An Eﬃcient Catalyst for the One-Pot Synthesis of 3,4-Dihydropyrimidin-2(1 H )-ones Both under �e�ux or Solvent-�ree Conditions

9H O eﬃciently catalyzes the three-component Biginelli reaction between an aldehyde, a 𝛽𝛽 -dicarbonyl compound, and urea or thiourea in re�uxing ethanol and solvent-free (SF) conditions to aﬀord the corresponding dihydropyrimidinones in high yields. e advantages of this method involve the easy procedure, the environmentally friendly process, and the low cost of the Lewis acid catalyst.


Experimental
2.1. General. Chemicals were purchased from Merck, Aldrich, and Acros companies and were used without further puri�cation. All yields refer to isolated products. e purity determination of the substrates and reaction monitoring were accompanied by thin-layer chromatography (TLC) and visualized under ultraviolet (UV) light. Melting points were determined using Electrothermal 9100 instrument in open capillaries and are uncorrected. All compounds are well known and were identi�ed by comparison of the spectroscopic data with those of the authentic samples.

Results and Discussion
In continuation of our work on the development of useful synthetic methodologies [23][24][25], we have observed that aluminum nitrate is an effective catalyst for the synthesis of Biginelli compounds (Figure 1). As a model reaction, we started to study the three-component aluminum nitrate catalyzed Biginelli condensation by examining the conditions required for the reaction involving benzaldehyde, urea, and ethyl acetoacetate to afford the corresponding 3,4dihydropyrimidinone in re�uxing ethanol. Initially, we turned our attention toward screening appropriate concentration of aluminum nitrate (Table 1). In the �rst stage, we carried out the model reaction in absence of any catalyst (entry 1, Table 1) for which the yield of product was negligible. Aerward, we selected 5 mol% aluminum nitrate to catalyze the model reaction and found that the desired 3,4-dihydropyridinone was obtained in 70% yield. e reaction worked well when the amount of Al(NO 3 ) 3 ⋅9H 2 O was increased from 10 to 15 mol%, but 15 mol% of Al(NO 3 ) 3 ⋅9H 2 O gave highest yield, and larger amount of catalyst did not improve the yields to a greater extent. Aer investigation of the in�uence of catalyst amount on the yield of the reaction, various solvents including CH 3 CN, EtOH, MeOH, Acetone, CHCl 3 , EtOH/H 2 O (1 : 1), and H 2 O were tested and compared with solvent-free conditions ( Table 2). As can be seen in Table 2, among the different solvents, ethanol gave the highest yield ( Table 2, entry 2), whereas water did not yield good results in aluminum nitratecatalyzed Biginelli reaction (Table 2, entry 7). Also, addition of catalytic amount of sodium dodecyl sulfate (SDS) only improved yield of product up to 5%. In addition, we prepared Al(DS) 3 by reaction of aluminum nitrate with SDS according to reported procedure [26] and used it as catalyst in the model reaction in water as solvent under the re�ux condition, but Al(DS) 3 did not improve yield of reaction in our hand. �e �nally identi�ed ethanol as the most e�cient solvent for aluminum nitrate-catalyzed Biginelli reaction. To investigate the versatility as well as the capacity of our method, the reactions were examined in solvent-free conditions.
In solvent-free conditions, the yield increased, and the reaction time decreased (Table 2, entry 12). In addition, at low temperature and long reaction times only smaller amounts of the desired products were obtained (Table 3, entry 1).
Aer optimizing the reaction conditions, various aromatic aldehydes carrying either electron-releasing or electron-withdrawing substituents in the ortho, meta, and para positions afforded good to excellent yields of the products both in re�uxing ethanol and solvent-free conditions. An important feature of this procedure is that despite the high oxidizing potential of aluminum nitrate, functional groups such as ethers and hydroxy survive under the reaction conditions. iourea was used with similar success to provide the corresponding 3,4-dihydropyrimidin-2(1H)-thiones which are also of interest with regard to their biological activities (Table 4,  We can reach a better conclusion by comparing the performance of the present work with some other recent reports available in the literature, as illustrated in Table 5. e mechanism of Biginelli reaction has been investigated thoroughly [33]. According to Kappe [34], the �rst step in the mechanism is believed to be the condensation between the aldehyde and urea. e iminium intermediate generated acts as an electrophile for the nucleophilic addition of the ketoester enol, and the ketone carbonyl of the resulting adduct undergoes condensation with the urea NH 2 to give the cyclized product ( Figure 2).

Conclusions
In conclusion, the present procedure provides an efficient and improved modi�cation of the Biginelli reaction. �ild reaction conditions, operational simplicity and easy workup, good to excellent yields, cheap and nontoxic catalyst, and short reaction times (in solvent-free conditions) are features of this new procedure.
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