A comparative study of the catalytic activity of nanosized oxides in the one-pot synthesis of highly substituted dihydropyridines

Abstract

A four-component reaction of aromatic aldehydes, ethyl cyanoacetate, arylamines, and dimethyl acetylenedicarboxylate has been achieved in the presence of nanosized oxides (ZnO NPs, CuO NPs, CeO₂ NPs, SnO NPs, MgO NPs and CaO NPs) as highly effective heterogeneous catalysts to produce polysubstituted dihydropyridines. Extraordinarily, the best results were obtained using CeO₂ nanoparticles as an efficient catalyst. This method provides several advantages, including mild reaction conditions, applicability to a wide range of substrates, reusability of the catalyst and minimal catalyst loading.

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1. Introduction

Dihydropyridines represent a common scaffold in numerous bioactive compounds, and have a number of pharmacological properties. These compounds are used as calcium-channel-modulating agents, treatments for cardiovascular disease,¹ effective MDR-modulators,² HIV-1 protease inhibitors,³ and for cleavage of DNA.⁴ Compounds containing this ring system, such as tacrine-dihydropyridines, have been designed for the treatment of Alzheimer's disease.⁵ Some other examples of dihydropyridines include such prominent drug molecules as nimodipine, nisoldipine, nitrendipine, amlodipine, nicardipine and nilvadipine, which have superior bioavailability, as well as a slower onset and prolonged effects. Dihydropyridines have been regarded as significant targets of organic synthesis. Therefore, finding efficient and simple methods for the synthesis of dihydropyridines is an attractive challenge. The synthesis of bioactive compounds should be facile, flexible, rapid and useful in organic synthesis. Multi-component reactions (MCRs) are very flexible, atom economic in nature, convergent, and simple, and are often considered for the development of environmentally benign synthetic methods. Thus, the synthesis of polysubstituted dihydropyridines by multicomponent reactions could enhance their efficiency from the economic and ecological points of view. MCRs enhance efficiency by combining several operational steps without the isolation of intermediates or changing of the reaction conditions.^6–10 Similarly, nanoparticles have received considerable attention with the aim of finding significant applications in organic reactions. In heterogeneous catalysis, understanding the catalyst surface and structure is important for understanding the mechanism of the catalytic system. Nanoparticles exhibit good catalytic activity, due to their large surface area and high number of active sites, which are mainly responsible for their catalytic activity. Ideally, introducing neat processes and utilizing eco-friendly and green catalysts, which can be simply recycled at the end of the reaction has received significant attention in recent years.^11–14

