Functionalized superparamagnetic Fe₃O₄ as an efficient quasi-homogeneous catalyst for multi-component reactions

Abstract

Tetrabutylammonium valinate ionic liquid [NBu₄][Val] supported on 3-chloropropyltriethoxysilane grafted superparamagnetic Fe₃O₄ NPs (VSF) was synthesized and characterized by Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), transmission electronic microscopy (TEM), scanning electronic microscopy (SEM), thermal gravimetric analysis (TGA), and vibrating sample magnetometer (VSM). The VSF catalyst was used as an efficient “quasi-homogeneous” catalyst for the multi-component synthesis of 1,4-dihydropyridines and 2-amino-4-(indol-3-yl)-4H-chromenes at room temperature. The VSF catalyst was recovered using an external magnet and recycled six times without a significant loss in the catalytic activity. Moreover, VSF as a “quasi-homogeneous” catalyst can bridge the gap between homogeneous and heterogeneous catalyses.

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Introduction

Superparamagnetic nanoparticles (MNPs) play a pivotal role in modern science and technologies due to their wide range of applications in various fields such as biotechnology/biomedicine, data storage, magnetic fluids, magnetic resonance imaging and heterogeneous catalysis.¹ The MNPs have been found as sustainable catalysts or catalyst supports in organic synthesis due to their unique properties including huge surface area, non-toxicity, recoverability with an external magnet, and avoidance of the work up/filtration of the catalyst.² Functionalized MNPs have been increasingly exploited in the area of biomedicine and catalysis.³ Several metal NPs or metal complexes including palladium,⁴ gold,⁵ ruthenium,⁶ copper,⁷ osmium,⁸ platinum and nickel,⁹ iridium/rhodium,¹⁰ vanadium,¹¹ and manganese¹² have been supported on the MNPs to explore their catalytic potential for various organic conversions. Ionic liquid functionalized ferrite materials were used as a support for the stabilization of various metal NPs.¹³ However, limited reports are available on metal free ionic liquid functionalized MNPs as recyclable catalysts for multicomponent reactions.¹⁴

Ionic liquids have been the subject of intense study for the last few decades due to their applications in various fields including homogeneous catalysis.¹⁵ Amino acid based ionic liquids (AAIL) have found interesting applications in catalysis,¹⁶ but their uses as immobilization or supporting on solid materials were found to be very limited.¹⁷ AAILs were either solids or liquids of extremely high viscosity, having limitations in efficiencies of heat and mass transfer processes. The physicochemical properties of AAIL may be tuned by changing either the cations or anions derived from amino or carboxylic acid functional groups of amino acid to overcome these limitations.¹⁸ Recently, tetraalkylammonium-based amino-acid ionic liquids [NBu₄][AA] ILs with lower viscosities were reported as an efficient medium for the absorption of CO₂,¹⁹ and also as ligands or catalysts for few organic conversions.²⁰

The field of “quasi-homogeneous” catalysis is the frontier between homogeneous and heterogeneous catalyses. This has the advantages offered by both heterogeneous catalysis, namely, the characteristic of the recovery and recyclability of the catalyst, and homogeneous catalysis, namely, the characteristic of low catalyst loading and the selectivity of the required product.²¹ In 1996, Bonnemann et al. demonstrated the quasi-homogeneous catalytic nature of platinum colloids for the enantioselective hydrogenation of ethylpyruvate to (R)-ethyllactate.²² Schuth et al. reported the efficient use of aluminum-stabilized copper colloids as a quasi-homogeneous catalyst for methanol synthesis.²³ Recently, Luo et al. reported the ionic liquid supported MNPs as “quasi-homogeneous” catalyst for the synthesis of benzoxanthenes.²⁴ In this context, we presumed that the immobilization or supporting of highly charged low viscous [NBu₄][AA] ILs on solid Fe₃O₄ NPs can exhibit the properties of quasi-homogeneous catalysts to bridge the gap between heterogeneous and homogeneous catalyses.

