In the first instance, optimal conditions were sought by a model reaction which was accomplished by applying various types of catalysts, solvents and also solvent-free conditions, with the anticipation to reduce the reaction time and increase product yield. When the reaction of substituted aldehyde (1 mmol), malononitrile (1.1 mmol), dimethylacetylenedicarboxylate (1.0 mmol) and dimethylaniline (1 mmol) were stirred together, no product formation took place in the presence of catalyst-free and solvent-free condition at RT, even after 12 h of reaction (Table
0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 20
40 60 80 100 120 140 160
Quantity Adsorbed (cm³/g STP)
Relative Pressure (P/Po) CeO2/ZrO2 N2 adsorption CeO2/ZrO2 N2 desorption
99 1, entry 1). The same reaction was then carried out in ethanol solvent under catalyst-free condition at RT and it was observed that no product was formed even after 12 h. The same reaction was conducted under reflux conditions, but the reaction did not afford the desired product (Table 1, entry 2 & 3). Subsequently the reaction was performed in the presence of different acidic catalysts, such as acetic acid (AcOH), FeCl3 and H3BO3 for their efficiency in catalyzing the reaction at RT but no reaction occured (Table 1, entries 4–6). Further, the same reaction was evaluated using base catalysts (inorganic or organic) such as NH4OAc, K2CO3, NaOH, TEA, DABCO, and piperidine, and low yield of product was obtained in the presence of these bases after 6 h (Table 1, entries 7–12). This was followed by pure oxide catalysts, such as Al2O3, SiO2 and ZrO2 which were performed in an ethanol solvent system at RT, the reaction showed moderate to good yields after 2.0-3.5 h reaction time (Table 1, entries 13-15). After having this positive result using zirconia oxide, we wanted to optimize the reaction condition by doping with various metal oxides, such as 2.5% Cu/ZrO2, Mn/ZrO2, and Ce/ZrO2 was screened in ethanol solvent at RT Those mixed oxide catalytic reactions afforded very good to excellent yields (82-95%) within 30 min reaction time (Table 1, entry 16-18). Remarkably, when CeO2/ZrO2 was used as catalyst, a reaction progressed impressively recording an excellent yield (95%) of functionalized 1,4-dihydropyridine-2,3-dicarboxylates at RT, within 20 min reaction time. Based on the evaluation of positive results, it is noticeably that ceria on zirconia catalyst revealed high surface areas which have most active sites showing more catalytic activity over other catalysts. Therefore, this study focused on one-pot, four-component reactions to achieve excellent yields. Mixed oxides offer greater surface area, smaller particle sizes and greater generation of catalytic active sites than the corresponding oxide homologues. [33] These aspects are of extreme importance since higher surface area favors adsorption of reaction molecules, while the small particle size is advantageous for minimal internal dispersion resistance of molecules in this manner increasing the catalytic activity.
We further investigated the effect of solvent in this reaction, because solvents can play a deciding outcome for many important multi-component reactions. [34] Attempts to optimize the solvent-system indicated that the activity of CeO2/ZrO2 was greatly affected by the solvent in which the reaction was performed (Table 2). The reaction proceeded efficiently in polar solvents such as methanol, ethanol and isopropyl alcohol, but not in non-polar solvents such as acetonitrile, DMF, n-hexane and toluene. EtOH solvent, which can disperse temperature
100 promptly, affords an optimum environment for formation of intermediates on the catalyst surface, and their consequent transformation to target products. In view of the green nature, short reaction and excellent yields, EtOH demonstrated to be the ideal solvent for the present procedure.
Table 1: This table shows the yield of the different catalysts for the model reaction
aReaction conditions: dimethylacetylenedicarboxylate (1 mmol), dimethylaniline (1 mmol), malononitrile (1.1 mmol), 2-methoxybenzaldehyde (1 mmol) and catalyst.
bIsolated yields; -- No reaction
Furthermore, we examined the amount of catalyst needed for reaction, because this has a major effect on the reactant transformation to product. When we increased the amount of catalyst 10 to 30 mg, the yield of the product continuously increased from 79 to 95% and further increase of the catalyst quantity did not increase the reaction yield of the product (Table 3). The outcome of the above promising result suggests that 30 mg of Ce/ZrO2 is most suitable for this reaction.