Metal oxides represent a broad class of materials that have been researched extensively because of their unique properties and potential applications in diverse fields.¹⁵ During the last decade, nanoparticle metal oxides have received significant attention as efficient catalysts in many organic reactions, due to their high surface-to-volume ratio and coordination sites, which provide a larger number of active sites per unit area in comparison with their heterogeneous counter sites. Nanocrystalline zinc oxide is one of the most broadly used surface materials for many chemical transformations, such as photoactivity and flame-retardancy,¹⁶ semiconductors¹⁷ and antibacterial materials.¹⁸ Tin and tin oxides are usually considered to be promising potential anode materials for lithium-ion batteries, due to their high theoretical reversible capacities, natural abundance and low cost.¹⁹ Among the heterogeneous basic catalysts, magnesium oxide is a versatile material that is used as a catalyst for several base-catalyzed organic transformations. Magnesium oxide (MgO), a highly effective heterogeneous basic catalyst, is used as an active catalyst in many reactions, including the synthesis of tetrahydrobenzopyran and 3,4-dihydropyrano[c]chromenes,²⁰ as well as 2-amino-4H-pyrans and 2-amino-5-oxo-5,6,7,8-tetrahydro-4H-chromenes.²¹ Nanocrystalline copper(II) oxides have been used as efficient heterogeneous catalysts in various organic transformations, such as C-arylation reactions,²² cross-coupling reactions,²³ and polyhydroquinoline.²⁴ Recently, calcium oxide nanoparticles have been used as active catalysts in many chemical transformations, including the adsorption of Cr(VI) from aqueous solutions,²⁵ the transesterification of sunflower oil,²⁶ and the catalyzed synthesis of highly substituted pyridines.²⁷ CeO₂ has received considerable attention because of its many attractive characteristics, such as its unique UV absorption abilities²⁸ and ferromagnetic properties,²⁹ and is a key component of the catalyst formulation for the dehydrogenation of ethylbenzene to styrene.³⁰ Recently, cerium nanoparticles have been used as a suitable catalyst in many reactions, including the synthesis of cyclic ureas,³¹ polyhydroquinolines,³² and 1,4-disubstituted-1,2,3-triazoles.³³ In the present research, CeO₂ nanoparticles were fabricated by a simple co-precipitation method. Compared with other techniques, this co-precipitation method is a simple and attractive procedure for the preparation of CeO₂ nanoparticles. Herein, we report the use of CeO₂ nanoparticles as an efficient catalyst for the preparation of 5-ethyl 2,3-dimethyl 6-amino-1-phenyl-1,4-dihydro-4-phenylpyridine-2,3,5-tricarboxylate derivatives by a four-component reaction of aromatic aldehydes, ethyl cyanoacetate, arylamines, and dimethyl acetylenedicarboxylate in ethanol at room temperature (Scheme 1). Moreover, we compared the catalytic activity of nanosized oxides (ZnO NPs, CuO NPs, SnO NPs MgO NPs and CaO NPs) in the one-pot synthesis of highly substituted dihydropyridines. The synthesis of 5-ethyl 2,3-dimethyl 6-amino-1-phenyl-1,4-dihydro-4-phenylpyridine-2,3,5-tricarboxylate derivatives has been reported using MCRs in the presence of catalysts, including NaOH,³⁴ Et₃N (ref. 35) and KF/Al₂O₃.³⁶

Scheme 1 Synthesis of highly substituted dihydropyridines.

2. Results and discussion

To begin, we prepared nanosized oxides by simple techniques. The particle size diameter (D) of the nanoparticles has been calculated using the Debye–Scherrer equation (D = Kλ/β cos θ), in which the β FWHM (full-width at half-maximum or half-width) is in radians and θ is the position of the maximum of the diffraction peak. K is the so-called shape factor, which usually has a value of about 0.9, and λ is the X-ray wavelength (1.5406 Å for Cu Kα). Fig. S1 shows the XRD spectra of the nanoparticles (see ESI†). Using the Debye–Scherrer equation, the average particle sizes of the as-synthesized nanoparticles were calculated, and the results show that nanoparticles were obtained with an average diameter of 10–50 nm as confirmed by XRD analysis. This pattern is in good agreement with the reported pattern for nanosized oxides. In order to investigate the morphology and particle size of nanoparticles, SEM images of the nanoparticles were obtained and are presented in Fig. S2 (see ESI†). The SEM image shows particles with diameters in the range of nanometers. The results show that the average particle sizes of CaO, ZnO, CuO, MgO, SnO and CeO₂ nanoparticles were found to be 35 nm, 24 nm, 40 nm, 18 nm, 28 nm, and 11 nm, respectively.

Initially, we carried out the MCR between 4-bromobenzaldehyde, ethyl cyanoacetate, dimethyl acetylenedicarboxylate and aniline at room temperature as a model reaction in the presence of different catalysts. Moreover, we observed the effects of different solvents on the progress of the reaction. Ethanol was found to be the best solvent, in which the product was obtained in 90% yield. Unfortunately, when the model reaction was carried out in water, the desired product was only obtained in 33% yield. The model reaction was carried out in the presence of various nanocatalysts, such as CaO, ZnO, CuO, MgO, SnO and CeO₂ nanoparticles. When the reaction was carried out using CaO, MgO and CeO₂ nanoparticles as the catalyst, the product was obtained in moderate to good yields of 65%, 72% and 90%, respectively. Therefore, metal oxides show different yields due to the different types of metal in the oxides. The chemical nature and the existing form of the catalyst play a vital role in the reaction. From the results, it is obvious that the CeO₂ nanoparticles are the best catalyst among those examined, as reported in Table 1. When 2, 4 and 6 mol% of CeO₂ nanoparticles were used, the yields were 85%, 90% and 90%, respectively. Consequently, 4 mol% of CeO₂ NPs was expedient, and excessive amounts of CeO₂ nanoparticles did not significantly change the yields. The size of the prepared CeO₂ nanoparticles was found to be 11 nm. Perhaps the increased surface area due to the small particle size increased the reactivity. The active sites of the CeO₂ nanoparticles are responsible for the accessibility of the substrate molecules on the surface of the catalyst. Nanoparticle catalysts are highly active, because most of the surface of the particles is available for catalysis, and the chemical reactions take place mainly on the surface of the particles. The chemistry of rare earth elements differs from the main group elements and transition metals due to the nature of the 4f orbitals, which are ‘buried’ inside the atom and are shielded from the atomic environment by the 4d and 5p electrons. Thus, the CeO₂ NPs may coordinate with the active groups more than other catalysts in the present reaction. These orbitals give rare earth elements inimitable catalytic, magnetic and electronic properties.