It is pertinent to study the catalytic potential of such a quasi-homogeneous catalyst in multi-component reactions for the construction of biologically relevant scaffolds in a single step. 1,4-Dihydropyridines (1,4-DHPs) are such privileged pharmacological scaffolds that exhibit significant biological activities in the treatment of cardiovascular diseases as calcium channel blockers.²⁵ Chromenes and indoles are another class of compounds found in a number of natural products with a wide range of biological activities.^26,27 2-Amino-4-(indol-3-yl)-4H-chromenes are hybrid molecules, which comprise the incorporation of two pharmacophores such as chromenes and indoles with the intention to impart dual biological activities.

In view of developing an efficient green approach for the synthesis of 1,4-dihydropyridines, very few MNPs such as nano-γ-Fe₂O₃, γ-Fe₂O₃–SO₃H, Fe₃O₄–CeO₂ and ZrO₂–Al₂O₃–Fe₃O₄ have been reported as recyclable catalysts.^28–31 To the best of our knowledge, there is no report on the one-pot synthesis of 2-amino-4-(indol-3-yl)-4H-chromenes via Knoevenagel/Pinner/Friedel–Crafts reaction using MNPs as recyclable catalysts. As a part of our ongoing work towards the development of efficient recyclable catalysts for the synthesis of biologically important molecules,³² we report, herein, the VSF as a quasi-homogeneous catalyst for the synthesis of 1,4-dihydropyridines and 2-amino-4-(indol-3-yl)-4H-chromenes.

Results and discussions

Synthesis and characterization of VSF catalyst

VSF nanomaterial was synthesized by the grafting of the tetrabutylammonium valinate [NBu₄][Val] ionic liquid (VIL) on 3-chloropropyltriethoxysilane coated Fe₃O₄ NPs using a simple conventional heating protocol (Scheme 1) and characterized by Fourier transform infrared spectroscopy (FT-IR), X-ray diffraction (XRD), transmission electronic microscopy (TEM), scanning electronic microscopy (SEM), thermal gravimetric analysis (TGA), and vibrating sample magnetometer (VSM).

Scheme 1 Synthesis of [NBu₄][Val]@Si@Fe₃O₄ (VSF) catalyst.

The XRD pattern of Fe₃O₄ clearly conforms to the formation of a cubic spinel structure with the diffraction peaks (2θ) at 30.16°, 35.53°, 43.33°, 53.64°, 57.39° and 62.76°, which correspond to the (2 2 0), (3 1 1), (4 0 0), (4 2 2), (5 1 1), and (4 4 0) phases, respectively (Fig. 1). The XRD pattern is in well agreement with the reported data (JCPDS no. 65-3107).³³ The mean crystallite size and the mean particle size were determined using the Scherrer formula and found to be 11.6 nm.

Fig. 1 X-ray diffraction patterns of (a) Fe₃O₄ NPs; (b) Si@Fe₃O₄; (c) VSF.

The calculated mean crystallite size is consistent with that measured from the TEM images. There were no considerable changes observed in the X-ray diffraction pattern and crystallite size of silica coated ferrite and VSF (Fig. 1b and c). However, the intensity of the related peaks of silica-coated and VSF are slightly reduced (Fig. 1).

The functional groups of the as-synthesized VSF material and its precursors were characterized from the FT-IR technique, as shown in Fig. 2. Three characteristic bands corresponding to Fe–O vibration and surface hydroxyl groups of Fe₃O₄ appeared at 581, 1622 and 3426 cm⁻¹, respectively (Fig. 2a). The characteristic bands of chloropropyl silane coated ferrite appeared at 1039, 1129 cm⁻¹ and 2940, 1415 cm⁻¹, which correspond to the Si–O–Si stretching and C–H stretching bands, respectively (Fig. 2b). The characteristic bands at 1666 cm⁻¹ correspond to the carbonyl functional group of [NBu₄][Val] (Fig. 2c). Moreover, the presence of functional groups in VSF such as Fe–O, Si–O–Si, C–H, and carbonyl conformed to the bands at 581, 1129 and 1039, 1415, 1657 cm⁻¹, respectively (Fig. 2d).

Fig. 2 FT-IR of (a) Fe₃O₄ NPs; (b) Si@Fe₃O₄; (c) VIL; (d) VSF.

