and urea or thiourea in the presence of lanthanum (III) nitrate hexahydrate (La(NO3)3.6H2O), as a highly efficient catalyst under solvent-free conditions. This protocol has numerous advantages: it is an inexpensive, non-toxic, simple reaction work-up catalyst with a high atom-economy, and shows excellent yields with short reaction times.


Materials and Methods
General. Melting points of all compounds were determined using an Electrothermal 9100. 1 H NMR spectra were recorded on a Bruker DRX-400 Avance instrument using DMSO-d 6 as a solvent. All reagents and solvents were purchased from Merck, Fluka, and other chemical companies, and used without further purification.

General procedure for preparation of 3,4-dihydropyrimidin-2-(1H)-ones/thiones derivatives (4a-o).
A mixture of aldehyde derivatives (1, 1.0 mmol), urea/thiourea (2, 1.5 mmol), and ethyl/methyl acetoacetate (3, 1.0 mmol) was heated under solvent-free conditions at 80°C for an appropriate time in the presence of lanthanum (III) nitrate hexahydrate (0.06 g). After completion of the reaction by thin layer chromatography, the mixture was cooled to room temperature and cold water was added. The precipitate was separated with filtration and crystallized from ethanol to afford the pure products (4a-o). Spectral data of all products are presented below:

Results and Discussion
We have developed a clean, eco-friendly, and simple methodology for one-pot three-component synthesis of 3,4-dihydropyrimidin-2-(1H)-ones/thiones derivatives by means of arylaldehyde derivatives (1, 1.0 mmol), urea/thiourea (2, 1.5 mmol), and ethyl/methyl acetoacetate (3, 1.0 mmol) in the presence of a catalytic amount of lanthanum (III) nitrate hexahydrate as a mild and efficient catalyst. This synthesis was achieved under thermal and solvent-free conditions with excellent yields and short reaction times.
To optimize the reaction conditions, the synthesis of compound 4a was used as a model reaction. We studied the effects of differing amounts of catalyst on the reaction in this protocol. No product could be detected in the absence of the catalyst at 80°C even after 360 min, indicating the need for a catalyst for this transformation (Table 1, entry 1). Optimized conditions for the reaction were determined by changing determinative parameters such as amount of catalyst and temperature. Thereafter, for determining the optimum quantity of catalyst, the model reaction was performed in the presence of different amounts of lanthanum (III) nitrate hexahydrate. Various loadings of catalyst, including 5%, 10%, 15%, and 20% by mass, were screened in our model reaction. By lowering the catalyst loading to 5% by mass, the corresponding product was obtained at a lower yield (Table 1, entry 2). By increasing the amount of catalyst from 5% to 10% and 15% by mass, the reaction time was reduced and the yield of the product increased (  Table 1. We also examined the influence of temperature on the reaction yield. No product could be detected under room temperature conditions after 360 min ( Table  1, entry 5). The reaction was investigated for temperatures running from 40°to 80°C. Results indicated that when the reaction proceeded using lanthanum (III) nitrate hexahydrate 15% by mass at 40°C for 75 min, the yield of corresponding product was low (42 %) ( Table 1, entry 6). The reaction time was decreased from 75 min to 20 min when the reaction temperature was increased from 40°to 80°C. The high yield of product was obtained at an 80°C temperature (Table 1, entry 4); yields of product at different temperature are reported in Table 1. The reaction was also carried out at a temperature of 90°C, but there was no significant change in yield or reaction time (Table 1, entry 9).
We therefore employed the optimized conditions of 15% by mass lanthanum (III) nitrate hexahydrate as a catalyst at 80°C for the condensation reaction of aryl aldehyde derivatives (1, 1.0 mmol), urea/thiourea (2, 1.5 mmol), and ethyl/methyl acetoacetate (3, 1.0 mmol) into their corresponding 3,4-dihydropyrimidin-2-(1H)ones/thiones derivatives. Encouraged by the results obtained from the above conditions, and to demonstrate the wide applicability and scope of this protocol, we used various aromatic aldehydes, bearing either electronwithdrawing functional groups or electron-donating groups such as Cl, Me, NO 2 , and OMe-substituted banzaldehydes, for the synthesis of corresponding 3,4dihydropyrimidin-2-(1H)-ones/thiones derivatives. The effects of substituents on the aromatic rings were estimated to be strong in terms of yield under these reaction conditions. Both classes of aromatic aldehydes, those with electron-releasing and those with electron-September 2018 Vol. 22  No. 3 withdrawing substituents in their aromatic rings, synthesized the appropriate products with high reaction yields and short reaction times. We also applied urea/thiourea and ethyl/methyl acetoacetate. In each of these substitutions, there was no significant difference in the reaction rate or product yields. The results are summarized in Table 2. The desirable features of this catalyst are its ease of handling, mild and environmentally benign properties, operational simplicity, high reaction yields, and short reaction times.

Conclusions
We have introduced lanthanum (III) nitrate hexahydrate as an economical and highly efficient catalyst for facile one-pot synthesis of 3,4-dihydropyrimidin-2-(1H)-ones/ thiones via three-component reactions of aryl aldehydes, urea/thiourea and ethyl/methyl acetoacetate under solventfree conditions. The promising features that have distinguished this approach from other reported methods of this synthesis include its high catalytic ability, low cost, ready availability, and simple reaction work-up, making this methodology more economical and industrially relevant. Additional advantages of this protocol include excellent yields and short reaction times under solvent-free conditions.