Novel biocompatible core/shell Fe3O4@NFC@Co(ii) as a new catalyst in a multicomponent reaction: an efficient and sustainable methodology and novel reusable material for one-pot synthesis of 4H-pyran and pyranopyrazole in aqueous media.

Today, due to the developing need for inexpensive catalysts, recyclable magnetic nanocatalysts immobilized on polysaccharides possess many advantages over classical heterogeneous catalysts. However, cellulose has been an appealing material in catalysis science and technology. In this work, by controlling the interaction between the inorganic complexes and the support material, we designed a high activity nanostructured combination of a magnetic nanoparticle Fe3O4@NFC@Co(ii) terminated complex as a multi-nuclear catalyst. This protocol involves an environment friendly approach using cobalt acetate. The magnetic nanostructure Fe3O4@NFC@Co(ii) can be used as a novel, green, and a powerful catalyst that demonstrates a short reaction time, high yield and easy procedure for the cascade Knoevenagel-Michael-cyclocondensation reaction for the one-pot synthesis of 4H-pyrans and pyranopyrazoles. The superparamagnetic nanocomposite could be conveniently separated by using an external magnet. Moreover, the catalyst could be reused at least five times in new reaction runs without a noticeable loss of activity. The prepared catalyst was characterized by FT-IR, XRD, VSM, FESEM, EDAX, TEM, ICP, and TGA techniques. The experiments were achieved with good yields and implied that the catalytic method was effective and convenient for heterocyclic synthesis. This journal is © The Royal Society of Chemistry.

Introduction

In cascade reactions, several raw materials are produced in several stages without the separation of any intermediates, changing reaction conditions, or adding reagents. Clean reaction conditions, high atomic economy and efficient complexity in one step are some advantages of this reaction.[1,2] Organic syntheses with a focus on “green chemistry”, find this attractive. Interest in this subject for several years has led to the emergence of new and benign methods such as water solvent syntheses, multicomponent reactions and reusable catalysts to save resources and energy.[3] Green chemistry emphasizes the development of environmentally benign chemical processes and technologies. The most important criterion for the efficiency and feasibility of a process is to minimize the number of synthesis and purification steps as much as possible. Multi-component reactions (MCR) in this area are a promising and great success in green chemistry.[4] In multi-component reactions, complex and valuable structures are synthesized very quickly and efficiently over a short period without limits introduced by intermediates. Therefore, by reducing the synthesis steps compared to traditional methods, the reaction will be faster and more efficient.[5] MCRs are a special category of organic reaction in which the product in question is created during the step of combining raw materials. The interest and effort from notable chemists towards multi-component reactions has led to the development and advancement of multi-component reactions to make them more responsive and optimized. Therefore, partial reactions are considered to be the best techniques in green chemistry. These reactions have become increasingly important in organic and pharmaceutical chemistry and have become one of the most effective and economical tools for the simultaneous synthesis of compounds.[6,7] Pyrans and pyranopyrazoles are a group of important heterocycles that have a large number of natural compounds in their structure and show different biological activity. Pyrans are widely used in cosmetics, pigments, and medicinal chemistry.[8-10] In addition, its compounds and derivatives play an important role in the biological-organic and chemical activities of biologics and are widely used as the main nucleus of photochromic materials.[11] Pyrans and the valuable derivatives of pyrans have been found in many natural products.[12] These compounds have been considered valuable due to their biological and medicinal properties,[13-20] such as their anti-bacterial,[21] anti-microbial,[22] anti-allergic,[23] anti-rheumatism[24] and anti-cancer[25] properties. Also, pyrans are used as memory enhancers to treat neurological diseases such as Alzheimer's,[26] Huntington's,[27] Parkinson's[28] and Down syndrome.[29] Also, pyranopyrazoles often have important roles based on their biological activity, which includes anti-inflammation[30] and insecticidal effects,[31] besides being identified as a screening kit for the Chk1 kinase inhibitor.[32] Different methods have been reported[33-40] for the synthesis of these derivatives. However, given the goal of green chemistry and planning to make more use of green and inexpensive compounds, we are looking for a way to introduce a catalytic system, which is environmentally friendly, cost-effective, and provides a high power and maximum efficiency in a short time. Today, nanocomposite catalysts are widely regarded by researchers as stable catalysts.[40] Among them, superparamagnetic nanoparticles are widely used due to their easy separation for a variety of organic artificial developments.[41-44] Polysaccharides with a common form of more than ten monosaccharides are very abundant in nature with sources such as seaweed and plants like wheat, rice, vegetables, etc.[45,46] Furthermore, the important benefits of these polysaccharides include safe use, non-toxic nature, easy production, abundant resources, and low-cost.[47] Cellulose is a polysaccharide material that is extracted from renewable sources and has been widely considered due to the simplicity of its environmentally-friendly production and low cost. Some of the most important commercial applications of cellulose are food paper, textiles, cosmetics, and pharmaceuticals.[48]