The surface morphology of Fe₃O₄ NPs and VSF was characterized from the scanning electronic microscopy (SEM) technique, as shown in Fig. 3. The results clearly showed that there was a change in the morphology of VSF (Fig. 3c and 3d) as compared with Fe₃O₄ NPs (Fig. 3a and 3b). Furthermore, the internal morphology and size of VSF NPs were characterized from transmission electronic microscopy (TEM), as shown in Fig. 4.

Fig. 3 Low to high magnified SEM images of (a), (b) Fe₃O₄ NPs and (c), (d) VSF.

Fig. 4 (a)–(d) Low to high magnified TEM images of VSF.

The particle size of VSF NPs was calculated from TEM and found to be varying from 7.35 nm to 12.5 nm, which is consistent with the result calculated from the PXRD data using the Scherrer formula.

The thermal stability and percentage of organic functional groups chemisorbed/grafted on Fe₃O₄ NPs were determined by TGA analyses (Fig. 5). The weight loss at a temperature of 150 °C can be attributed to the water desorption from the surface of MNPs (Fig. 5). The curve in (Fig. 5b) shows a weight loss of 4.4% in the temperature range of 150–550 °C corresponding to the decomposition of 3-chloropropyltriethoxysilane on Fe₃O₄. The curve in (Fig. 5c) shows a weight loss of 6.1% corresponding to the decomposition of [NBu₄][Val]. Moreover, the weight loss above 600 °C corresponds to the decomposition of Fe₃O₄ to 3FeO. The TGA calculations reveal that 6.1% of the ionic liquid was grafted on Fe₃O₄ NPs.

Fig. 5 TGA curves of (a) Fe₃O₄ NPs; (b) Si@Fe₃O₄; (c) VSF.

The magnetic properties of VSF, Si@Fe₃O₄, and Fe₃O₄ NPs were measured by vibrating a sample magnetometer (Fig. 6). The saturation magnetization of bare Fe₃O₄ was found to be 44.8 emu g⁻¹. There was a slight decrease in the magnetization of Si@Fe₃O₄ and VSF, namely, 36.1 and 37.3 emu g⁻¹, respectively. This slight decrease was due to the successful supporting of chloropropyl triethoxysilane and [NBu₄][Val] on Fe₃O₄ NPs, respectively. Moreover, the results indicate that these materials showed a typical superparamagnetic behavior with negligible remanence, Mr (emu g⁻¹), and coercivity, Hc (Oe), as shown in the inset (Fig. 6). The superparamagnetic behavior and high saturation magnetization of these materials are very beneficial in heterogeneous catalysis as it is easily recoverable by external magnetic fields.

Fig. 6 Magnetization curves of Fe₃O₄ NPs; Si@Fe₃O₄; and VSF.

VSF as a quasi-homogeneous catalyst for multi-component reactions

Initially, the catalytic potential of VSF NPs was investigated for the synthesis of 1,4-dihydropyridines via the Hantzsch reaction, as shown in Scheme 2. The optimization of the reaction conditions was studied for the model reaction between 1,3-cyclohexanedione, benzaldehyde, ethyl acetoacetate and ammonium acetate for the synthesis of 1,4-dihydropyridine 5a.

Scheme 2 VSF catalyzed one-pot synthesis of 1,4-dihydropyridines.

The reaction was performed in the presence of different VSF catalyst loading amounts under benign solvents such as water, EtOH and without solvent at room temperature (Table 1, entries 1–6). The results showed that 2 mol% of the catalyst and ethanol as a solvent was the best combination to afford product 5a in excellent yield within a short reaction time (Table 1, entry 5). When the reactions were performed in the presence of Fe₃O₄ and Si@Fe₃O₄ NPs under optimized conditions, product 5a was formed in moderate yields (entries 7 and 8). In the presence of [NBu₄][Val] as a catalyst, product 5a was formed in 60% yield (entry 9). Next, we studied the model reaction in the absence of a catalyst under optimized conditions; a trace amount of product formation was observed even after a prolonged reaction time (Table 1, entry 10). However, the catalytic activity of either Fe₃O₄ (heterogeneous) or [NBu₄][Val] (homogeneous) alone was found to be sluggish with moderate yields of 5a. The combined properties of VSF, a quasi-homogeneous catalyst, gave the best result to afford DHP 5a in 90% yield at room temperature (Table 1, entry 5).