Entry Catalyst Temperature Time (h) Yield (%)b
1 -- R.T. 12 --
2 -- R.T. 12 --
3 -- Reflux 12 --
4 AcOH R.T. 12 --
5 FeCl3 R.T. 12 --
6 H3BO3 R.T. 12 --
7 NH4OAc R.T. 8.0 27
8 K2CO3 R.T. 6.2 34
9 NaOH R.T. 6.5 25
10 TEA R.T. 7.0 24
11 DABCO R.T. 7.5 19
12 piperidine R.T. 7.0 22
13 Al2O3 R.T. 3.5 51
14 SiO2 R.T. 2.5 60
15 ZrO2 R.T. 2.0 76
16 2.5% CuO/ZrO2 R.T. 0.5 82
17 2.5% MnO2/Zr2 R.T. 0.4 89
18 2.5% CeO2/Zr2 R.T. 0.33 95
101 Table 2: Optimization of various solvent condition for the model reaction by 2.5% Ce/ZrO2 catalysta
Entry Solvent Yield (%)
1 CH3CN 15
2 DMF 19
3 n-hexane --
4 Toluene --
5 MeOH 75
6 EtOH 95
7 isopropyl alcohol 68
aReaction conditions: dimethylacetylenedicarboxylate (1 mmol), dimethylaniline (1 mmol), malononitrile (1.1 mmol), 2-methoxybenzaldehyde (1 mmol), catalyst (30 mg) and solvent (10 mL) were stirred at room temperature.
Table 3: Optimization of the amount of 2.5% Ce/ZrO2 as catalyst in the model reactiona Entry Catalyst (mg) Time (min) Yield (%)
1 10 45 75
2 20 35 84
3 30 20 95
4 40 20 95
5 50 15 94
aReaction conditions: dimethylacetylenedicarboxylate (1 mmol), dimethylaniline (1 mmol), malononitrile (1.1 mmol), 2-methoxybenzaldehyde (1 mmol), catalyst and ethanol (10 mL) solvent were stirred at room temperature.
To demonstrate the robustness of the new protocol, reactions with numerous aromatic aldehydes substituted with diverse electron-withdrawing or electron-releasing groups were assessed and obtained; the results are summarized in (Table 4). In all cases, all the substituted aromatic aldehydes, irrespective of electron-donating or electron-withdrawing groups showed exceptional reactivity in forming the respective pyridine derivatives in good to high yields.
Structures of all the isolated products 5a–l were deducted and validated by physical and spectroscopic data including IR, 1H NMR, 15N NMR, 13C NMR and HR-MS spectral analysis.
Some of the compounds details are showed in supplementary information.
102 Table 4: Synthesis of functionalized 1,4-dihydropyridine-2,3-dicarboxylates by 2.5% Ce/ZrO2 catalysta*
Entry R Product Yield (%) Mp °C
1 2-OMe 5a 95 215-216
2 2-F 5b 87 206-208
3 2-Cl 5c 90 220-221
4 2-Br 5d 88 239-240
5 4-Cl 5e 94 221-222
6 4-Br 5f 92 249-250
7 2,3-(OMe)2 5g 91 201-203
8 3,4-(OMe)2 5h 93 233–235
9 2,5-(OMe)2 5i 92 246–247
10 4-F 5j 87 227-228
11 2,4,6-(OMe)3 5k 89 186-188
12 4-MeO 5l 92 206-208
aReaction conditions: dimethylacetylenedicarboxylate (1 mmol), dimethyl aniline (1 mmol), malononitrile (1.1 mmol), substituted benzaldehyde (1 mmol), catalyst (30 mg) and ethanol solvent (10 mL) were stirred at room temperature.
* All the compounds are new; R = substituted benzaldehydes
3.5. Reusability of the catalyst
Commercial application for any catalyst can be realized if reusability thereof becomes a demonstrated advantage and we thus investigated the recovery and reusability of the CeO2/ZrO2
catalyst. The reusability of the catalyst was tested by separating the CeO2/ZrO2 from the reaction mixture by simple filtration under vacuum, washed with acetone, and drying in a vacuum oven at 80 °C for 4 h to reuse in consequent reactions. The recovered catalyst can be reused at least six runs in successive reactions without significant loss in product yield.
3.6. Conclusion
In this study, we report on a green and efficient one-pot protocol for the synthesis of functionalized 1,4-dihydropyridine-2,3-dicarboxylate derivatives through a four-component reaction between malononitrile, dimethylacetylenedicarboxylate, dimethylaniline and substituted aldehydes using 2.5% CeO2/ZrO2 as a catalyst in EtOH and at room temperature. This methodology has several advantages such as short reaction times (< 30 min), high product yields
103 (87-95%), ease of handling, facile and green work-up. The easy recoverable and reusable catalyst meets the industrial and environmental requirements and is versatile and cost effective.
3.7. Acknowledgements
The authors are thankful to the National Research Foundation (NRF) of South Africa, and University of KwaZulu-Natal, Durban, for financial support and research facilities.