The goal of our research team is to provide a novel multi-core catalyst that has high power, short reaction time, recyclability in multi-stage processes and non-toxic reactivity (Scheme 1). This protocol from both the economic and synthetic point of view possesses several advantages like reduced pollution, lower cost, and simplicity in processing, which are beneficial to the industry as well as to the environment. Water is a desirable medium due to its features that include eco-friendly, safe, non-toxic, non-flammable, clean, green, inexpensive, and readily available. Therefore, the metal is placed on the metal cavities covered with cellulose to achieve high performance and resistance to the synthesis of 4H-pyran (Scheme 2) and pyranopyrazole (Scheme 3) with a safe solvent, which these compounds have good medicinal properties. This catalyst Fe3O4@NFC@Co(ii) greatly reduced the cost of this transformation, and the resulting operation and work-up procedures were greatly simplified.

Scheme 1

The synthetic route for Fe3O4@NFC@Co(ii).

Scheme 2

Synthesis of 4H-pyrans promoted by Fe3O4@NFC@Co(ii) nanocatalyst.

Scheme 3

Synthesis of pyranopyrazoles promoted by Fe3O4@NFC@Co(ii) nanocatalyst.

Result and discussion

The design of organic reactions in aqueous environments is another area of progress in green chemistry. Water is a highly soluble and environmentally friendly solvent. This protocol provides flexibility in regulating complexity and molecular diversity. After the reactions were complete, the pure product was simply crystallized from ethanol without the use of any chromatographic method almost immediately. FT-IR spectra for the samples of Fe3O4 MNPs (a), Fe3O4 functionalized with nanofiber cellulose (Fe3O4@NFC) (b), Fe3O4@NFC@Co(ii) (c) are shown in Fig. 1. The FT-IR spectrum for the MNPs (a) shows a stretching vibration of the –OH group at about 3440 cm−1, which are attached to the surface iron atoms. The strong absorption at 581 cm−1 is characteristic of the Fe–O stretching vibration, which illustrates the existence of Fe3O4 components.

Fig. 1

FT-IR spectra of (a) Fe3O4, (b) Fe3O4@NFC and (c) Fe3O4@NFC@Co(ii).

In the FT-IR spectrum of Fe3O4@NFC (Fig. 1b), the existence of the anchored nanofiber cellulose is confirmed by the stretching vibration of the aliphatic C–H group that appears at 2920 cm−1, and also the broad band emerging at 3396–3432 cm−1 and 1064 cm−1, which is related to the O–H and C–O stretching vibrations, respectively. The FT-IR spectrum of catalyst Fe3O4@NFC@Co(ii) (Fig. 1c) is proof that metal cobalt has been successfully attached. In the FT-IR of the catalyst, the C–O bond shifted to a lower wavenumber and appears at 1036 cm−1, which illustrates the formation of NFC@Co(ii) complexes. The structure of the synthesized nanocatalyst was investigated by X-ray powder diffraction analysis (XRD) (Fig. 2). The XRD pattern shows the characteristic peaks of bare Fe3O4 at 2θ = 30.3°, 35.8°, 43.6°, 54.8°, 57.3°, and 63.2° corresponding to the reflections of the (220), (311), (400), (422), (511), and (440) planes. The XRD pattern of Fe3O4@NFC@Co(ii) catalyst matches well with the characteristic peaks of bare Fe3O4, which indicates the retention of the crystalline spinel ferrite core structure during functionalization of MNPs. Strong peaks at 2θ = 36.71°, 42.47° and 61.64° corresponding to the (111), (200) and (220) crystallographic phases in XRD pattern are related to CoO.[49] Also, new peaks appeared at 2θ = 18.7 and 20.3, which are attributed to the cellulose species. The XRD diagram of reused catalyst shows that the structure of the catalyst is stable during the reaction.

Fig. 2

XRD spectra of (a) Fe3O4, (b) CoO and (c) Fe3O4@NFC@Co(ii).

Thermogravimetric analysis (TGA) was used to determine the thermal stability and percentage of chemisorbed organic functional groups on the surface of the magnetic nanoparticles. Fig. 3 shows the TG/DTG thermogram for the Fe3O4@NFC@Co(ii) catalyst. The weight loss of about 4% in the TGA curve of Fe3O4, at temperatures below 300 °C is assigned to the removal of physically adsorbed organic solvents and surface –OH groups (Fig. 3). Moreover, the weight loss of about 3% in the temperature range between 300 and 700 °C may be due to the thermal crystal phase alteration from Fe3O4 to γ-Fe2O3.[24] There are three weight loss steps in the TGA curve of Fe3O4@NFC@Co(ii) (Fig. 3b). Firstly, a weight loss of about 1.5% below 200 °C is observed, which is owing to the removal of water molecules from the catalyst surface. The second and third steps of weight losses at 200–800 °C may correspond to the degradation of a nanofiber cellulose complex.

Fig. 3

TG/DTG thermogram for Fe3O4@NFC@Co(ii) catalyst.

