1 Introduction
The Biginelli reaction, one of the important and useful multicomponent reactions, offers an efficient way to get multifunctionalized 3,4-dihydropyrimidin-2(1H)-ones (DHPMs) and related heterocyclic compounds [1]. The Biginelli compounds, viz DHPMs are potent calcium channel blockers [2]. One of the important strategies for synthesis of this valuable class of compound is the one-pot condensation of an aldehyde, β-ketoester, and urea under acidic conditions, first reported by Biginelli. However, this reaction suffered from harsh condition, long reaction times and frequent low yield [3]. Over the past decades, several new methods for synthesis of DHPMs have been reported in the literature including microwave irradiation, ionic liquids, and by using Lewis acids as well as protic acids [4]. Despite the plethora of different catalysts published so far and also proved to be efficient in Biginelli reaction, the synthetic chemists may encounter the problem in finding the right one if the reaction is performed on larger scale as most of the reactions are associated with the high reaction temperature, prolonged reaction time, strong Lewis acidity of the catalyst and laborious work up procedures. Therefore, the discovery of new and inexpensive catalysts for the preparation of 3,4-dihydropyrimidin-2(1H)-ones under mild conditions is of prime importance.
Bis[(L)prolinato-N,O]Zn {[Zn(L-proline)2]} is an efficient, stable, inexpensive, recyclable, non-toxic Lewis acid catalyst which is soluble in water but insoluble in organic solvents, which allows simple and quantitative recovery of the catalyst. It has been extensively applied to various catalytic reactions including Aldol condensation [5], direct nitroaldol condensation [6], Hantzsch reaction [7], Knoevenagel condensation [8], Mannich reaction [9], Friedlander condensation [10] etc. It has also been used for the synthesis of 1,5-benzodiazepines [11], 1,2-disubstituted benzimidazoles [12], quinoxalines [13], pyrano[2,3-d]pyrimidines [12], pyrazoles [14], triazoles [15], dicoumarols [16], chromonyl chalcones [17], xanthenediones [18] and chromanones [19] etc. Further, there is much scope for exploration of this catalyst in the synthesis of various privileged medicinal scaffolds. In continuation of our research for developing economically viable and environmentally benign methodologies for organic synthesis [20–23] and to reveal the efficient utility of [Zn(L-proline]2 [8,10,16,17,19], we report herein, for the first time, a green, sequential, three-component protocol for the synthesis 3,4-dihydropyrimidin-2(1H)-ones by the reaction of active methylene compounds, urea and various aldehydes using [Zn(L-proline)2] in water. The catalyst was recyclable up to five cycles and identified first time by SEM-EDX analysis.
2 Results and discussion
As expected, the catalytic system is influenced by various reaction parameters, such as amount of the catalyst employed, effect of catalyst and solvent system. Therefore, in our initial investigation to established the optimum reaction conditions benzaldehyde (3a), ethyl acetoacetate (1a) and urea (2) in water were taken as a model substrate to study the generality of our methodology towards synthesis of 3,4-dihydropyrimidin-2(1H)-ones (4a–i).
2.1 Effect of catalysts
Various catalysts were employed to evaluate the capability and efficiency of the catalyst (Table 1). Initially, the model reaction was performed in the absence of any catalyst and no reaction occurred (entry 14). When the model reaction was examined with, FeCl3. 6H2O, Fe(NO3)2. 9H2O, AlCl3, PTS the reaction took longer time period for completion with lower yield of the product (entry 2–5). With Zn compounds such as Zn(CH3COO)2, Zn(NO3)2, ZnCl2, and ZnO again lower yields of the product were obtained after prolong heating (entry 6–9). With other catalysts NiCl2, L-proline, SnCl2. 2H2O either reactions were unsuccessful or products were obtained in traces (entry 10–12). When, model reaction was performed with Zn(L-histidine)2, the reaction was accelerated but a mixture of products was obtained in poor yield (entry 13). Thus, [Zn(L-proline)2] exhibited highest catalytic activity (entry 1) as compared to other catalysts.