Table 1 Optimization study for VSF catalyzed one-pot synthesis of 1,4-dihydropyridine 5a^a

Entry	Catal. (mol%)	Solvent	Time (min)	Yield^b (%)
a 1,3-Cyclohexanedione (1 mmol), aldehyde (1 mmol), ethylacetoacetate (1 mmol), NH4OAc (1.5 mmol), catalyst (mol%) and solvent (4 mL) at room temperature.b Isolated yield.
1	VSF (10)	Water	60	70
2	VSF (10)	EtOH	40	84
3	VSF (10)	No solvent	80	65
4	VSF (5)	EtOH	30	84
5	VSF (2)	EtOH	30	90
6	VSF (1)	EtOH	30	80
7	Fe3O4 (2)	EtOH	120	50
8	Si@Fe3O4 (2)	EtOH	120	40
9	[NBu4][Val] (2)	EtOH	30	60
10	No catalyst	EtOH	240	Trace

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With these interesting results, we investigated the generality of VSF catalyst for several substituted aryl aldehydes, 1,3-cyclohexanedione/dimedone and ammonium acetate under optimized conditions, as shown in Table 2. The aryl aldehydes having electron withdrawing groups such as NO₂, Cl, Br and CN at the para position showed less reactivity as compared with simple benzaldehyde (Table 2, entries 2–5). Moreover, the aldehydes bearing electron donating groups such as OMe and Me at the para and meta positions gave excellent yields within short reaction times (Table 2, entries 6–9).

Table 2 VSF catalyzed one-pot synthesis of 1,4-dihydropyridines^a

Entry	R	R^1	Product 5	Time (min)	Yield^b (%)
a 1,3-Cyclohexanedione (1 mmol), aldehyde (1 mmol), ethylacetoacetate (1 mmol), NH4OAc (1.5 mmol), VSF catalyst (2 mol%) and EtOH (4 mL) at room temperature.b Isolated yield.
1	H	H	5a	25	94
2	H	4-NO2	5b	40	87
3	H	4-Cl	5c	40	95
4	H	4-Br	5d	35	91
5	H	4-CN	5e	45	93
6	H	4-Me	5f	30	89
7	H	4-OMe	5g	20	93
8	H	3,4-OMe	5h	20	92
9	H	3-OMe	5i	20	93
10	Me	H	5j	25	94
11	H	4-OBn	5k	40	91
12	H		5l	40	85
13	EAA	H	5m	35	85

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A comparative study on the catalytic performance of VSF with other MNP catalysts for the synthesis of 1,4-dihydropyridines 5a, 5m and 5j are shown in Table 3. To our delight, VSF is the best quasi-homogeneous catalyst to afford products 5a and 5m in high yields at room temperature with turn over number values of 39.66 and 35.86, respectively. In contrast, other MNPs such as nano-γ-Fe₂O₃, γ-Fe₂O₃–SO₃H, Fe₃O₄–CeO₂ and ZrO₂–Al₂O₃–Fe₃O₄ are either required under the high temperature condition (80–90 °C) to yield the products or low TON values are obtained (Table 3).

Table 3 Comparative study of MNP catalysts for the synthesis of 1,4-dihydropyridines 5a, 5j and 5m

5	Catalyst	Time (min)	Temp. (°C)	Yield (%)	TON	Ref.
5m	γ-Fe2O3	25	90	95	6.53	28
5m	γ-Fe2O3–SO3H	60	90	98	9.44	29
5j	Fe3O4–CeO2	33	RT	93	3.75	30
5m	ZrO2–Al2O3–Fe3O4	90	80	94	43.34	31
5a	VSF	25	RT	94	39.66	—
5m	VSF	35	RT	85	35.86	—

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We further extended the scope of VSF catalyst for the synthesis of 2-amino-4-(indol-3-yl)-4H-chromenes via Knoevenagel/Pinner/Friedel–Crafts reaction, as shown in Scheme 3.

Scheme 3 VSF catalyzed one-pot synthesis of 2-amino-4-(indol-3-yl)-4H-chromenes.