The FESEM images of the Fe3O4@NFC@Co(ii) nanocatalyst at different magnifications are shown in Fig. 4. According to Fig. 5, the surface morphology of the catalyst shows similar and spherical particles with a size of less than 24 nm. The energy dispersive X-ray spectroscopy (EDS) spectrum shows the presence of various elements in the catalyst (Fig. 5).

Fig. 4

FESEM image (a) Fe3O4 and (b) Fe3O4@NFC@Co(ii).

Fig. 5

EDX image of Fe3O4@NFC@Co(ii).

The magnetic property of Fe3O4 nanoparticles and Fe3O4@NFC@Co(ii) were recorded at room temperature using the vibrating sample magnetometer (VSM) technique (Fig. 6). The magnetic measurement shows that Fe3O4@NFC@ Co(ii) has a saturated magnetization value of 53.23 emu g−1. The VSM curve of the Fe3O4 nanoparticles is 63.23 emu g−1, which has a higher magnetic value in comparison with the synthesized nanocatalyst. Reduction in the magnetic property of Fe3O4@NFC@Co(ii) is due to the coating of cellulose and the attached organic layers on Fe3O4 nanoparticles. The morphology and nanoparticle size of the catalyst were characterized by scanning electron microscopy.

Fig. 6

VSM pattern (a) Fe3O4 and (b) Fe3O4@NFC@Co(ii).

The loading amount of Co on the Fe3O4@NFC was determined by inductively coupled plasma atomic emission spectrometry (ICP-AES). The ICP analysis showed that the amount of cobalt in the catalyst was 1.63 × 10−3 mol g−1. The particle size distribution of Fe3O4@NFC@Co(ii) was evaluated using TEM, which demonstrated that the average diameter of the particles was 16 nm. TEM images also showed that the NPs are spherical and relatively monodispersed (Fig. 7).

Fig. 7

TEM image (a and b) and particle size distribution histogram (c) of Fe3O4@NFC@Co(ii).

Catalytic study

After the preparation of Fe3O4@NFC@Co(ii), its catalytic activities were evaluated for the 4H-pyrane and pyranopyrazole reaction. For this purpose, hydrazine hydrate, ethyl acetoacetate, benzaldehyde, and malononitrile were used in the model pyranopyrazole reaction and malononitrile, ethyl acetoacetate and various aldehydes were used in a model 4H-pyrane reaction to optimize the reaction conditions; the results are discussed in Table 1. The reaction of benzaldehyde (1 mmol) with malononitrile (1 mmol) and ethyl acetoacetate (1 mmol) for 4H-pyrane and benzaldehyde (1 mmol), hydrazine hydrate (1 mmol), malononitrile (1 mmol), and ethyl acetoacetate (1 mmol) for pyranopyrazole was chosen as a simple model reaction to optimize the reaction conditions, including catalyst amount, solvent, base, and effect of temperature (Table 1). When the reactions were attempted without a catalyst, it was found that only a low yield of product was obtained even after 1 h. This result suggests that a catalyst plays a critical role in these reactions. Initially, different solvents such as H2O, dimethylformamide (DMF), tetrahydrofuran (THF), polyethylene glycol (PEG-400), acetonitrile (CH3CN), toluene, dioxane, ethanol, and no solvent were examined (entries 1–9) in the presence of 1 mol% of Fe3O4@NFC@Co(ii).

Optimization of the catalyst, synthesis condition, and solvent for the synthesis of 4H-pyran in the model reactiona

Entry	Solvent	Catalyst (mol%)	Temp (°C)	Time (min)	Con. yieldb	Yieldc (%)
1	EtOH	1	70	60	85	75
2	DMF	1	100	30	70	65
3	THF	1	60	60	40	25
4	Dioxane	1	100	60	90	75
5	CH3CN	1	100	60	60	45
6	Toluene	1	100	60	90	80
7	PEG-400	1	70	60	95	88
8	H2O	1	70	15	100	98
9	Neat	1	70	60	98	90
10	Neat	1	70	30	75	60
11	H2O	0.5	70	45	90	80
12	H2O	0.7	70	30	95	87
13	H2O	1	70	15	100	97
14	H2O	1.2	70	15	100	98
15	H2O	1	25	60	80	65
16	H2O	1	45	30	93	85
17	H2O	1	55	15	100	97
18	H2O	1	65	15	100	98
19	H2O	1	75	15	100	98

Reaction conditions: aldehyde (1.0 mmol), malononitrile (1.0 mmol), ethyl acetoacetate (1.0 mmol), catalyst (1 mol%) and H2O (2 mL), 55 °C.

Conversion yield (%).

Isolated yield (%).

