Nickel ferrite nanoparticles: an efficient and reusable nanocatalyst for a neat, one-pot and four-component synthesis of pyrroles

Abstract

In this study nickel ferrite magnetic nanoparticles were applied as an efficient and reusable catalyst in the four-component synthesis of substituted pyrroles under neat conditions. The reaction was conducted using various amounts of catalyst at different temperatures and finally, application of 5 mol% of catalyst at 100 °C was determined as the optimum reaction condition. Results showed that nickel ferrite nanoparticles could catalyze the reaction at relatively short times (3–4 h) with high to excellent yields (70–96%). The catalyst could be recovered easily using an external magnetic field and reused nine times without any significant activity lost.

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Introduction

Multicomponent reactions (MCRs) are defined as reactions in which more than two reactants directly convert into their products from one-pot reactions. The first MCRs were accomplished in 1838 by Laurent and Gerhardt.¹ They synthesized benzoylazotide via a four-component reaction. Since then, MCRs have been extensively used as an effective pathway in modern organic and pharmaceutical chemistry.^2,3 In contrast to the multistep syntheses, the MCRs propose remarkable benefits such as high atom economy, being less time consuming and the avoidance of costly purification processes and circumvention of different organic transformations. In addition, the synthesis of complicated frameworks from available substrates can be accomplished in a one-pot procedure without the need for any intermediate isolation. Moreover, the application of novel MCRs with green and eco-friendly approaches is demanded in by pharmaceutical industry and in organic synthesis.⁴

Pyrroles are among the most prominent organic frameworks possessing important pharmaceutical and biological characteristics.^5,6 For example, TCMDC 123812, BM 212 and NB-2 act as antimalarial,⁷ antibacterial⁸ and antiviral agents, respectively⁹ (Fig. 1).

Fig. 1 Some bioactive pyrrole derivatives.

Numerous investigations exist in the development of new and efficient approaches for the synthesis of pyrrole and its derivatives.¹⁰ Among them, metal-catalyzed reactions have taken considerable attention and many metal species have been applied in the preparation of pyrroles.¹¹ The investigation of nickel-catalyzed reactions received great attention recently.¹² However, nickel-catalyzed synthesis of pyrroles has been less studied^13,14 and reports on nickel-catalyzed multicomponent synthesis of pyrroles is rare.¹⁵ Moreover, the reported methods suffer from some drawbacks such as harshness of reaction conditions, long reaction times, expensive catalysts, low yields, irrecoverability of catalysts and the presence of even trace amounts of remaining metal in the end-product. The latter is very important, especially in pharmaceutical synthesis because of the negative effects of metals on health. Therefore, these methodologies were modified and various types of homogeneous and heterogeneous metal-based catalysts were employed in these reactions.

As the demand for “Green Chemistry” continually increases, it looks as if designing efficient and recoverable supported heterogeneous catalysts has changed into a heated debate for many a piece of research in synthetic organic chemistry and in material science and engineering. Recently, magnetic nanoparticles have received great attention as heterogeneous catalysts in organic synthesis due to their easy separation, catalytic activity, convenient synthesis, operational simplicity, eco-friendliness, and recoverability using an external magnetic field.¹⁶ The latter could result in remarkable catalyst recovery without the need for filtration or loss of the catalyst.¹⁷

Nanosized spinel ferrite particles have benefited from important physical and chemical characteristics due to the synergistic effects between the two metals. In the spinel ferrites of MFe₂O₄, the metallic cations M²⁺ and Fe³⁺ can occupy octahedral and tetrahedral sites. If the M²⁺ cations occupy tetrahedral sublattices in the cubic closed packed O²⁻ lattice, the spinel ferrite is a normal spinel, otherwise, the ferrite is an inverse spinel. If both of the sublattices contain M²⁺ and Fe³⁺ cations, the ferrite is a mixed spinel. The occupations of cations at these sites have an important effect on the properties of spinels, such as magnetic behavior, conductivity and catalytic activity.¹⁸ One of them is nickel ferrite (NiFe₂O₄); possessing fascinating magnetic and electromagnetic properties. NiFe₂O₄ is a soft ferrite with low coercivity, high saturation magnetization, chemical stability, chemical hardness, electrical resistivity and reasonable cost.¹⁹ For these reasons, it is extensively used as an excellent material for magnetic resonance imaging enhancement, magnetic recording media and electronic devices.^20–22

Recently, magnetic nanoparticle CoFe₂O₄ supported Mo ([CoFe₂O₄@SiO₂–PrNH₂–Mo(acac)₂]) has been used for a one-pot synthesis of polysubstituted pyrroles via four-component reaction of aldehydes, amines, 1,3-dicarbonyl compounds, and nitromethane.²³ Although the catalyst is recoverable and the reaction times are generally short, the preparation of supported catalyst is time-consuming and needs to undergo several steps. Therefore, it seems logical to directly apply spinel ferrites to catalyze the reaction. Previously, the application of CuFe₂O₄ in three-component preparation of polysubstituted pyrroles was investigated;²⁴ however, no reports have been observed on direct application of spinel ferrites in four-component preparation of pyrroles.