Table 1 Optimization of reaction conditions using different catalysts^a

Entry	Catalyst (mol%)	Solvent	Time (min)	Yield^b % [Ref.]
a 4-Bromobenzaldehyde (2 mmol), ethyl cyanoacetate (2 mmol), dimethyl acetylenedicarboxylate (2 mmol) and aniline (2 mmol).b Isolated yield.c In this case times of reaction is in hour unit.
1	None	EtOH	24^c	0
2	NaOH (10)	EtOH	480	85 (ref. 34)
3	Et3N (30)	EtOH	600	86 (ref. 35)
4	CaO NPs (10)	EtOH	250	65
5	ZnO NPs (10)	EtOH	275	59
6	CuO NPs (15)	EtOH	250	52
7	MgO NPs (6)	EtOH	210	72
8	SnO NPs (8)	EtOH	250	54
9	MgO NPs (6)	CH3CN	220	63
10	CeO2 NPs (4)	H2O	290	33
11	CeO2 NPs (4)	DMF	180	60
12	CeO2 NPs (4)	CH3CN	160	75
13	CeO2 NPs (2)	EtOH	160	85
14	CeO2 NPs (4)	EtOH	140	90
15	CeO2 NPs (6)	EtOH	137	90
16	MgO NPs (4)	EtOH	140	61
17	SnO NPs (4)	EtOH	140	38
18	CuO NPs (4)	EtOH	140	35
19	ZnO NPs (4)	EtOH	140	40
20	CaO NPs (4)	EtOH	140	47

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We also investigated the recycling of the nanosized oxide catalysts under reflux conditions in ethanol. The results showed that the CeO₂ NPs can be reused several times without a noticeable loss of catalytic activity (yields 90% to 89%) (Fig. 1). The extreme stability of the CeO₂ nanoparticles is the mainspring of their continuous and high catalytic activity. The morphology of the CeO₂ nanoparticles was investigated by scanning electron microscopy (SEM) before use, and after reusing the nanoparticles five times; the images are shown in Fig. S3 (see ESI†). Interestingly, the shape and size of the nanoparticles remained unchanged before and after the reaction. We suppose that this is also a possible reason for the extreme stability of the CeO₂ nanoparticles presented herein.

Fig. 1 Recycling of nanosized oxides as catalysts.

A series of aromatic aldehydes and amines were investigated (Table 2). The results gave excellent yields using aromatic aldehydes bearing either electron-withdrawing substituents or electron-donating substituents.

Table 2 Synthesis of 5-ethyl 2,3-dimethyl 6-amino-1-phenyl-1,4-dihydro-4-phenylpyridine-2,3,5-tricarboxylate derivatives using CeO₂NPs^a

Entry	5a–i	R	R′	Product	Time (min)	Yield^b (%)	M.P. °C, (ref.)
a Aromatic aldehydes (2 mmol), ethyl cyanoacetate (2 mmol), dimethyl acetylenedicarboxylate (2 mmol), aromatic amine (2 mmol).b Isolated yield.
1	5a				151	85	185–186 (ref. 35)
2	5b				142	88	129–130 (ref. 35)
3	5c				146	84	152–153 (ref. 35)
4	5d				143	87	136–140
5	5e				140	90	138–141
6	5f				153	81	181–182 (ref. 35)
7	5g				148	85	186–187 (ref. 35)
8	5h				150	84	191–192 (ref. 35)
9	5i				144	85	142–144

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All the products were well characterized by IR, ¹H NMR and ¹³C NMR.