In solvents like PEG, water or no solvent (entries 6–9), high yields were observed, but the highest yields were obtained in water for the 4H-pyrane and pyranopyrazole reactions. Examination of the effect of solvent (Tables 1 and 2) for the 4H-pyrane and pyranopyrazole reaction shows that the conversion yield is a function of solvent polarity. Reactions in non-polar solvents have low conversion and in polar solvents, more complete conversion is achieved, except for in dioxane, tetrahydrofuran and toluene. When we analyzed the products, unfortunately instead of completing the reaction, a mixture of product and alkylidyne intermediate (I) and (III) (Schemes 4 and 5) was created. CH3CN is a polar solvent, so in the process of reacting, we found that due to its low nucleophilic power, it may not be a suitable solvent for the development of the reaction.[50] As a result, we noticed an isolated yield in PEG, water and no solvent, where water has a good conversion yield for both reactions. In the next step, this model reaction was examined with different temperatures including room temperature, 40, 50, 60, and 80 °C for both reactions, and the best results were obtained at 55 °C for 4H-pyrane and 50 °C for pyranopyrazole. Increasing the temperature to 75 °C did not effectively increase the yield of the product (Tables 1 and 2, entry 19). Finally, to optimize the catalyst amount, different quantities of catalyst were appraised in the model reaction. As shown in Tables 1 and 2 for the 4H-pyrane and pyranopyrazole reactions, the lack of catalyst resulted in a low yield of the product after 24 h but experiments showed that 1 mol% of catalyst for both 4H-pyrane and pyranopyrazole is an adequate amount for the completion of the reactions. Using more of the catalysts did not effectively increase the yield or decrease the time of the reactions (Tables 1 and 2, entry 11–14). The 4H-pyrane derivatives and pyranopyrazole derivatives were obtained in satisfactory yields and the results are summarized in Table 3. However, the results of the 4H-pyrane and pyranopyrazole reactions depend on the type of halide, the positions of the substitution groups on the aromatic ring, the effect of various electron donating and electron withdrawing groups, and the catalyst activity. The suggested mechanism for the 4H-pyrane and pyranopyrazole reaction in the presence of the Fe3O4@NFC@Co(ii) catalyst is outlined in Schemes 2 and 3.[28]

Optimization of the catalyst, synthesis conditions, and solvent for the synthesis of pyranopyrazole in the model reactiona

Entry	Solvent	Catalyst (mol%)	Temp (°C)	Time (min)	Con. yieldb	Iso. yieldc
1	EtOH	1	70	60	75	67
2	DMF	1	100	30	85	75
3	THF	1	60	60	83	70
4	Dioxane	1	100	60	90	80
5	CH3CN	1	100	60	60	50
6	Toluene	1	100	60	97	91
7	PEG-400	1	70	60	97	91
8	H2O	1	70	15	100	98
9	Neat	1	70	60	95	90
10	Neat	1	70	30	65	55
11	H2O	0.5	70	45	90	85
12	H2O	0.7	70	30	98	90
13	H2O	1	70	15	100	98
14	H2O	1.2	70	15	100	98
15	H2O	1	25	60	80	70
16	H2O	1	40	30	95	85
17	H2O	1	50	15	100	98
18	H2O	1	60	15	100	95
19	H2O	1	75	15	100	95

Reaction conditions: hydrazine hydrate 96% (1 mmol) and ethyl acetoacetate (1 mmol), aldehyde (1 mmol), malononitrile (1 mmol), water (2 mL) catalyst (1 mol%) and H2O (2 mL), 50 °C.

Conversion yield (%): calculated based on benzaldehyde consumption.

Isolated yield (%): calculated based on the product pyranopyrazole.

Scheme 4

Possible reaction mechanism for one-pot synthesis of polyfunctionalized 4H-pyrans over Fe3O4@NFC@Co(ii).

Scheme 5

Possible reaction mechanism for one-pot synthesis of polyfunctionalized pyranopyrazole over Fe3O4@NFC@Co(ii).

Multicomponent reaction for the synthesis of tri-substituted 4H-pyrans and tetra-substituted pyranopyrazoles