The catalytic activity of NiFe₂O₄ magnetic nanomaterials (NMNs) in organic synthesis was less studied. Nickel ferrite is mostly used in photocatalytic and hydrothermal degradation of organic compounds,^25–27 harsh oxidation of toluene,²⁸ ozonation of phenols²⁹ and they were used as support for palladium-catalyzed Heck and Suzuki reactions.^30–32 Recently we utilized NMNs as highly active recyclable heterogeneous for cyanation of aryl and heteroaryl halides.³³

In order to shed more light on this area, we decided to apply nickel ferrite nanoparticles as a recyclable and reusable catalyst in four-component synthesis of substituted pyrroles. Another advantage of these catalytic systems is that although heterogeneous catalysts usually suffer from leaching, this phenomenon is not observed in the case of NMNs because of their specific ferromagnetic nature.

We report, herein, a facile, efficient, eco-friendly and one-pot process for the four-component synthesis of pyrroles with NMNs as recyclable catalyst. All the reactions were resulted in very good to excellent yields. The catalyst is stable in air, moisture and elevated temperatures and none of these parameters can cause to its deactivation. In addition, the reactions were performed under neat conditions (Scheme 1).

Scheme 1 The preparation of different substituted pyrroles.

Results and discussion

Characterization of catalyst

NiFe₂O₄ nanoparticles were prepared by the co-precipitation method as explained in the experimental section and fully characterized.³³

Catalytic application of NMNs

The catalytic application of NMNs was investigated in four-component synthesis of substituted pyrroles. In order to optimize the reaction conditions, the preparation of 1a was selected as a model reaction (Table 1). The reaction did not proceed in the absence of catalyst at 100 °C (Table 1, entry 1). Therefore, the model reaction was repeated in the presence of 1, 5, 10 and 20 mol% of NiFe₂O₄. Using 5 mol% of the catalyst, the best results regarding reaction time and yield was obtained (Table 1, entry 3). When 1 mol% of catalyst was used, the reaction time was long (8 h) and the reaction produced 1a in yield 66% (Table 1, entry 2). The yield of the model reaction and its completion time were similar using 5 and 10 mol% of the catalyst (Table 1, entries 3 and 4) but it is more affordable to use 5 mol% of catalyst as the optimum amount. Repetition of reaction at ambient temperature had no promising effect on the yield (Table 1, entry 6).

Table 1 Screening the different reaction conditions for optimization 1a

Entry	NiFe2O4 (mol%)	Temperature (°C)	Time (h)	Yield^a (%)
a Isolated yield.
1	—	100	15	Trace
2	1	100	8	66
3	5	100	3	95
4	10	100	3	95
5	20	100	3.5	88
6	5	rt	12	40

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Having these optimum reaction conditions in hands, various numbers of pyrroles (1a–1l) were synthesized for more evaluation of NiFe₂O₄ catalytic activity. Results are summarized in Table 2.

Table 2 Nanoparticles catalyzed formation of highly substituted pyrroles

Entry	R^1	R^2	R^3	Ar	Time (h)	Products	Yield^a (%)
a Isolated yield.
1	C6H4CH2	Me	OMe	Ph	3	1a	95
2	C6H4CH2	Me	OMe	p-MeC6H4	3	1b	82
3	C6H4CH2	Me	OMe	p-NO2C6H4	4	1c	87
4	C6H4CH2	Me	OMe	p-ClC6H4	4	1d	96
5	C6H4CH2	Me	OMe	p-Me2NC6H4	3	1e	93
6	C6H4CH2	Me	OMe	2-Furyl	3	1f	94
7	C6H4CH2	Me	Me	m-NO2C6H4	4	1g	81
8	C6H4CH2	Me	OEt	p-ClC6H4	4	1h	92
9	p-MeOC6H4	Me	OMe	p-ClC6H4	4	1i	80
10	p-BrC6H4	Me	OMe	Ph	3	1j	82
11	p-BrC6H4	Me	OEt	p-ClC6H4	4	1k	80
12	p-MeOC6H4	Me	Ph	p-ClC6H4	4	1l	90

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In general the reaction was proceeded easily for benzylamine and substituted anilines to produce the desired pyrroles in high yields (80–96%). There exists no significant difference among the yields for benzylamine and aniline derivatives. Moreover, to extend the scope of the reaction with respect to aldehyde, various aromatic aldehydes with different substituents like Me, Me₂N, NO₂, Cl, and furyl were examined. In general, the electronic properties of the substituents of aromatic aldehydes have no effects on the reactivity. Both electrons-donating and electron-withdrawing groups reacted smoothly to produce the substituted pyrroles. Furan-2-carbaldehyde, as a heteroaromatic aldehyde, could participate in the reaction effectively and produce 1f in 94% yield (Table 2, entry 6).

