Magnetic core–shell titanium dioxide nanoparticles as an efficient catalyst for domino Knoevenagel–Michael-cyclocondensation reaction of malononitrile, various aldehydes and dimedone

Abstract

Magnetic core–shell titanium dioxide nanoparticles (Fe₃O₄@SiO₂@TiO₂) were efficiently used for the preparation of tetrahydrobenzo[b]pyran derivatives via a one-pot three component condensation reaction of various aldehydes, dimedone and malononitrile at 100 °C under solvent-free conditions. The catalyst was synthesized and characterized by several techniques including X-ray diffraction (XRD), transmission electron microscopy (TEM), field-emission scanning electron microscopy (FESEM) and energy-dispersive X-ray spectroscopy (EDX).

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Multi-component reactions (MCRs) have achieved a significant role in combinatorial chemistry due to their ability to prepare target compounds with more efficiency and atomic economy by the reaction of three or more compounds together in a single step. Also, MCRs increase the simplicity and synthetic efficiency of conventional organic syntheses.^1–5

Magnetic nanoparticles (MAGNPs) can offer very promising properties as catalyst supports because of their large specific surface areas and magnetic properties, that facilitate the separation of the catalyst upon reaction completion.^6,7 MAGNPs have been prepared and widely used as novel magnetically separated catalysts in traditional metal catalyzed reactions,⁸ organocatalysis, and enzymatic catalysis.⁹ MAGNPs of Fe₃O₄ are particularly robust, chemically stable as well as readily available with an inherent low toxicity and cost. Preparation of them is also generally very simple, making them an efficient and important alternative to conventional heterogeneous catalyst supports (e.g. alumina and silica).¹⁰

The synthesis of tetrahydrobenzo[b]pyran derivatives is important due to their significant anti-coagulant, diuretic, spasmolytic, anti-cancer, and anti-anaphylactic properties.¹¹ 2-amino-4H-pyran derivatives can be widely used as photoactive materials.¹² Additionally, substituted 4H-pyrans are observed as units in the structure of some natural products.^13,14 Several protocols have been reported for the preparation of tetrahydro-4H-benzopyran derivatives.^15–22 However, some of them suffer from the drawbacks such as the use of toxic metals, the use of volatile organic solvents, high cost and low yields.

Herein, in continuation, magnetic core–shell titanium dioxide nanoparticles (Fe₃O₄@SiO₂@TiO₂) was successfully used as catalyst for the synthesis of tetrahydrobenzo[b]pyrans via the one-pot three component reaction of various aldehydes, dimedone and malononitrile at 100 °C under solvent-free conditions (Scheme 1).

Scheme 1 Preparation of tetrahydrobenzo[b]pyrans.

Initially, magnetic core–shell titanium dioxide nanoparticles (Fe₃O₄@SiO₂@TiO₂) were prepared by the reaction of nano-Fe₃O₄ with tetraethyl orthosilicate and tetrabutyl titanate respectively according the previous literature (Fig. 1).²³

XRD pattern of the catalyst (Fe₃O₄@SiO₂@TiO₂) was studied in a domain of 5–70° (Fig. 2). As shown at Fig. 2, XRD patterns exhibited diffraction lines of a high crystalline nature at about 2θ ≈ 25.3°, 37.7°, 48.1°, 53.9°, 55.0° and 62.7° which is in good compliance with the previous literature (JCPDS 21-1272).^24,25 Peak width (FWHM), size and inter planer distance studies of the catalyst could be worked out in the 25.3 to 62.7° and results have been displayed in Table 1. As example, calculations for the highest diffraction line 25.3° proved that an FWHM of 0.0157 a crystallite size of the catalyst of ca. 9 nm via the Scherrer equation [D = Kλ/(β cos θ)] and an inter planer distance of 0.3548 nm (sing the same highest diffraction line at 25.3°) was calculated to be via the Bragg equation: d_hkl = λ/(2 sin θ), (λ: Cu radiation (0.154178 nm) were obtained. Crystallite sizes as obtained from the various diffraction lines using the Scherrer equation were found to be in the nanometer range (7.5–11.6 nm).

Fig. 1 Preparation of Fe₃O₄@SiO₂@TiO₂.

Fig. 2 XRD diagram of Fe₃O₄@SiO₂@TiO₂.