Entry	Aldehyde	Product	Time (min)	Yielda (%)	TON	TOF	Mp (°C)		Ref.
							Obtained	Reported
1	Benzaldehyde	1a	15	97	107.7	430	209–210	208–210	51
2	4-Chlorobenzaldehyde	1b	15	93	103.3	413.2	172	172–174	51
3	4-Bromobenzaldehyde	1c	10	92	102.2	638.8	178–179	178	52
4	4-Hydroxybenzaldehyde	1d	15	90	100	400	177	175–177	53
5	4-Methoxybenzaldehyde	1e	20	95	105.5	319.8	137	135–137	52
6	4-Methylbenzaldehyde	1f	20	85	94.4	286.2	174–176	175–177	51
7	4-Fluorobenzaldehyde	1g	10	94	104.4	652.7	274–276	274–277	51
8	4-Nitrobenzaldehyde	1h	15	88	97.7	391.1	182–183	180–183	54
9	3-Nitrobenzaldehyde	1i	15	83	92.2	368.8	190	189–191	55
10	2-Nitrobenzaldehyde	1j	15	90	100	400	181–182	181–183	56
11	2-Chlorobenzaldehyde	1k	10	95	105.5	659.7	194–195	193–195	55
12	2-Bromobenzaldehyde	1l	15	95	105.5	422.2	186	185–187	55
13	Benzaldehyde	2a	15	98	108.8	435.5	262–263	261–263	57
14	4-Chlorobenzaldehyde	2b	15	95	105.5	422.2	231–233	231	57
15	4-Bromobenzaldehyde	2c	15	90	100	400	172–174	172–174	58
16	4-Hydroxybenzaldehyde	2d	20	90	100	303	254–256	255–257	59
17	4-Methoxybenzaldehyde	2e	20	88	97.7	296.3	211–212	210–212	60
18	4-Methylbenzaldehyde	2f	25	88	97.7	234	213–215	212–215	61
19	4-Fluorobenzaldehyde	2g	15	90	100	400	239–241	240–242	62
20	4-Nitrobenzaldehyde	2h	20	95	105.5	319.8	247–249	246–248	60
21	3-Nitrobenzaldehyde	2i	20	92	102.2	309.7	194	192–194	60
22	2-Nitrobenzaldehyde	2j	20	95	105.5	319.8	216	216–218	57
23	2-Chlorobenzaldehyde	2k	20	85	94.4	286.2	241–243	240–242	60
24	2-Bromobenzaldehyde	2l	20	83	92.2	279.5	232–233	232–235	61

Isolated yield.

Recyclability of the catalyst

The recycling of the heterogeneous catalysts is an important aspect for commercial applications. To analyze this, the recovery and reusability of the catalyst were examined for the 4H-pyrane reaction of benzaldehyde with malononitrile and ethyl acetoacetate, and the pyranopyrazole reaction of benzaldehyde, hydrazine hydrate, malononitrile, and ethyl acetoacetate as model reactions under the optimized conditions. After the completion of the reaction, the catalyst was simply separated from the reaction mixture using an external magnet and washed with water and ethanol to remove organic residuals, dried, and reused for the next runs. As shown in Fig. 8, the recycled catalyst does not show any significant changes in its activity, which showed that the catalyst was stable and can be reused for the next successive cycles. The catalyst Fe3O4@NFC@Co(ii) was analyzed after five steps of recycling by IR and FESEM, as shown in Fig. 9. As shown in the recycling table, there was not much change in the structure of the catalyst morphology or the IR spectrum with several washing steps in these reactions.

Fig. 8

Recycling activity of the Fe3O4@NFC@Co(ii) NPs.

Fig. 9

FESEM image and FTIR spectra of Fe3O4@NFC@Co(ii): (a) fresh (IR), (b) after 4H-pyran and (c) after pyranopyrazole.

Suggested reaction mechanism

Based on our results, we proposed a mechanism for the one-pot synthesis of polyfunctionalized 4H-pyrans from aldehydes, malononitrile, and an ethyl acetoacetate compound (Scheme 4) and the synthesis of polyfunctionalized pyranopyrazole from aldehydes, malononitrile, hydrazine hydrate and an ethyl acetoacetate compound (Scheme 5). In Scheme 4, the surface metal ions of the catalyst act as active Lewis acids to enolize malononitrile and acetyl acetate in the reaction pathways to prepare the corresponding enols as powerful nucleophiles. Then, the enol of malononitrile attacks benzaldehyde to form an olefin intermediate (I). Therefore, the Knoevenagel condensation reaction takes place between malononitrile and benzaldehyde to form intermediate (I). The Michael addition reaction happens between intermediate (I) and enol (II), forming acetyl acetate derivates to yield intermediate (III). Then, with subsequent steps of intramolecular nucleophilic addition and tautomerization, intermediates (IV) and (V) are formed. Finally, the polyfunctionalized 4H-pyrans are obtained by H+ abstraction from the catalyst. In Scheme 5, the proposed mechanism consists of two parts: the first part involves the formation of pyrazolone from the hydrazine with ethyl acetate, which is converted to pyrazole if Fe3O4@NFC@Co(ii) is present. The other part is the formation of phenylidene malononitrile from the concentration of malononitrile from the Knoevenagel condensation with benzaldehyde in the presence of the Fe3O4@NFC@Co(ii) catalyst. At the end of the reaction, the Michael's addition combination of (II) was created by intermediates (III) and (IV), which, after an intramolecular nucleophilic attack on the nitrile group, first formed a ring and then a tautomerization gave the pyranopyrazole.