In order to find the optimum reaction condition, a model reaction between salicylaldehyde, indole and malononitrile using 2 mol% VSF catalyst in the presence of various polar and non-polar solvents was studied. Interestingly, when water was used as the solvent, the reaction proceeded smoothly to afford product 9a in an excellent yield of 93% (Table 4, entry 6). However, organic solvents such as EtOH, DMSO, CH₃CN, THF and CH₂Cl₂ gave product 9a in poor to moderate yields of 40–60% (entries 1–5). The reason for the high catalytic activity of the VSF catalyst in water as the solvent can be the tendency of water to enhance the rate of organic reactions due to interactions such as hydrogen bonding and the “Breslow effect,” wherein the hydrophobic aggregation of organic molecules decreases the area of a non-polar surface, which, in turn, reduces the activation energies.³⁴

Table 4 Effect of solvent on VSF catalyzed one-pot synthesis of 2-amino-4-(indol-3-yl)-4H-chromene 9a^a

Entry	Solvent	Time (min)	Yield^b (%)
a Reaction conditions: indole (1 mmol), salicylaldehyde (1 mmol), malononitrile (1 mmol), VSF catalyst (2 mol%), and solvent (1.5 mL) were stirred at room temperature.b Isolated yield.
1	EtOH	90	60
2	DMSO	90	55
3	CH3CN	90	50
4	THF	90	43
5	CH2Cl2	90	40
6	Water	30	93

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Next, we examined the generality of the VSF catalyst for the synthesis of substituted 2-amino-4-(indol-3-yl)-4H-chromenes 9a–9g from various substrates such as indoles (6a–6c), 2-hydroxy aromatic aldehydes (7a, 7b) and active methylene compounds (8a, 8b), as shown in Table 5. Interestingly, almost all the substrates afforded the desired products selectively in good to excellent yields of 80–94% within short reaction times (Table 5, entries 1–7).

Table 5 VSF catalyzed one-pot synthesis of 2-amino-4-(indol-3-yl)-4H-chromenes^a

Entry	Indole 6	Aldehyde 7	Comp. 8	Product 9	Time (min)	Yield^b (%)
a Reaction conditions: indoles (1 mmol), 2-hydroxyaromatic aldehydes (1 mmol), malononitrile (1 mmol), VSF catalyst (2 mol%), and water (1.5 mL) were stirred at room temperature.b Isolated yield.c Fe3O4 used as a catalyst.
1	6a	7a	8a	9a	15, 60^c	94, 55^c
2	6a	7a	8b	9b	30	85
3	6b	7a	8a	9c	20	87
4	6b	7a	8b	9d	35	82
5	6c	7a	8a	9e	15	90
6	6c	7a	8b	9f	30	83
7	6a	7b	8a	9g	35	87

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The plausible mechanism of VSF catalyzed one-pot synthesis of 2-amino-4-(indol-3-yl)-4H-chromene 9a is depicted in Fig. 7. Probably, the high catalytic activity of the VSF catalyst is due to the presence of active sites such as low-coordinated sites and surface vacancies of nano Fe₃O₄, and carboxylate anion and ammonium ions from ionic liquids can act as the conjugate base and acid, respectively. Moreover, the combination of both these properties makes VSF as an efficient quasi-homogeneous catalyst. The basic sites of VSF can promote the Knoevenagel condensation between salicylaldehyde 7a and malononitrile 8a to afford olefinic product 10, followed by a Pinner reaction to yield iminochromene intermediate B. Furthermore, the Friedel–Crafts alkylation of indole 6a with iminochromene B results in the formation of 2-amino-4-(indol-3-yl)-4H-chromene 9a.

Fig. 7 Plausible mechanism of VSF catalyzed one-pot synthesis of 2-amino-4-(indol-3-yl)-4H-chromene 9a.

The recyclability of VSF catalyst was investigated for the reaction between 1,3-cyclohexanedione, benzaldehyde, ethyl acetoacetate and ammonium acetate in the synthesis of 1,4-dihydropyridine 5a, as shown in Fig. 8.

Fig. 8 Recycling study of VSF catalyst for the synthesis of 1,4-dihydropyridine 5a.

After the completion of reaction, the catalyst was separated from the reaction mixture magnetically using an external magnet. The catalyst was washed with ethanol 3–4 times in order to remove the residual product, dried at 70 °C and used for the next cycle. The procedure was repeated six times: there was no significant loss in the catalytic activity of the VSF catalyst (Fig. 8).