A plausible mechanism for the preparation of highly substituted dihydropyridines using CeO₂ NPs is shown in Scheme 2. First, we assumed that the reaction occurs via a Knoevenagel condensation between ethyl cyanoacetate and the aldehyde to form the intermediate I₁ on the active sites of the CeO₂ NPs, which makes the aldehydes more electrophilic. Then, arylamine added to acetylenedicarboxylate to give the intermediate I₂. Michael addition of I₂ to I₁ yielded the adduct I₃. Migration of the hydrogen atom provided the intermediate I₄, and subsequent intramolecular addition of the amino group to the C≡N gave the cyclic intermediate I₅. Finally, the N-aryl dihydropyridine was formed by the tautomerization of the imino group to the amino group. The likely role of the CeO₂ NPs is the activation of the nitrile for transformation into the amine.

Scheme 2 Proposed mechanism for the four-component reaction.

3. Experimental

3.1. Chemicals and apparatus

The products were isolated and characterized by physical and spectral data. ¹H NMR and ¹³C NMR spectra were recorded using a Bruker Avance-400 MHz spectrometer in the presence of tetramethylsilane as an internal standard. The IR spectra were recorded on a Magna 550 FTIR apparatus using KBr plates. Melting points were determined using an Electro Thermal 9200 instrument, and are not corrected. The elemental analyses (C, H, N) were obtained from a Carlo ERBA Model EA 1108 analyzer. Powder X-ray diffraction (XRD) was carried out on a Philips diffractometer (X'pert Company) with monochromatized Cu Kα radiation (λ = 1.5406 Å). The microscopic morphology of the products was visualized by SEM (LEO 1455VP and MIRA 3 TESCAN).

3.2. Preparation of CaO nanoparticles

Calcium oxide nanoparticles were prepared in accordance with the procedure reported by Tang et al.³⁷ NaOH (1 g) was added to a mixture of ethylene glycol (12 mL) and Ca(NO₃)₂·4H₂O (6 g) and the solution was stirred vigorously at room temperature for 10 min; the gel solution was maintained for about 5 h in a static state. Afterwards, the product was washed using water and dried under vacuum. Finally, the prepared CaO nanoparticles were calcinated at 700 °C for 3 h. The sample was characterised by X-ray diffraction (XRD) and scanning electron microscopy (SEM). The average crystallite size of CaO was found to be 35 nm.

3.3. Preparation of ZnO nanoparticles

Zinc oxide nanoparticles were prepared according to the procedure reported by Shen et al.³⁸ In a typical procedure, zinc acetate (9.10 g, 0.05 mol) and oxalic acid (5.4 g, 0.06 mol) were combined by grinding in an agate mortar for 1 h at room temperature. Afterwards, the formed ZnC₂O₄·2H₂O nanoparticles were calcinated at 450 °C for 30 min to produce ZnO nanoparticles under thermal decomposition conditions. The crystallite size of ZnO was found to be 24 nm.

3.4. Preparation of CuO nanoparticles

Copper(II) oxide nanoparticles were prepared according to the procedure reported by Jang et al.³⁹ A solution of copper acetate (1.0 g) and acetic acid (1.0 mL) in 250 mL of distilled water was heated at 100 °C. Then, 0.8 g of NaOH was added quickly under vigorous stirring. The reaction mixture was cooled to room temperature and the obtained black powders were separated by centrifugation. The collected precipitate was then washed several times with distilled water and ethanol, and dried at 100 °C for 10 h. The results show that spherical CuO nanoparticles were obtained, with an average diameter of 40 nm as confirmed by XRD analysis.