Experimental section

Materials and methods

Cellulose nanofibers were purchased from Sigma Aldrich. Iron(iii) chloride, iron(ii) sulfate, cobalt(ii) acetate, and sodium hydroxide were purchased from Sigma Aldrich. All chemicals were used without further purification. The FT-IR spectra were recorded on a JASCO FT/IR 4600 FT-IR spectrometer. The thermal analysis (TGA) was carried out using a TGA Q600 TA instrument at a heating rate of 10 °C min−1 in air. The powder X-ray diffraction (XRD) was performed with a Philips PW1730. The scanning electron microscopy (FESEM) and the energy dispersive X-ray spectroscopy (EDS) characterization of catalysts was performed using an electron microscope Tescan MIRA3. The melting points of the products were measured by an electrothermal 9100 apparatus. ICP experiments were accomplished using a Varian Vista Pro CCD simultaneous ICP-OES instrument. Magnetic properties of the nanoparticles were measured with a vibrating sample magnetometer (VSM). Transmission electron microscopy (TEM) was performed on a Philips EM208 microscope and was operated at 100 kV.

Preparation of the magnetic Fe3O4 nanoparticles (MNPs)

MNPs were synthesized through the co-reduction of Fe(iii) and Fe(ii) ions with a molar ratio of 2 : 1 in the presence of ammonium hydroxide. In general, a 100 mL solution containing FeCl3·6H2O (2 mmol) and FeSO4·7H2O (1 mmol) was prepared and heated at 80 °C under N2 atmosphere and strongly stirred. Then, 5 mL of 25% NH4OH was slowly injected into this mixture in one step. The black MNPs were instantly formed after adding the ammonia solution to the Fe2+/Fe3+ salt solution. The mixture was stirred for 120 min and then cooled to ambient temperature. Then, dark MNPs were magnetically separated from the solution and washed three times with deionized water.[62]

Preparation of the NFC@Fe3O4 (nanofiber Cellulose@Fe3O4)

To a suspension of Fe3O4 nanoparticles (1.15 g, 5.0 mmol) in deionized water (50 mL), 50 mL of NFC (0.5 g, 2.5 mmol) solution was added drop-wise at room temperature. The mixture was vigorously stirred for 2 h at room temperature and then neutralized with water.[63] After the foam had subsided, the resulting Fe3O4@NFC precipitate was isolated using an external magnet, washed twice with deionized water, and dried at 60 °C under vacuum for 6 h.

Preparation of the Fe3O4@NFC@Co(ii)

Based on this method, an excess amount of cobalt(ii) acetate in 5 mL ethanolic solution was used to disperse 1 g of Fe3O4@NFC and allowed to react for 2 h at 80 °C under vigorous stirring. Finally, the solid product was separated from the residual cobalt solution by a magnet. Then, the obtained solid product was washed several times with ethanol and dried in an oven at 60 °C for 12 h.

Catalytic procedure for synthesis of 4H-pyran derivatives

A mixture of aldehyde (1.0 mmol), malononitrile (1.0 mmol), ethyl acetoacetate (1.0 mmol), water (2 mL), and Fe3O4@NFC@Co(ii) (1 mol%) were stirred magnetically in an oil-bath maintained at 55 °C for an appropriate time as mentioned in Table 2. After completion of the reaction as monitored by TLC using n-hexane : ethyl acetate (60 : 40) as the eluent, the reaction mixture was allowed to cool to room temperature and then crystallized with ethanol to form a pure crystal of the 4H-pyran (1a–l). The catalyst used in the reaction was reusable for up to 5 cycles (as shown in Fig. 8).

General procedure for synthesis pyranopyrazole derivatives

A mixture of hydrazine hydrate 96% (1 mmol), ethyl acetoacetate (1 mmol), aldehyde (1 mmol), malononitrile (1 mmol), water (2 mL) and Fe3O4@NFC@Co(ii) (1 mol%) as catalyst were added successively at room temperature under an open atmosphere with vigorous stirring. After completion of the reaction, the reaction mixture was dissolved in ethanol and then the catalyst was separated magnetically. The magnetic Fe3O4 nanoparticles were washed three times with ethanol and then dried at 50 °C for 5 h. The product obtained was pure by TLC. However, the products were further purified by recrystallization from ethanol to form a pure crystal of the pyranopyrazole (2a–l).

Selected spectral data

The physical and spectral data of selected products are represented below.

Ethyl 6-amino-5-cyano-2-methyl-4-phenyl-4H-pyran-3 carboxylate (Table 3, entry 1)

Off-white solid; IR (KBr): 3402.49 (NH2), 3329.96 (NH2), 2972.32 (C–H), 2190.34 (CN), 1692.10 (CO), 1652.27, 1609.54, 1375.88, 1259.12, 1120.31, 1062.19 cm−1. 1H-NMR (400 MHz, DMSO-d6) δ = 1.21–1.30 (3H, CH3, t), 2.50 (3H, CH3, s), 3.81–4.05 (2H, CH2, q), 4.60 (H, CH, s), 6.26 (2H, NH2, s), 7.67–7.88 (5H, H-Ar, m) ppm. 13C-NMR (100 MHz, DMSO-d6): δ = 12.53, 15.37, 55.53, 61.81, 108.85, 119.22, 125.51, 125.72, 127.53, 127.78, 142.85, 152.53, 154.37, 166.85 ppm.