Conclusions

We have developed VSF as a superparamagnetic quasi-homogeneous catalyst to bridge the gap between homogeneous and heterogeneous catalyses for the multi-component synthesis of 1,4-dihydropyridines and 2-amino-4-(indol-3-yl)-4H-chromenes. The present protocol can provide a superior alternative to the existing methods with advantages such as the catalyst being non-toxic, superparamagnetic and easily recoverable with an external magnet and the avoidance of the work up/filtration and high activity/selectivity with excellent yields. The high catalytic activity of the VSF catalyst is due to the presence of active sites such as low-coordinated sites, surface vacancies of nano Fe₃O₄, and carboxylate anion and ammonium ions from [NBu₄][Val] ionic liquid.

Experimental

Powder X-ray diffraction (PXRD) patterns were recorded using a Siemens D500 instrument that used Cu-Kα radiation (l ∼ 1.54050 Å) and equipped with the AT Diffract software. The crystalline phases were identified by comparison with JCPDS ®les.10. TGA analysis (Perkin Elmer, Pyris Diamond) with a heating rate of 10 °C min⁻¹ in nitrogen atmosphere was used to study the thermal decomposition behavior of the samples with respect to α-Al₂O₃ as the reference. Fourier transform infrared (FT-IR) spectra were recorded on a Perkin Elmer device, and the samples were prepared by mixing the samples with KBr. Scanning electron microscopy (SEM) measurement was performed on a JEOL JSM-6610LV electron microscope. The superparamagnetic properties of the samples were studied using a superconducting quantum interference device (SQUID) magnetometer. The transmission electron microscopy (TEM) measurement was performed on a JEOL 2100F transmission electron microscope. The samples were supported on carbon-coated copper grids for the TEM experiment. The melting points were measured using a Buchi B-540 melting-point apparatus and are uncorrected. The ¹H and ¹³C NMR spectra were measured on a Brucker AC-200 instrument.

Procedure for the preparation of Fe₃O₄ MNPs

The Fe₃O₄ nanoparticles were prepared according to Massart's method. An aqueous solution of 2 eq. FeCl₃·6H₂O (5.8 g in 50 mL water) was mixed with an aqueous solution of 1 eq. FeCl₂·4H₂O (2.2 g in 50 mL water). The mixture was stirred vigorously at 85 °C for 30 min, and then 10 mL of ammonia (28% aqueous solution) was added quickly. The reaction was further stirred for another 30 min at 85 °C to afford Fe₃O₄ nanoparticles as a black precipitate. The obtained Fe₃O₄ NPs were collected using an external magnet, washed with water followed by ethanol, and dried at 80 °C in an oven.

General procedure for the synthesis of [NBu₄][Val] ionic liquid

[NBu₄][Val] ionic liquid was prepared by a modified literature method.³⁵ Tetrabutylammonium hydroxide solution (40%, 10 mmol) was added to an aqueous suspension of valine (10 mmol). The resultant reaction mixture was stirred at room temperature for 12 h. The water was removed in vacuo at 80 °C, and the resultant residue was dissolved in CH₃CN (40 mL) and filtered to remove the unreacted valine. The filtrate was dried over Na₂SO₄, filtered and excess of the solvent was removed in vacuo to afford the desired tetrabutylammonium valinate ionic liquid as low viscous colourless oil.

Procedure for the preparation of Fe₃O₄@Si(CH₂)₃-NVIL (VSF)

The supporting of the [NBu₄][Val] ionic liquid on silica grafted ferrite is illustrated in Scheme 1. In a typical procedure, 3 g of Fe₃O₄ and 3-chloropropyltriethoxysilane (6 mmol) in 40 mL of dry toluene was refluxed under nitrogen for 12 h. The obtained grafted Fe₃O₄@Si(CH₂)₃–Cl was filtered out, washed twice with dry toluene and once with anhydrous diethyl ether, and dried at 75 °C for 6 h in vacuum. Then, [NBu₄][Val] ionic liquid (10 mmol) was added to the round bottom flask containing Fe₃O₄@Si(CH₂)₃–Cl (1 mmol) and K₂CO₃ (5 mmol) in 50 mL of dry toluene and the mixture was refluxed for 24 h. The resulting solid was filtered out, washed and dried in a similar manner to give Fe₃O₄@Si(CH₂)₃-NVIL (VSF). After the usual workup and washings, the material was dried at 75 °C for 5 h in a vacuum oven.