The difference between the reaction times for substrates having electron-withdrawing and electron-donating groups are not significant. This is probably attributed to the large surface area of nanoparticles, which decreases the activation energy and accelerates the reactions. However, the reaction times for the aldehydes having electron-withdrawing groups are generally longer (Table 2, entries 3, 4, 7–9, 11 and 12).

A plausible mechanism for the reaction is depicted in Scheme 2, initially, the carbonyl group of the β-diketone/β-ketoester compound is activated in the presence of nickel ferrite nanoparticles; condensation between this activated carbonyl compound and the primary amine in the next step results in the formation of enamine I. On the other hand, nitrostyrene II is produced from the condensation between the aldehyde and nitromethane reacts with I to produce compound III. Finally, the desired pyrrole is formed as a result of ring closure and aromatization thorough an intramolecular attack of amine followed by the elimination of an HNO and H₂O from the molecule.^23,34

Scheme 2 Proposed mechanism.

To investigate the catalyst recyclability, the synthesis of 1a was selected as model reaction. The reaction was ran nine times under the optimized reaction conditions. After each run, the magnetic nanoparticles of the catalyst were collected completely using an external magnetic field, washed two times with double distilled water and reused in the next experiment under the same reaction conditions. Also, in order to have a reasonable comparison, the reaction time was kept constant in all these runs. Results showed that the catalyst could be recycled nine times without significant activity loss and even after the nine runs, the yields remained still high (Fig. 2).

Fig. 2 Recycling experiment.

Experimental

Materials and characterization methods

All materials used are commercially available and were purchased from Merck and used without any additional purification. ¹H NMR and ¹³C NMR spectra were recorded on a Bruker (Avance DRX-500) spectrometer using CDCl₃ as solvent at room temperature. Chemical shifts, δ, were reported in ppm relative to tetramethylsilane as an internal standard. XRF analysis was recorded on SpectroXepos Spectrometer. The characterization of the samples is done by: crystallographic phase identification performed on a Sradi P diffractometer with Cu Kα radiation, a graphite monochromator on the diffracted beam and oscillation counter. FTIR spectra of samples were taken using an ABB Bomem MB-100 FTIR spectrophotometer. The morphology of the catalyst was observed using a Philips XL30 scanning electron microscope (SEM). Magnetic measurements were carried out at room temperature and by using an AGFM magnetometer.

Synthesis of nickel ferrite (NiFe₂O₄)

In a round bottom flask equipped with a magnetic stirring bar, the solutions of iron nitrate (Fe(NO₃)₃·9H₂O) (270 mL, 0.1 M) and nickel nitrate (Ni(NO₃)₂·6H₂O) (270 mL, 0.05 M) were mixed together and vigorously stirred at 70 °C. A solution of NaOH (23 mL, 5 M) was added to this mixture until the pH reaches 10. The suspension was maintained at 70 °C for 2 h and after completion of precipitation, the residue was washed with double distilled water (3 × 25 mL) and was dried in an oven at 100 °C for 24 h. Eventually, it was calcinated at 500 °C for 3 h.

General procedure for the preparation of pyrrole (1a–1l)

To a stirred mixture of NiFe₂O₄ nanoparticles (5 mol%) in nitromethane (2 mmol), aryl aldehyde (1 mmol), 1,3-dicarbonyl compound (1 mmol) and amine (1 mmol) were added. The reaction mixture was stirred at 100 °C and the reaction progress was monitored by TLC. After completion, the reaction mixture was cooled at room temperature and ethyl acetate was added for extraction (3 × 5 mL). Then, NMNs were recovered with an external magnet washed with ethyl acetate, and used for subsequent cycles after drying under vacuum. Pure products were obtained by evaporation of the solvent, followed by recrystallization from ethanol or by column chromatography on silica gel using ethyl acetate/hexane as the. The structure of the products was confirmed using NMR spectroscopic data (¹H-NMR, ¹³C-NMR).

