New Efficient Synthesis of 3,4-Dihydropyrimidin-2(1H)-ones Catalyzed by Benzotriazolium-Based Ionic Liquids under Solvent-Free Conditions

An efficient synthesis of novel 3,4-dihydropyrimidin-2(1H)-ones (DHPMs) and their derivatives, using Brønsted acidic ionic liquid [C2O2BBTA][TFA] as a catalyst, from the condensation of aryl aldehyde, β-ketoester and urea was described. Reactions proceeded smoothly for 40 min under solvent-free conditions and gave the desirable products with good to excellent yields (up to 99%). The catalyst could be easily recycled and reused with similar eﬃcacies for at least six cycles.

Currently, ionic liquids (ILs) have been widely used as environmentally benign reaction media and catalysts in organic synthesis owing to their unique properties of non-volatility, excellent solubility, high thermal stability and recyclability [19,20]. In particular, the synthesis of task-specific ILs (TSIL) with special functions according to the requirement of a specific reaction has become an attractive field. Extensive effort has been focused on the elucidation of the mechanism of Lewis acid-catalyzed Biginelli reactions in ionic liquids [21]. Sharma et al. [22] reported highly recyclable amino acid ionic liquids as a catalyst, particularly glycine nitrate, for the one-pot, three-component Biginelli condensation under microwave irradiation (MW). Recently, Kandasamy and co-workers realized the synthesis of 1-alkyl

Results and Discussion
The  [27], we explored the relationship between the catalyst and solvents (Table 1, entries 1-8). When molecular solvents, such as H2O, MeOH, CH3CN or toluene, were employed, the reaction afforded a mixture of benzaldehyde, ethyl acetoacetate and urea under similar conditions, and DHPMs were obtained only in a very low yield (<19%). When no catalyst was used in this reaction system, the reaction did not give the desired product. This showed that ionic liquid plays a very important role in the reaction system (Table 1, entry 9). The influence of the reaction time on the yield was also investigated as shown in Table 1, entries 8, [15][16][17][18][19]. It turned out that although the reaction time was increased to 40 min, the yield did not change significantly ( Table 1,  [TFA] was one of its most important benefits, which was also investigated in the reaction of aryl aldehyde, β-ketoester and urea. After separation of the product, the filtrate containing catalyst was vacuumed to remove water and the resulting catalyst was reused directly for the next run. As shown in Table 1

Results and Discussion
The  [27], we explored the relationship between the catalyst and solvents ( Table 1, entries 1-8). When molecular solvents, such as H 2 O, MeOH, CH 3 CN or toluene, were employed, the reaction afforded a mixture of benzaldehyde, ethyl acetoacetate and urea under similar conditions, and DHPMs were obtained only in a very low yield (<19%). When no catalyst was used in this reaction system, the reaction did not give the desired product. This showed that ionic liquid plays a very important role in the reaction system (Table 1, entry 9). The influence of the reaction time on the yield was also investigated as shown in Table 1, entries 8, [15][16][17][18][19]. It turned out that although the reaction time was increased to 40 min, the yield did not change significantly ( Table 1,   The recycling performance of TSIL [C 2 O 2 BBTA][TFA] was one of its most important benefits, which was also investigated in the reaction of aryl aldehyde, β-ketoester and urea. After separation of the product, the filtrate containing catalyst was vacuumed to remove water and the resulting catalyst was reused directly for the next run. As shown in Table 1 was an efficient and recyclable catalyst for the preparation of 3,4-dihydropyrimidin-2(1H)-ones derivatives.
In order to explore the scope and limitations of this reaction, we extended the procedure to various aryl-substituted aldehydes carrying either electron-donating or -withdrawing groups in the ortho, meta, and para positions. In general, the reaction proceeded easily under the best conditions and the adducts were isolated in excellent yields and high purity. In addition, compared to the reported synthetic method of 6-methyl-2-oxo-4-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxylate (Table 2, entry 3a) by using HCl as a catalyst and ethonal as a solvent [28], our strategy has the advantages of higher yield (96% vs. 78%) and shorter reaction time (40 min vs. 3 h). The obtained results indicated that the electron-donating or -withdrawing groups at the aryl ring did not seem to affect the reaction significantly in terms of yield (Table 2, entries 3a-3o). Thiourea has been used with similar success to provide the corresponding S-dihydropyrimidinones analogues, which are also of interest due to their biological activities (Table 2, entries 3p-3t). The use of different substituted β-ketoester as a 1,3-dicarbonyl moiety in place of ethyl acetoacetate also gave similar results, as shown in Table 2 (entries 3u-3ab).