3.5. Preparation of MgO nanoparticles

We prepared magnesium oxide nanoparticles (NPs) in this study using an ultrasound technique. A solution of 1 mol L⁻¹ sodium hydroxide was added drop-wise to a solution prepared from dissolving 2 g of Mg(NO₃)₂·6H₂O and 0.5 g polyvinyl pyrolydon (PVP) as a surfactant. Then, the reaction mixture was sonicated for 30 min (ultrasonic power 90 W). The prepared gel was centrifuged and washed several times with deionized water and ethanol, and finally calcined in a furnace at 600 °C for 2 h. The crystallite size diameter (D) of the MgO NPs was calculated using the Debye–Scherrer equation (D = Kλ/β cos θ). The results show that hexagonal MgO NPs⁴⁰ were obtained with an average diameter of 18 nm. Nano magnesium oxide has a network crystalline structure consisting of Lewis bases and Lewis acids. All these factors contribute to the efficiency of nano magnesium oxide as a catalyst.

3.6. Preparation of SnO nanoparticles

Tin oxide nanoparticles were prepared according to a procedure reported in the literature.^41,42 A 100 mL aqueous solution of 10⁻² M was prepared by dissolving 0.225 g of tin(II) chloride (SnCl₂·2H₂O) in dilute HCl. The solution was continuously stirred, and diluted NH₄OH was added drop-wise to obtain a precipitate. The solution pH was increased to 5. The precipitate was washed several times to remove excess ions. The precipitate was dispersed in water and maintained under microwave irradiation for 18 min. The sample was characterised by X-ray diffraction (XRD) and scanning electron microscopy (SEM). The size of the prepared SnO nanoparticles under microwave conditions was reduced to 28 nm.

3.7. Preparation of CeO₂ nanoparticles

Nano CeO₂ was prepared according to a procedure reported in the literature, with some modifications.⁴³ CeO₂ nanoparticles were prepared by a co-precipitation technique with post-annealing in air. Briefly, 3 g of highly pure Ce(NO₃)₃·6H₂O was dissolved in a mixture of 50 mL deionised water and 20 mL alcohol. Then, an appropriate amount of aqueous ammonia solution (28 wt%) was added to the above solution till the pH value reached 8. Afterward, the mixture was stirred for 4 h at room temperature, and then dried at 80 °C for 6 h. The solid was then treated at 700 °C for 2 h to obtain the CeO₂ nanoparticles. The XRD pattern is in good agreement with the reported pattern for CeO₂ nanoparticles (JCPDS no. 43-1002). The crystalline size was calculated from the FWHM using Scherrer's formula, and was observed to be 11 nm.

3.8. General procedure for the preparation of 5-ethyl 2,3-dimethyl 6-amino-1-phenyl-1,4-dihydro-4-phenylpyridine-2,3,5-tricarboxylate derivatives

A mixture of aldehyde (2 mmol), ethyl cyanoacetate (2 mmol) and 4 mol% of CeO₂ NPs was stirred in 3 mL ethanol at room temperature for 30 minutes. Then, a solution of dimethyl acetylenedicarboxylate (2 mmol) and aromatic amine (2 mmol) in 2 mL ethanol was added. The entire solution was stirred at room temperature for 140–160 minutes (Table 2). The reaction was monitored by TLC. After the completion of the reaction, the solvent was concentrated and the reaction mixture was diluted with CHCl₃; the catalyst was isolated by centrifugation and the heterogeneous catalyst was recovered. The CHCl₃ was evaporated, and the separated solid was filtered and washed with ethanol to obtain pure product. The structures of the products were fully established on the basis of their ¹H NMR, ¹³C NMR and FTIR spectra.

3.9. Spectral data

5-Ethyl 2,3-dimethyl 6-amino-1-(4-chlorophenyl)-1,4-dihydro-4-phenylpyridine-2,3,5-tricarboxylate (5a). White solid; m.p. 185–186 °C; IR (KBr): ν_max 3380, 3269, 2953, 1745, 1712, 1653, 1490 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 1.24 (t, J = 6 Hz, 3H, CH₃), 3.48 (s, 3H, OCH₃), 3.64 (s, 3H, OCH₃), 4.10 (q, J = 6 Hz, 2H, CH₂), 5.01 (s, 1H, CH), 6.17 (brs, 2H, NH₂), 7.20 (1H, ArH), 7.27 (5H, ArH), 7.47 (3H, ArH) ppm; ¹³C NMR (100 MHz, CDCl₃) δ 169.5, 166.1, 164.0, 150.9, 146.7, 141.0, 136.4, 134.0, 131.9, 130.1, 128.1, 127.8, 126.4, 108.2, 80.6, 59.5, 52.6, 51.9, 37.0, 14.4 ppm; anal. calcd for C₂₄H₂₃ClN₂O₆: C, 61.21; H, 4.92; N, 5.95. Found C, 61.39; H, 4.82; N, 5.85.

