An Efficient Synthesis of 3,4-Dihydropyrimidin-2(1H)-Ones and Thiones Catalyzed by a Novel Brønsted Acidic Ionic Liquid under Solvent-Free Conditions

We report here an efficient and green method for Biginelli condensation reaction of aldehydes, β-ketoesters and urea or thiourea catalyzed by Brønsted acidic ionic liquid [Btto][p-TSA] under solvent-free conditions. Compared to the classical Biginelli reaction conditions, the present method has the advantages of giving good yields, short reaction times, near room temperature conditions and the avoidance of the use of organic solvents and metal catalyst.


Results and Discussion
To evaluate the effect of the catalyst under different conditions systematically, we carried out the reaction of benzaldehyde, ethyl acetoacetate and urea as a model reaction and the results are presented in Table 1. Initially the effect of amount of [Btto][p-TSA] on the reaction was examined (entries 1-7) and 5 mol % of [Btto][p-TSA] afforded the best result (entry 5). Then, the influence of the reaction time on the yield was tested (entries 5, [8][9][10]. It was found that higher yield was obtained when the reaction time was 30 min (Table 1, entry 10). The influence of the reaction temperature on the yield was investigated subsequently (entries 10, [11][12]. It was found that 90 °C was still the best reaction temperature ( Table 1, entry 10). For the sake of much milder condition to be developed, the reaction temperature at 30 °C was examined at last ( In order to study the scope of the procedure, a series of DHPMs were synthesized with the optimized conditions. The results are listed in Table 2. In all cases studied, the three-component reaction proceeded smoothly to give the corresponding DHPMs in excellent yields. Most importantly, aromatic aldehydes carrying either electron donating or electron withdrawing substituents reacted very well to give the corresponding DHPMs with high purity in good yields. Notably, this procedure is compatible with a wide range of functional groups such as methoxy, halides, nitro, hydroxy, etc. Beside those above, some sensitive groups also showed to be well tolerated by this method. For instance, furfural and cinnamaldehyde could afford the corresponding products in excellent yields as well. Thiourea has been used with similar success to provide corresponding S-dihydropyrimidinones analogues, which are also of interest due to their biological activities (entries 4q-s). The use of methyl acetoacetate as 1,3-dicarbonyl substrate in place of ethyl acetoacetate also gave good to excellent yields, as shown in Table 2 (entries 4t-u). At the same time, in order to further investigate this MCR at room temperature, a series of DHPMs were synthesized by using the new reaction set-up at room temperature. The results are summarized in Table 3. It can be observed that all the aldehydes have reacted with β-ketoester and urea at room temperature smoothly to afford the corresponding DHPMs in good to excellent yields. These much milder reaction conditions might make this useful method be promising in biorthogonal chemistry.

Experimental Section
All new compounds were characterized by 1 H NMR, 13 C NMR, MS spectra. The 1 H NMR and 13 C NMR spectra were obtained on a Varian Inova-400 spectrometer using CDCl3, D2O as solvent (shown in details in data part) and TMS as an internal standard. LC-MS analyses have been performed on a HP-1100 LC-MS. Melting points were determined using a Büchi B-540 instrument. All melting points are uncorrected.

General Procedure for the Synthesis of 3,4-Dihydropyrimidine-2(1H)-Ones and Thiones
To a mixture of aldehyde (3 mmoL), ethyl acetoacetate (3 mmoL), urea or thiourea (4.5 mmoL) and [Btto][p-TSA] (0.15 mmoL) was heated at 90 °C with no solvent for 30 min or at 30 °C under solvent-free condition for 10 h with magnetic stirring. The completion of the reaction was monitored by TLC. After cooling, the reaction mixture was poured onto crushed ice and stirred for 5 min. The separated solid was filtered under suction, washed with cold water thoroughly and then recrystallized from ethanol to afford the pure product. All products are known compounds, which were characterized by mp, IR and 1 H-NMR spectra. The results are summarized in Tables 2 and 3.

Conclusions
In conclusion, we have developed a novel Brønsted acidic ionic liquid [Btto][p-TSA] as an efficient catalyst for the synthesis of 3,4-dihydropyrimidin-2-(1H)-ones and thiones analogs by multicomponent Biginelli reaction for the first time. Our method offers several advantages such as mild reaction conditions, short reaction times, being environment-friendly and affording good yields.

Acknowledgments
We gratefully acknowledge support from the Natural Science Foundation of Xinjiang Uygur Autonomous Region of China (2012211A015).

Author Contributions
Yonghong Zhang designed and performed research and analyzed the data, wrote the paper as well. Bin Wang performed NMR. Chenjiang Liu, Xiaomei Zhang and Jianbin Huang were the supervisor of the work. All authors read and approved the final manuscript.

Conflicts of Interest
The authors declare no conflict of interest.