Effect of various catalysts for model reactions in water.
| Entrya | Catalyst | Timeb | Yieldc (%) |
| 1 | Zn(L-proline)2 | 5 min | 92 |
| 2 | FeCl3.6H2O | 12 h | 35 |
| 3 | Fe(NO3)2.9 H2O | 12 h | 25 |
| 4 | AlCl3 | 8 h | 45 |
| 5 | PTS | 8 h | 68 |
| 6 | Zn(CH3COO)2 | 4.5 h | 45 |
| 7 | Zn(NO3)2 | 6 h | 42 |
| 8 | ZnCl2 | 6 h | 39 |
| 9 | ZnO | 6 h | 52 |
| 10 | L-proline | 8 h | Trace |
| 11 | SnCl2. 2H2O | 48 h | Trace |
| 12 | NiCl2 | 48 h | No reaction |
| 13 | Zn(L-histidine)2 | 2 h | 35 |
| 14 | No catalyst | No reaction | No reaction |
a Reaction of ethylacetoacetate (1a), urea (2) and benzaldehyde (3a) in the presence of [Zn(L-proline)2] (10 mol %) catalyst in water.
b Reaction progress monitored by TLC.
c Isolated yield.
In order to prove the efficiency of [Zn(L-proline)2] for the synthesis of 4a, a comparison with other reported Zn catalysts was also made (Table 2). It is thus, clear from the table that [Zn(L-proline)2] is superior to other Zn compounds in terms of time, yield and reaction condition.
Comparison of the results obtained using [Zn(L-proline)2] with other reported Zn catalysts for synthesis of 4a.
| Entry | Catalysts | Solvents | Time | Yield (%) |
| 1 | ZnO | Solvent-free | 19 min | 97 [24] |
| 2 | Zn(BF4)2 | Water | 3 h | 73 [25] |
| 3 | Zn(ClO4)2 | Solvent-free | 15 min | 95 [26] |
| 4 | ZnBr2 | Solvent-free | 0.7 h | 94 [27] |
| 5 | ZnCl2/natural phosphate | Toluene | 48 h | 98 [28] |
| 6 | Zn(HSO4)2 | Solvent-free | 2.5 h | 74 [29] |
| 7 | Zn(NH2SO3)2 | Ethanol | 3 h | 96 [30] |
| 8 | Zn(OTf)2 | Solvent-free | 20 h | 94 [31] |
| 9 | Zn(OAc)2 | Ethanol | 4.5 h | 85 [32] |
| 10 | Zn[(L-proline)2] | Water | 5 min | 92 |
2.2 Loading of the catalyst
The effect of catalyst loading on the synthesis of 4a was investigated by varying the catalyst amount from 0 to 15 mol % (Table 3). It was observed that increase in catalyst amount from 0 to 10 mol % increased the yield of the product from 74 to 92%. Further increases in the amount of catalyst had no significant change in the product formation. Thus, optimum catalyst loading was found to be 10 mol % for the formation of 3,4-dihydropyrimidin-2(1H)-ones.
Effect of catalyst loading on the synthesis of 4aa.
| Entry | Catalyst (mol %) | Timeb | Yieldc (%) |
| 1 | 0 | – | – |
| 2 | 2.5 | 1 h | 74 |
| 3 | 5 | 8 min | 89 |
| 4 | 10 | 5 min | 92 |
| 5 | 15 | 5 min | 92 |
a Reaction of ethylacetoacetate (1a), urea (2) and benzaldehyde (3a) in the presence of [Zn(L-proline)2] (10 mol%) catalyst in water.
b Reaction progress monitored by TLC.
c Isolated yield.