Table 1 XRD data for the catalyst (Fe₃O₄@SiO₂@TiO₂)

Entry	2θ	Peak width [FWHM]	Size [nm]	Inter planer distance [nm]
1	25.3	0.0157	9.0	0.3548
2	37.7	0.0122	12.0	0.2383
3	48.1	0.0200	7.5	0.1889
4	53.9	0.0157	9.9	0.1699
5	55.0	0.0095	16.4	0.1667
6	62.7	0.0139	11.6	0.1480

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To further prove the nanostructure of Fe₃O₄@SiO₂@TiO₂, TEM measurements were performed as displayed in Fig. 3. TEM micrograph confirm the presence of more or less spherical nanoparticles with a mean diameter of 9.0 nm (Fig. 3).

Fig. 3 Transmission electron micrographs (TEM) of Fe₃O₄@SiO₂@TiO₂.

In another investigation, the FSEM micrographs of the catalyst showed that the particles have not completely agglomerated. Also, particles of the catalyst were observed in nano scale (Fig. 4).

Fig. 4 FSEM micrographs of Fe₃O₄@SiO₂@TiO₂.

Energy-dispersive X-ray spectroscopy (EDX) from the obtained nanomaterials (Fig. 5) provided the presence of the expected elements in the structure of the catalyst, namely iron, oxygen, silicon, and titanium.

Fig. 5 Energy-dispersive X-ray spectroscopy (EDX) of the catalyst.

After the characterization and identification of the catalyst, to optimize the reaction conditions, as model reaction, the solvent-free condensation of 4-chlorobenzaldehyde, dimedone and malononitrile was examined using different amounts of Fe₃O₄@SiO₂@TiO₂ at range of 50–110 °C. The best results were obtained in the presence of 0.01 gram of Fe₃O₄@SiO₂@TiO₂ at 100 °C. Increasing the reaction time did not improve the results (Table 2). The model reaction was tested in the presence of SiO₂, Fe₃O₄ and TiO₂ separately under optimized conditions in comparison with Fe₃O₄@SiO₂@TiO₂. The results showed that Fe₃O₄@SiO₂@TiO₂ is better than other catalysts in this reaction condition (Table 2).

Table 2 Effect of different amounts of the catalyst and temperature on the reaction between 4-chlorobenzaldehyde, dimedone and malononitrile

Catalyst	Amount of catalyst (g)	Temp. (°C)	Time (min)	Yield^a (%)
a Isolated yield.
Fe3O4@SiO2@TiO2	0.01	50	35	65
Fe3O4@SiO2@TiO2	0.01	80	20	78
Fe3O4@SiO2@TiO2	0.01	90	15	85
Fe3O4@SiO2@TiO2	0.01	100	10	96
Fe3O4@SiO2@TiO2	0.01	110	10	96
Fe3O4@SiO2@TiO2	0.005	100	40	60
Fe3O4@SiO2@TiO2	0.02	100	10	96
Fe3O4@SiO2@TiO2	—	100	180	17
Fe3O4	0.01	100	15	81
SiO2	0.01	100	60	30
TiO2	0.01	100	50	32

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In the next step, the model reaction was examined using 0.01 g of Fe₃O₄@SiO₂@TiO₂ with various solvents under reflux conditions in comparison with the solvent-free conditions. The results are depicted in Table 3. As can be seen in Table 3, indicates that the solvent-free condition was the best condition in this reaction.

Table 3 Effect of different solvents of the catalyst and temperature on the reaction between 4-chlorobenzaldehyde, dimedone and malononitrile under reflux condition

Entry	Solvent	Time (min)	Yield^a (%)
a Isolated yield.b The reaction was proceeded in the absence of solvent at 100 °C.
1	Ethanol	90	38
2	Chloroform	130	36
3	Acetone	140	34
4	Dichloromethane	180	28
5	Acetonitrile	95	48
6^b	—	10	96

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To study the generality and scope of the catalyst, we extended our study using Fe₃O₄@SiO₂@TiO₂ (0.01 g) with various aromatic aldehydes to give a series of tetrahydrobenzo[b]pyran derivatives under solvent-free conditions (Table 4). Various aromatic aldehydes containing electron-withdrawing substituents, electron-releasing substituents and halogens on their aromatic rings were utilized successfully in the reaction, and obtained the corresponded products in high yields and in short reaction times.