5-Ethyl 2,3-dimethyl 6-amino-4-(4-chlorophenyl)-1,4-dihydro-1-phenylpyridine-2,3,5-tricarboxylate (5b). White solid; m.p. 129–130 °C; IR (KBr): ν_max 3426, 3278, 2951, 1749, 1714, 1657, 1597, 1503 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 1.20 (t, J = 6.8 Hz, 3H, CH₃), 3.41 (s, 3H, OCH₃), 3.63 (s, 3H, OCH₃), 4.05 (q, J = 6.8 Hz, 2H, CH₂), 4.98 (s, 1H, CH), 6.24 (brs, 2H, NH₂), 7.26 (m, 2H, ArH), 7.33–7.38 (m, 2H, ArH), 7.51 (m, 5H, ArH) ppm; ¹³C NMR (100 MHz, CDCl₃) δ 169.4, 166.0, 163.9, 151.2, 145.6, 141.5, 135.2, 131.8, 130.5, 130.4, 129.9, 129.3, 128.2, 107.2, 79.8, 59.4, 52.4, 51.9, 36.6, 14.5 ppm; anal. calcd for C₂₄H₂₃ClN₂O₆: C, 61.21; H, 4.92; N, 5.95. Found C, 61.38; H, 4.85; N, 5.87.

5-Ethyl 2,3-dimethyl 6-amino-4-(4-chlorophenyl)-1,4-dihydro-1-m-tolylpyridine-2,3,5-tricarboxylate (5c). White solid; m.p. 152–153 °C; IR (KBr): ν_max 3453, 3275, 2978, 2947, 1734, 1710, 1664, 1596, 1500 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 1.21 (t, J = 6.6 Hz, 3H, CH₃), 2.41 (s, 3H, CH₃), 3.43 (s, 3H, OCH₃), 3.63 (s, 3H, OCH₃), 4.06 (q, J = 6.6 Hz, 2H, CH₂), 4.97 (s, 1H, CH), 6.25 (brs, 2H, NH₂), 7.26–7.33 (m, 8H, ArH) ppm; ¹³C NMR (100 MHz, CDCl₃) δ 169.4, 166.1, 163.8, 151.3, 145.7, 141.6, 140.2, 135.1, 131.8, 131.1, 130.9, 129.6, 129.3, 128.2, 127.3, 107.1, 79.2, 59.4, 52.4, 61.8, 36.7, 21.2, 14.4 ppm; anal. calcd for C₂₅H₂₅ClN₂O₆: C, 61.92; H, 5.20; N, 5.78. Found C, 61.88; H, 5.16; N, 5.81.

5-Ethyl 2,3-dimethyl 6-amino-1,4-dihydro-1,4-diphenylpyridine-2,3,5-tricarboxylate (5d). White solid; m.p. 136–140 °C; IR (KBr): ν_max 3378, 3269, 2955, 1744, 1713, 1656, 1595, 1492 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 1.21 (t, J = 6 Hz, 3H, CH₃), 3.43 (s, 3H, OCH₃), 3.63 (s, 3H, OCH₃), 4.06 (q, J = 6 Hz, 2H, CH₂), 5.02 (s, 1H, CH), 6.23 (brs, 2H, NH₂), 7.19 (m, 1H, ArH), 7.29 (m, 3H, Ar), 7.42 (m, 3H, ArH), 7.52 (m, 3H, ArH) ppm; ¹³C NMR (100 MHz, CDCl₃) δ 169.6, 166.3, 164.1, 151.3, 147.0, 141.4, 135.4, 130.5, 130.3, 129.8, 128.1, 127.8, 126.3, 107.7, 80.3, 59.4, 52.4, 51.8, 37.1, 14.4 ppm; anal. calcd for C₂₄H₂₄N₂O₆: C, 66.04; H, 5.54; N, 6.42. Found C, 66.12; H, 5.47; N, 6.51.