Ethyl-6-amino-4-(4-chlorophenyl)-5-cyano-2-methyl-4H-pyran-3-carboxylate (Table 3, entry 2)

Off-white solid; IR (KBr): 3409.17 (NH2), 3332.69 (NH2), 2979.48 (C–H), 2193.69 (CN), 1693.41 (CO), 1650.55, 1609.34, 1489.39, 1335.42, 1266.26, 1174.09, 1120.47 cm−1. 1H-NMR (400 MHz, DMSO-d6) δ = 1.01–1.09 (3H, CH3, t), 2.50 (3H, CH3, s), 3.81–4.03 (2H, CH2, q), 4.28 (H, CH, s), 6.26 (2H, NH2, s), 7.29–7.52 (4H, H-Ar, d, d) ppm. 13C-NMR (100 MHz, DMSO-d6): δ = 14.33, 17.37, 38.18, 58.53, 61.65, 107.85, 118.82, 128.54, 128.72, 130.53, 130.78, 131.51, 141.88, 155.55, 158.67, 165.85 ppm.

Ethyl 6-amino-4-(4-bromophenyl)-5-cyano-2-methyl-4H-pyran-3-carboxylate (Table 3, entry 3)

Off-white solid; IR (KBr): 3408.10 (NH2), 3330.18 (NH2), 2979.27 (C–H), 2194.09 (CN), 1689.50 (CO), 1645.77, 1608.19, 1483.62, 1374.06, 1262.54, 1180.44, 1068.31 cm−1. 1H-NMR (400 MHz, DMSO-d6) δ = 1.31–1.39 (3H, CH3, t), 2.29 (3H, CH3, s), 3.88–4.00 (2H, CH2, q), 4.55 (H, CH, s), 6.96 (2H, NH2, s), 7.29–7.89 (4H, H-Ar, d, d) ppm. 13C-NMR (100 MHz, DMSO-d6): δ = 14.39, 17.33, 38.15, 58.42, 61.54, 107.84, 119.15, 131.25, 131.51, 143.58, 156.50, 159.25, 165.41 ppm.

Ethyl 6-amino-5-cyano-4-(4-hydroxyphenyl)-2-methyl-4H-pyran-3-carboxylate (Table 3, entry 4)

1H-NMR (400 MHz, DMSO-d6) δ = 0.84–0.89 (3H, CH3, t), 2.25 (3H, CH3, s), 3.77–3.87 (2H, CH2, q), 4.24 (H, CH, s), 6.59 (2H, NH2, s), 6.71–6.90 (4H, H-Ar, d, d), 9.09 (OH, s) ppm. 13C-NMR (100 MHz, DMSO-d6): δ = 14.25, 17.00, 37.52, 58.29, 61.48, 107.87, 115.31, 119.15, 131.24, 136.61, 155.14, 156.77, 159.20, 164.92 ppm.

Ethyl 6-amino-5-cyano-4-(4-methoxyphenyl)-2-methyl-4H-pyran-3-carboxylate (Table 3, entry 5)

1H-NMR (400 MHz, DMSO-d6) δ = 1.31–1.35 (3H, CH3, t), 2.12 (3H, CH3, s), 3.74 (CH3, s), 3.93–3.4 (2H, CH2, q), 4.44 (H, CH, s), 6.83 (2H, NH2, s), 6.91–7.10 (4H, H-Ar, d, d) ppm. 13C-NMR (100 MHz, DMSO-d6): δ = 14.59, 17.61, 38.45, 55.25, 56.48, 61.64, 108.25, 114.30, 119.58, 130.90, 136.73, 155.38, 157.85, 159.72, 165.25 ppm.

Ethyl 6-amino-5-cyano-2-methyl-4-(p-tolyl)-4H-pyran-3-carboxylate (Table 3, entry 6)

1H-NMR (400 MHz, DMSO-d6) δ = 1.31–1.35 (3H, CH3, t), 2.12 (3H, CH3, s), 2.35 (CH3, s), 3.93–4.05 (2H, CH2, q), 4.44 (H, CH, s), 6.83 (2H, NH2, s), 7.07–7.57 (4H, H-Ar, d, d) ppm. 13C-NMR (100 MHz, DMSO-d6): δ = 14.59, 17.61, 21.43, 38.13, 58.36, 61.48, 107.31, 119.58, 128.36, 135.99, 141.51, 155.63, 159.87, 165.71 ppm.

Ethyl 6-amino-5-cyano-4-(4-fluorophenyl)-2-methyl-4H-pyran-3-carboxylate (Table 3, entry 7)

1H-NMR (400 MHz, DMSO-d6) δ = 1.13–1.24 (3H, CH3, t), 2.46 (3H, CH3, s), 4.02–4.07 (2H, CH2, q), 4.34 (H, CH, s), 6.91 (2H, NH2, s), 7.12–7.43 (4H, H-Ar, d, d) ppm. 13C-NMR (100 MHz, DMSO-d6): δ = 13.81, 17.61, 37.93, 56.81, 61.48, 107.31, 115.77, 119.14, 130.90, 139.45, 155.72, 159.12, 159.26, 165.14 ppm.