2.3 Effect of solvents
Since [Zn(L-proline)2] is homogeneous in water, therefore, to further explore the scope of this protocol, the investigation was carried out using model reaction in different solvents with varying polarity and protic nature. It was observed that in THF, n-hexane no reaction was observed and starting materials were recovered (Table 4, entry 10, 11), whereas in CH2Cl2 and CH3CN lower yield of the product (4a) was obtained after longer time period (Table 4, entry 2, 3). In acetic acid, methanol, isopropanol and ethanol relatively high yield of the product was obtained (Table 4, entry 4–7), but the reaction was completed in longer time period. When the model reaction was carried out in [Zn(L-proline)2]-water catalytic system at reflux temperature, a significant improvement was observed and the product was obtained in 92%. Further in a comparative study using other green solvents, the model reaction was also performed in PEG-400 and glycerol and it was observed that the reaction completed relatively in shorter time but with mixture of products (entries 8, 9). These results revealed that water is the best solvent in terms of reduced reaction time and maximum yield of the products. Thus, H2O was chosen as the reaction medium for all other reactions.
Effect of various solvents on model reactiona.
| Entry | Solvent | Timeb | Yieldc (%) |
| 1 | Water | 5 min | 92 |
| 2 | CH2Cl2 | 48 h | 35 |
| 3 | CH3CN | 48 h | 38 |
| 4 | Acetic acid | 7 h | 76 |
| 5 | EtOH | 6 h | 68 |
| 6 | MeOH | 6 h | 64 |
| 7 | Isopropanol | 8 h | 58 |
| 8 | PEG-400 | 5 h | 56 (mixture) |
| 9 | Glycerol | 3.5 h | 68 (mixture) |
| 10 | n-Hexane | No reaction | No reaction |
| 11 | THF | No reaction | No reaction |
a Reaction of ethylacetoacetate (1a), urea (2) and benzaldehyde (3a) in the presence of [Zn(L-proline)2] (10 mol%) catalyst.
b Reaction progress monitored by TLC.
c Isolated yield.
Encouraged by the remarkable results obtained with the above reaction conditions and in order to show the generality and scope of this new protocol, we performed the reaction with a variety of aromatic aldehydes (3a–e) and active methylene compounds (1a–b) and the results obtained are summarized in Table 5. All the reactions proceeded smoothly and the reaction was completed within 5 to 10 min to afford the products (4a–i) in excellent yields (81–92%) (Table 5) (Scheme 1). All the products were characterized by 1H NMR, 13C NMR, IR, and mass spectra and compared with authentic samples.
[Zn(L-proline)2] catalyzed synthesis of 3,4-dihydropyrimidin-2(1H)-ones (4a–i).
| Entry | Product | Time (min)a | Yield (%)b |
| 1 | 4a | 5 | 92 |
| 2 | 4b | 9 | 82 |
| 3 | 4c | 8 | 85 |
| 4 | 4d | 7 | 88 |
| 5 | 4e | 5 | 89 |
| 6 | 4f | 6 | 78 |
| 7 | 4g | 7 | 84 |
| 8 | 4h | 8 | 88 |
| 9 | 4i | 9 | 81 |
a Reaction progress monitored by TLC.
b Isolated yields.
[Zn(L-proline)2] catalyzed synthesis of 3,4-dihydropyrimidin-2(1H)-one derivatives (4a–i).
2.4 Reusability of the catalyst
After completion of the model reaction in specified time, (Table 6) the crude product obtained was extracted with dichloromethane, and the catalyst was recovered by separation of aqueous and organic phases. The catalyst present in the aqueous medium was used for the subsequent cycle. The same procedure was applied to all recycling studies. The results (Table 6) revealed that the catalyst exhibited good catalytic activity up to five cycles.
Recycling study of catalyst for the model reactiona.
| Catalyst recycle | Time (min)b | Yieldc (%) |
| I | 5 | 92 |
| II | 5 | 92 |
| III | 5 | 92 |
| IV | 5 | 92 |
| V | 5 | 92 |
| VI | 10 | 88 |
a Reaction of ethylacetoacetate (1a), urea (2) and benzaldehyde (3a) in the presence of [Zn(L-proline)2] (10 mol%) catalyst in water.
b Reaction progress monitored by TLC.
c Isolated yield.
The identity of the recovered catalyst was checked by SEM-EDX (Fig. 1 b) and it was observed that there was no change in the morphology of the catalyst as compared to fresh catalyst (Fig. 1 a).
SEM images of the fresh (a) and recovered catalyst (b).