5-Ethyl 2,3-dimethyl 6-amino-4-(4-bromophenyl)-1,4-dihydro-1-phenylpyridine-2,3,5-tricarboxylate (5e). White solid; m.p. 138–141 °C; IR (KBr): ν_max 3490, 3292, 2951, 1739, 1712, 1662, 1602, 1497 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 1.23 (t, J = 6.8 Hz, 3H, CH₃), 3.41 (s, 3H, OCH₃), 3.64 (s, 3H, OCH₃), 4.08 (q, J = 6.8 Hz, 2H, CH₂), 4.98 (s, 1H, CH), 6.24 (brs, 2H, NH₂), 7.29 (m, 2H, ArH), 7.41 (m, 4H, ArH), 7.51 (m, 3H, ArH) ppm; ¹³C NMR (100 MHz, CDCl₃) δ 169.4, 165.9, 163.9, 150.9, 145.9, 141.3, 136.7, 133.8, 131.9, 131.2, 130.3, 129.6, 120.2, 107.6, 80.2, 59.6, 52.6, 52.0, 36.7, 14.4 ppm; anal. calcd for C₂₄H₂₃BrN₂O₆: C, 55.93; H, 4.50; N, 5.44. Found C, 55.82; H, 4.41; N, 5.50.

5-Ethyl 2,3-dimethyl 6-amino-1-(4-chlorophenyl)-1,4-dihydro-4-(4-methoxy phenyl)pyridine-2,3,5-tricarboxylate (5f). White solid; m.p. 181–182 °C; IR (KBr): ν_max 3390, 3274, 2950, 1742, 1712, 1655, 1608, 1500 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 1.23 (t, J = 6.8 Hz, 3H, CH₃), 3.46 (s, 3H, OCH₃), 3.63 (s, 3H, OCH₃), 3.73 (s, 3H, OCH₃), 4.07 (q, J = 6.8 Hz, 2H, CH₂), 4.94 (s, 1H, CH), 6.14 (brs, 2H, NH₂), 6.83 (d, 2H, ArH), 7.25 (m, 4H, ArH), 7.45 (d, J = 8, 2H, ArH) ppm; ¹³C NMR (100 MHz, CDCl₃) δ ppm; 169.5, 166.2, 164.0, 158.1, 150.8, 140.8, 139.2, 136.4, 134.0, 131.9, 130.1, 128.7, 113.5, 108.4, 80.8, 59.4, 55.2, 52.6, 51.9, 36.1, 14.4; anal. calcd for C₂₅H₂₅ClN₂O₇: C, 59.94; H, 5.03; N, 5.59. Found C, 59.83; H, 5.09; N, 5.49.

5-Ethyl 2,3-dimethyl 6-amino-1-(4-chlorophenyl)-1,4-dihydro-4-(3-nitrophenyl)pyridine-2,3,5-tricarboxylate (5g). Light yellow solid; m.p. 186–187 °C; IR (KBr): ν_max 3437, 3223, 3108, 2987, 2954, 1751, 1710, 1663, 1603, 1524 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 1.25 (t, 3H, CH₃), 3.49 (s, 3H, OCH₃), 3.65 (s, 3H, OCH₃), 4.09 (m, 2H, CH₂), 5.11 (s, 1H, CH), 6.26 (brs, 2H, NH₂), 7.40 (d, J = 7.5 Hz, 2H, ArH), 7.47 (td, J = 8.4 Hz, J = 2 Hz, 1H, ArH), 7.51 (d, J = 7.5 Hz, 2H, ArH), 7.72 (d, J = 7.2 Hz, 1H, ArH), 8.06 (d, J = 7.5 Hz, 1H, ArH), 8.32 (1H, ArH) ppm; ¹³C NMR (100 MHz, CDCl₃) δ 169.0, 165.6, 163.5, 151.2, 149.0, 148.3, 141.8, 136.8, 134.0, 133.4, 131.8, 130.3, 128.9, 122.9, 121.5, 107.0, 79.7, 59.7, 52.7, 52.1, 37.2, 14.4 ppm; anal. calcd for C₂₄H₂₂ClN₃O₈: C, 55.87; H, 4.30; N, 8.15. Found C, 55.83; H, 4.19; N, 8.26.