Representative spectroscopic data

Methyl 1-benzyl-2-methyl-4-phenyl-1H-pyrrole-3-carboxylate (1a). Oil (yield: 86%, 0.263 g) (found: C, 78.70; H, 6.24; N, 4.62. Calc. for C₂₀H₁₉NO₂: C, 78.66; H, 6.27; N, 4.59%). IR (KBr) (ν_max/cm⁻¹): 3400, 3017, 1687, 1525, 1454, 1284, 1215. δ_H (500 MHz, CDCl₃): 2.50 (s, 3H, Me), 3.70 (s, 3H, COOMe), 5.09 (s, 2H, CH₂), 6.62 (s, 1H, CH), 7.10–7.49 (m, 10H, Ph); δ_C (125 MHz, CDCl₃): 11.1, 50.6, 50.7, 111.1, 120.4, 126.1, 126.3, 126.6, 127.6, 127.9, 129.0, 129.4, 135.9, 136.5, 136.8, 165.9.

Methyl 1-benzyl-4-(4-chlorophenyl)-2-methyl-1H-pyrrole-3-carboxylate (1d). Oil (yield: 96%, 0.326 g) (found: C, 70.65; H, 5.38; N, 4.18. Calc. for C₂₀H₁₈ClNO₂: C, 70.69; H, 5.34; N, 4.12%). IR (KBr) (ν_max/cm⁻¹): 3018, 1687, 1526, 1284, 1125, 765. δ_H (500 MHz, CDCl₃): 2.50 (s, 3H, Me), 3.70 (s, 3H, COOMe), 5.09 (s, 2H, CH₂), 6.58 (s, 1H, CH), 7.08 (d, J = 7.3 Hz, 2H, Ph), 7.30–7.33 (m, 5H, Ph), 7.37 (d, J = 7.2 Hz, 2H, Ph); δ_C (125 MHz, CDCl₃): 11.2, 50.5, 50.6, 110.9, 120.6, 125.1, 127.6, 127.7, 127.9, 129.0, 129.1, 129.3, 130.7, 132.0, 134.5, 165.7.

Methyl 1-benzyl-4-(furan-2-yl)-2-methyl-1H-pyrrole-3-carboxylate (1f). Oil (yield: 94%, 0.278 g) (found: C, 73.17; H, 5.83; N, 4.78. Calc. for C₁₈H₁₇NO₃: C, 73.20; H, 5.80; N, 4.74%). IR (KBr) (ν_max/cm⁻¹): 2917, 1700, 1595, 1489, 1280, 1207. δ_H (500 MHz, CDCl₃): 2.44 (s, 3H, Me), 3.87 (s, 3H, COOMe), 5.09 (s, 2H, CH₂), 6.42 (d, J = 3.3 Hz, 1H, CH), 6.76 (d, J = 3.3 Hz, 1H, CH (furyl)), 6.96 (s, 1H, CH (furyl)), 7.07 (d, J = 7.1 Hz, 1H, CH (furyl)), 7.30–7.39 (m, 5H, Ph); δ_C (125 MHz, CDCl₃): δ 11.2, 29.8, 50.7, 107.1, 109.9, 111.1, 115.7, 120.5, 126.8, 127.5, 127.9, 129.0, 136.7, 140.1, 149.3, 165.7.

Ethyl 1-benzyl-4-(4-chlorophenyl)-2-methyl-1H-pyrrole-3-carboxylate (1h). Oil (yield: 92%, 0.326 g) (found: C, 71.32; H, 5.65; N, 4.01. Calc. for C₂₁H₂₀ClNO₂: C, 71.28; H, 5.70; N, 3.96%). IR (KBr) (ν_max/cm⁻¹): 3018, 1686, 1528, 1454, 1284, 1065. δ_H (500 MHz, CDCl₃): 1.21 (t, J = 7.1 Hz, 3H, –OCH₂CH₃), 2.50 (s, 3H, CH₃), 4.21 (q, J = 7.1 Hz, 2H, –OCH₂CH₃), 5.10 (s, 2H, CH₂), 6.61 (s, 1H, CH), 7.11 (d, J = 7.3 Hz, 2H, Ph), 7.32–7.35 (m, 5H, Ph), 7.39 (d, J = 7.1 Hz, 2H, Ph); δ_C (125 MHz, CDCl₃): 11.6, 14.2, 50.6, 59.5, 110.9, 120.6, 125.1, 127.6, 127.7, 127.9, 128.9, 129.0, 129.4, 130.6, 131.9, 134.4, 165.8.

Conclusions

In conclusion and for the first time, nickel ferrite magnetic nanoparticles were applied as efficient nanocatalysts in four-component synthesis of pyrroles under neat conditions. The reaction yields are high and the catalyst can be recovered using an external magnet and reused several times without losing the essential activity.

Notes and references

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