3 Experimental
3.1 General
Melting points were taken in Riechert Thermover instrument and are uncorrected. The IR spectra were recorded on Perkin Elmer spectrometer in KBr. 1H NMR, 13C NMR spectra were recorded on a Bruker DRX-300 Spectrometer using tetra methyl silane (TMS) as an internal standard. DART-MS recorded on a JEOL-Accu TOF JMS-T100LC mass spectrometer having a DART source. Chemical shifts are reported in ppm downfield from TMS as internal standard. The micro analytical data were collected on Elementar vario EL III elemental analyzer. Other chemicals were purchased from Sigma-Aldrich chemicals Pvt. Ltd. and Otto chemie Pvt. Ltd. and were used without further purification. The purity of all compounds was checked on silica gel (E-Merck G254) plates using iodine vapors as visualizing agents. The SEM-EDX characterization of the catalyst was performed on a JEOL JSM-6510 scanning electron microscope, equipped with energy dispersive X-ray spectrometer, operating at 20 kV.
3.2 Synthesis of [Zn(L-proline)2] complex
A mixture of (L)-Proline (10 mmol) and potassium hydroxide (10 mmol) was dissolved in absolute ethanol (25 mL) and magnetically stirred for 15 min in a round-bottomed flask at room temperature. Zn(NO3)2.6H2O (5 mmol) was dissolved in minimum quantity of double distilled water and added in drops to the above solution. The contents were vigorously stirred for 6 h by using a magnetic stirrer. The [Zn(L-proline)2] complex was obtained as a white solid. It was collected by filtration and dried at 70 °C in vacuum for 6 h. Formation of [Zn(L-proline)2] complex was confirmed by the EDX spectrum (Fig. 2) which showed the presence of Zn, C, O and N.
EDX spectrum of the catalyst.
3.3 [Zn(L-proline)2] catalyzed synthesis of 3,4-dihydropyrimidin-2(1H)-ones derivatives (4a–i) in aqueous medium
A mixture of active methylene compounds (1a–b) (1 mmol), urea (2) (1 mmol), aromatic aldehydes (3a–e) (1 mmol) and [Zn(L-proline)2] (10 mol %) was refluxed in water (12 mL) for the specified time (Table 5). After completion of the reaction, monitored by TLC, the reaction mixture was allowed to cool to room temperature. The crude product was extracted with dichloromethane, dried over anhydrous Na2SO4 and concentrated to furnish 4a–i. The recrystallization of crude products (4a–i) was done with chloroform-methanol mixture (1:4 v/v). The catalyst was recovered by simple separation of aqueous and organic phases. The catalyst present in the aqueous layer was used for the subsequent cycle.
3.4 Spectral data of the products
3.4.1 5-Ethoxycarbonyl-6-methyl-4-phenyl-3,4-dihydropyrimidin-2(1H)-one (4a)
M.p. 202–204 °C; Anal. calcd. for C14H16N2O3 (%) C 64.60, H 6.19, N 10.76. Found. C 64.47, H 6.24, N 10.71. IR (KBr, cm−1): 1650 (C = O), 1729 (C = O), 3122 (NH), 3245 (NH). 1H NMR (300 MHz, DMSO-d6): δ 1.11 (t, J = 7.2 Hz, 3H, CH3), 2.24 (s, 3H, CH3), 4.01 (q, J = 7.2 Hz 2H, OCH2), 5.17 (s, 1H, H-4), 7.48-7.22 (m, 5H, Ar-H), 7.74 (br s, 1H, NH), 9.20 (br s, 1H, NH). MS-ESI (m/z, %): 261.14 (M+ +1).
3.4.2 5-Acetyl-6-methyl-4-phenyl-3,4-dihydropyrimidin-2(1H)-one (4b)
M.p. 232–235 °C. Anal. calcd. for C13H14N2O2: C 67.81, H 6.12 N 12.16. Found. C 67.73, H 6.22, N 12.11. IR (KBr, cm−1): 1650 (C = O), 1706 (C = O), 3267 (NH); 1H NMR: (300 MHz, DMSO-d6) δ 2.10 (s, 3H, CH3), 2.28 (s, 3H, CO-CH3), 5.25(s, 1H, H-4), 7.35-7.23 (m, 5H, Ar-H), 7.83 (s, 1H, NH), 9.19 (s, 1H, NH). MS-ESI (m/z, %): 231.13 (M+ +1).