General procedure for the synthesis of 1,4-dihydropyridines (5a–5m)

A mixture of 1,3-cyclohexanedione 1 (1 mmol), aldehyde 2 (1 mmol), ethyl-acetoacetate 3 (1 mmol), ammonium acetate 4 (1.5 mmol), and VSF nanoparticles (2 mol%) in ethanol (4 mL) were stirred at room temperature. After the completion of the reaction (monitored by TLC), the superparamagnetic VSF catalyst was separated from the reaction mixture using an external magnet. The obtained crude products (5a–5m) were purified by recrystallization from hot ethanol. The purified compounds were characterized by IR, ¹H NMR, ¹³C NMR, HRMS, and elemental analysis.

Ethyl-4-(4-(benzyloxy)phenyl)-2-methyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate (5k). Off white solid; mp 250–253 °C; IR (KBr) 3294, 3215, 3081, 2938, 1697, 1607, 1490, 1384, 1224, 1176, 1080 cm⁻¹; ¹H NMR (400 MHz; DMSO; Me₄Si) δ = 9.08 (brs, 1H), 7.40–7.29 (m, 5H), 7.02 (d, J = 7.9 Hz, 2H), 6.80 (d, J = 8.5 Hz, 2H), 4.99 (s, 2H), 4.81 (s, 1H), 3.96 (q, J = 7.3 Hz, 2H), 2.46–2.45 (m, 2H), 2.25 (s, 3H), 2.19–2.16 (m, 2H), 1.90–1.68 (m, 4H), 1.11 (t, J = 7.3 Hz, 3H) ppm. ¹³C NMR (100 MHz; DMSO; Me₄Si) δ = 194.62, 167.04, 156.30, 151.11, 144.56, 140.35, 137.28, 128.36, 127.47, 114.00, 111.24, 103.64, 69.00, 58.98, 36.70, 34.64, 26.07, 20.76, 18.19, 14.14 ppm. HRMS (ES): calcd 417.1940, found 417.1937; anal. calcd for C₂₆H₂₇NO₄: C, 74.80; H, 6.52; N, 3.35; found: C, 74.79; H, 6.51; N, 3.36.

Ethyl-2-methyl-5-oxo-4-(3-(prop-2-yn-1-yloxy)phenyl)-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate (5l). White solid; mp 260–263 °C; IR (KBr) 3279, 3243, 3077, 2941, 1701, 1607, 1488, 1381, 1221, 1037 cm⁻¹; ¹H NMR (400 MHz; DMSO; Me₄Si) δ = 9.14 (brs, 1H), 7.09 (t, J = 7.3 Hz, 1H), 6.75 (d, J = 7.3 Hz, 1H), 6.72–6.69 (m, 2H), 4.87 (s, 1H), 4.67 (s, 2H), 3.98 (q, J = 7.3 Hz, 2H), 3.53 (s, 1H), 2.26 (s, 3H), 2.18 (s, 3H), 1.87–1.74 (m, 3H), 1.12 (t, J = 7.3 Hz, 3H) ppm. ¹³C NMR (100 MHz; DMSO; Me₄Si) δ = 194.52, 166.71, 156.93, 151.51, 149.29, 145.00, 128.64, 120.41, 114.25, 111.37, 110.87, 103.31, 79.31, 77.93, 59.06, 55.07, 36.67, 35.34, 26.11, 20.74, 18.21, 14.14 ppm. HRMS (ES): calcd 365.1627, found 365.1630; anal. calcd for C₂₂H₂₃NO₄: C, 72.31; H, 6.34; N, 3.83; found: C, 72.30; H, 6.36; N, 3.82.

General procedure for the synthesis of 2-amino-4-(indol-3-yl)-4H-chromene derivatives (9a–9f)

A mixture of indoles 6 (1 mmol), 2-hydroxy aromatic aldehydes 7 (1 mmol), active methylene compounds 8 (1 mmol), and (2 mol%) VSF nanoparticles in 1.5 mL of water were stirred at room temperature. After the completion of the reaction (monitored by TLC), the superparamagnetic VSF catalyst was separated from the reaction mixture using an external magnet. The obtained crude products were recrystallized from ethanol to get pure compounds (9a–9f).