5-Ethyl 2,3-dimethyl 6-amino-1-(4-chlorophenyl)-1,4-dihydro-4-p-tolylpyridine-2,3,5-tricarboxylate (5h). White solid; m.p. 191–192 °C; IR (KBr): ν_max 3389, 3274, 2950, 1742, 1712, 1654, 1607, 1498 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 1.25 (t, J = 6.6 Hz, 3H, CH₃), 2.32 (s, 3H, CH₃), 3.47 (s, 3H, OCH₃), 3.64 (s, 3H, OCH₃), 4.09 (q, J = 6.6 Hz, 2H, CH₂), 4.97 (s, 1H, CH), 6.16 (brs, 2H, NH₂), 7.10 (d, J = 7.2 Hz, 2H, ArH), 7.28 (d, J = 7.2 Hz, 2H, ArH), 7.33 (d, J = 7.8 Hz, 2H, ArH), 7.47 (d, J = 7.8 Hz, 2H, ArH) ppm; ¹³C NMR (100 MHz, CDCl₃) δ 169.5, 166.2, 164.0, 150.9, 143.8, 140.9, 136.4, 135.8, 134.1, 131.9, 130.1, 128.9, 127.6, 108.4, 80.8, 59.5, 52.6, 51.9, 36.5, 21.1, 14.4 ppm; anal. calcd for C₂₅H₂₅ClN₂O₆: C, 61.92; H, 5.20; N, 5.78. Found C, 61.81; H, 5.15; N, 5.82.

5-Ethyl 2,3-dimethyl 6-amino-1,4-dihydro-4-(4-isopropyl phenyl)-1-phenylpyridine-2,3,5-tricarboxylate (5i). White solid; m.p. 142–144 °C; IR (KBr): ν_max 3391, 2956, 1747, 1709, 1657, 1597, 1495 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 1.26 (m, 3H, CH₃), 1.30–1.58 (6H, CH₃), 2.89 (m, 1H, CH), 3.43 (s, 3H, OCH₃), 3.66 (s, 3H, OCH₃), 4.10 (q, J = 6 Hz, 2H, CH₂), 5.00 (s, 1H, CH), 6.25 (brs, 2H, NH₂), 7.17 (m, 2H, ArH), 7.28 (d, J = 6 Hz, 2H, ArH), 7.33 (d, 2H, J = 5.9 Hz, ArH), 7.42 (m, 1H, ArH), 7.51 (m, 2H, ArH) ppm; ¹³C NMR (100 MHz, CDCl₃) δ 169.6, 166.3, 164.1, 151.3, 147.0, 141.4, 135.4, 130.5, 130.3, 129.8, 128.1, 127.8, 126.3, 107.7, 80.3, 59.4, 52.4, 51.8, 37.1, 33.6, 24.3, 14.4 ppm; anal. calcd for C₂₇H₃₀N₂O₆: C, 67.77; H, 6.32; N, 5.85. Found C, 67.81; H, 6.15; N, 5.79.

4. Conclusions

In conclusion, we compare the catalytic activity of nanosized oxides in the one-pot synthesis of highly substituted dihydropyridines. An efficient, environmentally benign, atom economical and simple methodology for the preparation of polysubstituted dihydropyridines in the presence of CeO₂ nanoparticles is reported. The procedure offers several advantages, including cleaner reaction profiles, use of easily available reagents, low cost, high yields, shorter reaction times and simple experimental conditions, reusability of the catalyst and minimal catalyst loading. This green nanocatalyst could be used for other significant organic reactions and transformations. Further explorations of similar protocols are underway in our laboratory. Moreover, this recoverable catalyst will provide a regular platform for heterogeneous catalysis, green chemistry, and environmentally benign protocols in the near future.

Acknowledgements

The authors acknowledge a reviewer who provided helpful insights. The authors are grateful to the University of Kashan for supporting this work by Grant no. 159196/XXI.

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c4ra14557g

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