3.4.3 5-Ethoxycarbonyl-6-methyl-4-(3-nitrophenyl)-3,4-dihydropyrimidin-2(1H)-one (4c)
M.p. 227–229 °C. Anal. calcd. for C14H15N3O5: C 55.08, H 4.94, N 13.76. Found. C 55.16, H 4.97, N 13.70. IR (KBr, cm−1): 1627 (C = O), 1706 (C = O), 3100 (NH), 3223 (NH); 1H NMR (300 MHz, DMSO-d6) δ 1.11 (t, J = 7.2 Hz, 3H, CH3), 2.26 (s, 3H, CH3), 4.01 (q, J = 6.9 Hz, 2H, OCH2), 5.30 (s, 1H, H-4), 8.14-7.62 (m, 4H, Ar-H), 7.90 (br s, 1H, NH), 9.37 (s, 1H, NH). MS-ESI (m/z, %): 306.13 (M+ +1).
3.4.4 5-Acetyl-6-methyl-4-(3-nitrophenyl)-3,4-dihydropyrimidin-2(1H)-one (4d)
M.p. 220–225 °C. Anal. calcd. for C13H13N3O4: C 56.72, H 4.76, N 15.26. Found. C 56.63, H 4.85, N 15.16. IR (KBr, cm−1): 1683 (C = O), 3275 (NH); 1H NMR: (300 MHz, DMSO-d6) δ 2.05 (s, 3H, CH3), 2.33 (s, 3H, CO-CH3), 5.67 (s, 1H), 7.45-7.27 (m, 4H, Ar-H), 7.72 (s, 1H, NH), 9.26 (s, 1H, NH). 13C NMR: (75 MHz, DMSO-d6): δ 19.55, 21.21, 109.9, 121.58, 122.77, 129.97, 130.64, 133.46, 146.92, 148.36, 152.46, 194.52. MS-ESI (m/z, %): 276.13 (M+ +1).
3.4.5 5-Ethoxycarbonyl-6-methyl-4-(4-hydroxyphenyl)-3,4-dihydropyrimidin-2(1H)-one (4e)
M.p. 227–229 °C. Anal. calcd. for C14H16N2O4: C 60.86, H 5.83, N 10.13. Found. C 60.72, H 5.89, N 10.16. IR (KBr, cm−1): 1646 (C = O), 1690 (C = O), 3122 (NH), 3246 (NH), 3515 (OH); 1H NMR (300 MHz, DMSO-d6): δ 1.12 (t, J = 7.2 Hz, 3H, CH3), 2.23 (s, 3H, CH3), 4.01 (q, J = 7.2 Hz, 2H, OCH2), 5.04 (s, 1H, H-4), 6.69 (d, 2H, J = 8.4 Hz, Ar-H), 7.04 (d, 2H, J = 8.4 Hz, Ar-H), 7.60 (br s, 1H, NH), 9.09 (br s, 1H, NH), 9.31 (s, 1H, OH). 13C NMR (75 MHz, DMSO-d6): δ 14.55, 18.19, 53.92, 59.56, 100.26, 115.45, 127.85, 135.89, 152.65, 157.01, 165.89. MS-ESI (m/z, %): 277.14 (M+ +1).
3.4.6 5-Acetyl-6-methyl-4-(4-hydroxyphenyl)-3,4-dihydropyrimidin-2(1H)-one (4f)
M.p. 231–234 °C. Anal. calcd. for C13H14N2O3: C 63.40, H 5.73, N 11.37. Found. C 63.48, H 5.82, N 11.33. IR (KBr, cm−1): 1647 (C = O), 1687 (C = O), 3120 (NH), 3283 (NH), 3516 (OH). 1H NMR (300 MHz, DMSO-d6): δ 2.10 (s, 3H, CH3), 2.22 (s, 3H, CO-CH3), 5.04 (s, 1H), 6.69 (d, 2H, J = 8.4 Hz, Ar-H), 7.04 (d, 2H, J = 8.4 Hz, Ar-H), 7.60 (s, 1H, NH), 9.09 (s, 1H, NH), 9.31 (s, 1H, OH). ESI-MS (%): 247.08 (M+ +1).