2-Amino-4-(5-bromo-1H-indol-3-yl)chroman-3-carbonitrile (9c). Yellow solid; mp 180–182 °C; IR (KBr) 3449, 3382, 3320, 3241, 3206, 3083, 2852, 2346, 2372, 2195, 1661, 1612, 1583, 1491, 1449, 1456, 1422, 1405, 1332, 1273, 1259, 1227, 1076, 1098, 1042, 845, 882, 794, 752, 580, 521 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ (ppm) 8.20 (br s, 1H), 7.39 (br s, 1H), 7.22–7.16 (m, 4H), 7.05–6.95 (m, 3H), 5.02 (s, 1H), 4.63 (s, 2H); ¹³C NMR (100 MHz, CDCl₃) δ (ppm) 159.59, 148.75, 135.86, 129.66, 128.55, 127.54, 125.43, 124.13, 122.60, 121.81, 120.42, 118.84, 116.58, 113.12, 60.49, 32.70; HRMS (ES): calcd 367.0320, found 367.0322; anal. calcd for C₁₈H₁₄BrN₃O: C, 58.71; H, 3.83; N, 11.41; found: C, 58.72; H, 3.82; N, 11.41.

Ethyl-2-amino-4-(5-bromo-1H-indol-3-yl)-4H-chromene-3-carboxylate (9d). Yellow solid; mp 145–147 °C; IR (KBr) 3412, 3318, 2958, 2926, 1731, 1666, 1607, 1518, 1483, 1455, 1399, 1297, 1227, 1185, 1043, 883, 750, 654 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ (ppm) 7.93 (br s, 1H), 7.74 (s, 1H), 7.21–7.13 (m, 4H), 7.04–6.96 (m, 2H), 6.28 (s, 1H), 5.24 (s, 1H), 4.12–4.04 (m, 2H), 1.16 (t, J = 7.3 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ (ppm) 169.43, 160.24, 148.98, 134.76, 127.69, 126.37, 124.71, 124.18, 123.30, 122.96, 122.72, 121.83, 115.60, 112.60, 112.18, 59.44, 31.02, 14.30; HRMS (ES): calcd 412.0423, found 412.0421; anal. calcd for C₂₀H₁₇BrN₂O₃: C, 58.13; H, 4.15; N, 6.78; found: C, 58.12; H, 4.13; N, 6.79.

2-Amino-4-(2-methyl-1H-indol-3-yl)-4H-chromene-3-carbonitrile (9e). Yellow solid; mp 202–204 °C; IR (KBr) 3331, 2961, 2933, 2185, 1646, 1604, 1576, 1486, 1457, 1394, 1224, 1040, 744, 593, 562 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ (ppm) 7.86 (br s, 1H), 7.23 (d, J = 8.5 Hz, 1H), 7.16–7.14 (m, 1H), 7.08–7.00 (m, 3H), 6.96–6.95 (m, 2H), 6.92–6.88 (t, J = 7.3 Hz), 5.10 (s, 1H), 4.52 (s, 2H), 2.47 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ (ppm) 158.84, 148.70, 135.43, 131.97, 129.49, 127.90, 126.93, 124.94, 122.67, 121.06, 120.16, 119.34, 118.15, 115.94, 113.87, 60.56, 31.23, 11.57; HRMS (ES): calcd 367.0320, found 367.0322; anal. calcd for C₁₉H₁₅N₃O: C, 75.73; H, 5.02; N, 13.94; found: C, 75.72; H, 5.04; N, 14.01.

Acknowledgements

DSR acknowledges the Council of Scientific and Industrial Research (02(0049)/12/EMR-II), New Delhi, India and University of Delhi, Delhi, India for their financial support. UCR is thankful to UGC for the award of a senior research fellowship (SRF). We thank USIC-CIF, University of Delhi, for assisting to aquire analytical data.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: ¹H NMR and ¹³C NMR spectra of selected compounds. See DOI: 10.1039/c4ra06803c

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