Experimental Section
All melting points were determined using a Büchi B-540 instrument. All melting points are uncorrected. All new compounds were characterized by IR, 1 H-and 13 C-NMR spectra. The IR spectra were obtained as potassium bromide pellets with a FTS-40 spectrometer (BIO-RAD, Hercules, CA, USA). The 1 H-NMR spectra were measured on a Varian Inova-400 spectrometer (at 400 and 100 MHz, respectively) using TMS as an internal standard in CDCl 3 or DMSO-d 6 .

General Procedure for the Synthesis of 1-Butyl-3-carboxymethyl-benzotriazolium Trifluoroacetate
[C 2 O 2 BBTA][TFA]: benzotriazole (0.2 mol) and chlorobutane (0.24 mol) were dissolved in 30% aqueous solution of sodium hydroxide (100 mL). Tetrabutylammonium bromide (1 g) was added and the solution was stirred 24 h at 80˝C until two phases formed. The top organic phase and bottom water phase were separated with separating funnel. Any remaining water in the organic phase was removed by decompressing Ratovapor at 70˝C [46].

Experimental Section
All melting points were determined using a Büchi B-540 instrument. All melting points are uncorrected. All new compounds were characterized by IR, 1 H-and 13 C-NMR spectra. The IR spectra were obtained as potassium bromide pellets with a FTS-40 spectrometer (BIO-RAD, Hercules, CA, USA). The 1 H-NMR spectra were measured on a Varian Inova-400 spectrometer (at 400 and 100 MHz, respectively) using TMS as an internal standard in CDCl3 or DMSO-d6.

General Procedure for the Synthesis of 1-Butyl-3-carboxymethyl-benzotriazolium Trifluoroacetate
[C2O2BBTA][TFA]: benzotriazole (0.2 mol) and chlorobutane (0.24 mol) were dissolved in 30% aqueous solution of sodium hydroxide (100 mL). Tetrabutylammonium bromide (1 g) was added and the solution was stirred 24 h at 80 °C until two phases formed. The top organic phase and bottom water phase were separated with separating funnel. Any remaining water in the organic phase was removed by decompressing Ratovapor at 70 °C [46].

General Procedure for the Synthesis of 3,4-Dihydropyrimidin-2(1H)-(thio)ones
A mixture of aryl aldehyde (2 mmol), β-ketoester (2 mmol), urea (2 mmol) and [C2O2BBTA][TFA] (0.2 mmol) were heated at 90 °C under solvent-free conditions for 40 min with stirring (Scheme 1). After cooling, the reaction mixture was poured onto crushed ice (30 g) and stirred for 10 min. The separated solid was filtered under suction, washed with cold water (30 mL) and then recrystallized from ethanol to afford the pure product. The resulting precipitate was filtered under suction. The results are summarized in Table 2. All products (except 3l-3m, 3y-3ab) are known compounds, which were characterized by IR, 1 H and 13 C-NMR spectra.   After cooling, the reaction mixture was poured onto crushed ice (30 g) and stirred for 10 min. The separated solid was filtered under suction, washed with cold water (30 mL) and then recrystallized from ethanol to afford the pure product. The resulting precipitate was filtered under suction. The results are summarized in Table 2. All products (except 3l-3m, 3y-3ab) are known compounds, which were characterized by IR, 1 H and 13 C-NMR spectra.

Conclusions
In summary, we have reported an efficient and convenient method for the synthesis of a series of novel dihydropyrimidin-2(1H)-ones using aryl aldehyde, β-ketoester and urea as substrates and employing Brønsted acidic ionic liquid [C 2 O 2 BBTA][TFA] as a catalyst. This method offers several advantages including high yields, short reaction times, and a simple work-up procedure. It also has the ability to tolerate a wide variety of substituted groups in all three components, which is lacking in existing procedures.