3.4.7 5-Ethoxycarbonyl-6-methyl-4-(2-chlorophenyl)-3,4-dihydropyrimidin-2(1H)-one (4g)
M.p. 214–216 °C. Anal. calcd. for C14H15N2O3Cl: C 57.05, H 5.12, N 9.50. Found. C 57.12, H 5.29, N 9.46. IR (KBr, cm−1): 1650 (C = O), 1700 (C = O), 3115 (NH), 3230 (NH); 1H NMR (300 MHz, DMSO-d6): δ 1.01 (t, J = 6.9 Hz, 3H, CH3), 2.30 (s, J = 6.9 Hz, 3H, CH3), 3.92 (q, 2H, OCH2), 5.63 (s, 1H), 7.25–7.41 (m, 4H, Ar-H), 7.68 (br s, 1H, NH), 9.25 (br s, 1H, NH). ESI-MS (m/z, %): 295.11(M+ +1).
3.4.8 5-Acetyl-6-methyl-4-(2-chlorophenyl)-3,4-dihydropyrimidin-2(1H)-one (4h)
M.p. 303–305 °C. Anal. calcd. for C13H13N2O2Cl: C 58.98, H 4.95, N 10.58. Found. C 58.92, H 4.97, N 10.63. IR (KBr, cm−1): 1625 (C = O), 1708 (C = O), 3092 (NH), 3246 (NH). 1H NMR: (300 MHz, DMSO-d6) δ 2.05 (s, 3H, CH3), 2.33 (s, 3H, CO-CH3), 5.67 (s, 1H), 7.45-7.27 (m, 4H, Ar-H), 7.72 (s, 1H, NH), 9.26 (s, 1H, NH). ESI-MS (m/z, %): 265.09 (M+ +1).
3.4.9 5-Ethoxycarbonyl-6-methyl-4-(4-chlorophenyl)-3,4-dihydropyrimidin-2(1H)-one (4i)
M.p. 213–215 °C. Anal. calcd. for C14H15N2O3Cl: C 58.98, H 4.95, N 10.58. Found. C 58.94, H 5.02, N 10.56. IR (KBr, cm−1): 1651 (C = O), 1718 (C = O), 3120 (NH), 3243 (NH). 1H NMR (300 MHz, DMSO-d6): δ 1.10 (t, J = 7.2 Hz, 3H, CH3), 2.24 (s, 3H, CH3), 4.01 (q, J = 6.9 Hz, 2H, OCH2), 5.14 (s, 1H, H-4), 7.25-7.23 (d, 2H, J = 8.4 Hz), 7.40-7.37 (d, 2H, J = 8.1 Hz), 7.78 (br s, 1H, NH), 9.26 (s, 1H, NH). ESI-MS (m/z, %): 295.10 (M+ +1).
4 Conclusion
In conclusion, a practical, efficient, ecofriendly and convenient method for the synthesis of a series of biologically relevant 3,4-dihydropyrimidin-2(1H)-ones is described using [Zn(L-proline)2]-water catalytic system. Short reaction time, high yields, clean process, simple methodology, easy workup, and green sustainable conditions are the key features involved in the present protocol. These features will enable this protocol to find widespread applications in the field of organic synthesis.
Acknowledgments
Financial assistance in the form of major research project [F.No. 37-15/2009 (SR)] from University Grants commission, New Delhi, is gratefully acknowledged. The author would also like to thank Prof. R.C. Kamboj, department of Chemistry, Kurukshetra University, India for spectral data and University Sophisticated Instrument Facility (USIF), AMU, Aligarh for providing SEM-EDX facilities.