Table 4 The solvent-free synthesis of tetrahydrobenzo[b]pyrans from dimedone, arylaldehydes and malononitrile catalyzed by Fe₃O₄@SiO₂@TiO₂ at 95 °C

Product	Time (min)	Yield^a (%)	M.p. °C (L)
a Isolated yield.
	20	93	229–230 (230–231)^22
	10	96	208–210 (215–216)^22
	8	94	218–219 (217–218)^31
	5	96	183–186 (192–194)^32
	8	93	250–252 (—)^35
	5	93	260–263 (252–254)^21
	4	96	214–217 (216–217)^22
	6	96	207–208 (215)^13
	6	97	228–230 (228–230)^33
	6	96	150–152 (152–154)^18
	5	96	178–180 (186–187)^22
	5	98	210–212 (—)^36
	12	90	216–217 (215–218)^29
	10	96	214–216 (207–209)^30
	12	92	208–212 (199–201)^26
	10	90	200–202 (194–196)^29
	6	95	202–204 (210)^13
	20	88	212–213 (217–218)^28
	180	75	217–219 (210–212)^27
	8	91	215–218 (216–218)^34
	8	98	215–218 (208–210)^29
	15	95	248–250

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The synthesis of tetrahydrobenzo[b]pyrans was studied using butyraldehyde as aliphatic aldehydes in the optimized condition reaction. The expected product was obtained in 68% of yield and in 90 min reaction time.

Ethyl cyanoacetate as an active methylene compound, instead of malononitrile, was reacted with 4-chlorobenzaldehyde and dimedone in the synthesis of pyran derivatives. In this reaction, the desired product was prepared in 28% of yield after 120 minutes.

In a proposed mechanism that is shown in Scheme 2, at first, malononitrile is reacted to carbonyl group of aldehyde which is activated by the Fe₃O₄@SiO₂@TiO₂ to give intermediate I after removing one molecule of H₂O. Dimedone converts to enole form after tautomerisation and attacks to cyanoolefin compound (I) as Michael acceptor to give II. Eventually, cyclocondensation of II produces III which is converted to desired product.

Scheme 2 Proposed mechanism for the synthesis of tetrahydrobenzo[b]pyrans.

In another study, reusability of the catalyst was tested upon the condensation of 4-chlorobenzaldehyde, (1 mmol), dimedone (1 mmol) and malononitrile (1 mmol). The reaction mixture was extracted by warm ethanol to separate from the catalyst. Afterward, the reused catalyst was used for another reaction. We observed that the catalytic activity of the catalyst was restored within the limits of the experimental errors for six successive runs (Fig. 6).

Fig. 6 The reaction of 4-chlorobenzaldehyde, dimedone and malononitrile in the presence of reused Fe₃O₄@SiO₂@TiO₂ at 100 °C under solvent-free conditions.

Conclusions

In summary, we have introduced a new and highly efficient protocol for the synthesis of tetrahydrobenzo[b]pyran compounds by the one-pot multi-component condensation reaction of various aldehydes, dimedone and malononitrile at 100 °C using magnetic core–shell titanium dioxide nanoparticles Fe₃O₄@SiO₂@TiO₂ under solvent-free conditions.³⁷

Acknowledgements

The authors gratefully acknowledge the Bu-Ali Sina University Research Council and Center of Excellence in Development of Environmentally Friendly Methods for Chemical Synthesis (CEDEFMCS) for providing support to this work.

Notes and references

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37. General procedure for the synthesis of tetrahydrobenzo[b]pyrans using Fe₃O₄@SiO₂@TiO₂: a mixture of dimedone (1 mmol), malononitrile (1 mmol), aldehyde (1 mmol) and Fe₃O₄@SiO₂@TiO₂ (0.01 g) was added to a 10 mL round-bottomed flask connected to a reflux condenser and stirred in an oil-bath at 100 °C. After completion of the reaction, as monitored by TLC, the reaction mixture was extracted with warm ethanol (10 mL) to separate the catalyst. Crude products were soluble in warm ethanol and separated from the catalyst. The catalyst easily collected by a magnet and washed with ethyl acetate to reuse for another reaction. Then, the solid residue (crude product) was purified by the recrystallization in a mixture of ethanol and water (9/1) to give the desired product.

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c4ra16300a

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