Ethyl 6-amino-5-cyano-2-methyl-4-(4-nitrophenyl)-4H-pyran-3-carboxylate (Table 3, entry 8)

1H-NMR (400 MHz, DMSO-d6) δ = 1.13–1.24 (3H, CH3, t), 2.40 (3H, CH3, s), 3.94–4.01 (2H, CH2, q), 4.28 (H, CH, s), 6.88 (2H, NH2, s), 7.50–8.11 (4H, H-Ar, d, d) ppm. 13C-NMR (100 MHz, DMSO-d6): δ = 14.84, 17.61, 38.47, 58.05, 61.48, 107.91, 119.58, 124.03, 127.03, 144.60, 150.69, 155.74, 159.68, 165.58 ppm.

Ethyl 6-amino-5-cyano-2-methyl-4-(3-nitrophenyl)-4H-pyran-3-carboxylate (Table 3, entry 9)

1H-NMR (400 MHz, DMSO-d6) δ = 1.12–1.21 (3H, CH3, t), 2.12 (3H, CH3, s), 3.94–4.01 (2H, CH2, q), 4.29 (H, CH, s), 6.91 (2H, NH2, s), 6.91–8.40 (4H, H-Ar, m) ppm. 13C-NMR (100 MHz, DMSO-d6): δ = 14.90, 17.61, 37.32, 58.05, 61.88, 107.91, 119.77, 120.81, 121.81, 134.61, 143.59, 145.89, 155.81, 159.72, 165.14 ppm.

Ethyl 6-amino-5-cyano-2-methyl-4-(2-nitrophenyl)-4H-pyran-3-carboxylate (Table 3, entry 10)

1H-NMR (400 MHz, DMSO-d6) δ = 1.12–1.22 (3H, CH3, t), 2.12 (3H, CH3, s), 3.94–4.01 (2H, CH2, q), 4.24 (H, CH, s), 6.91 (2H, NH2, s), 7.21–7.82 (4H, H-Ar, m) ppm. 13C-NMR (100 MHz, DMSO-d6): δ = 14.84, 17.61, 34.41, 58.36, 61.16, 107.77, 119.58, 124.66, 126.23, 129.88, 130.19, 134.16, 146.78, 155.92, 160.60, 165.71 ppm.

Ethyl 6-amino-4-(2-chlorophenyl)-5-cyano-2-methyl-4H-pyran-3-carboxylate (Table 3, entry 11)

Off-white solid; IR (KBr): 3425.19 (NH2), 3330.20 (NH2), 2963.27 (C–H), 2194.16 (CN), 1684.50 (CO), 1642.77, 1610.19, 1473.62, 1265.54, 1185.44 cm−1. 1H-NMR (400 MHz, DMSO-d6) δ = 0.84–0.91 (3H, CH3, t), 2.33 (3H, CH3, s), 3.78–3.94 (2H, CH2, q), 4.87 (H, CH, s), 6.74 (2H, NH2, s), 6.94–7.14 (4H, H-Ar, m) ppm. 13C-NMR (100 MHz, DMSO-d6): δ = 13.79, 18.03, 56.02, 60.04, 105.44, 119.05, 127.75, 128.35, 129.25, 129.75, 131.81, 142.08, 157.74, 158.45, 165.11 ppm.

Ethyl 6-amino-4-(2-bromophenyl)-5-cyano-2-methyl-4H-pyran-3-carboxylate (Table 3, entry 12)

Off-white solid; IR (KBr): 3422.29 (NH2), 3328.93 (NH2), 2964.12 (C–H), 2191.86 (CN), 1685.40 (CO), 1642.27, 1611.12, 1474.10, 1261.14, 1174.34 cm−1. 1H-NMR (400 MHz, DMSO-d6) δ = 2.52–2.56 (3H, CH3, t), 2.31 (3H, CH3, s), 3.48–3.92 (2H, CH2, q), 4.87 (H, CH, s), 6.84 (2H, NH2, s), 7.33–7.51 (4H, H-Ar, d, d) ppm. 13C-NMR (100 MHz, DMSO-d6): δ = 13.61, 18.06, 37.55, 56.14, 60.06, 106.19, 119.03, 122.60, 128.35, 128.66, 129.74, 132.46, 143.78, 157.70, 158.35, 165.11 ppm.

6-Amino-3-methyl-4-phenyl-2,4-dihydropyrano[2,3-c] pyrazole-5-carbonitrile (Table 3, entry 13)

Off-white solid; IR (KBr): 3400 (NH2), 3200 (NH), 2195 (CN), 1640 (CN), 1610–1490 (CC), 1390 (C–N), 1055 (C–O) cm−1. 1H-NMR (400 MHz, DMSO-d6) δ = 2.52 (3H, CH3, s), 4.71 (1H, CH-pyrano, s), 6.81 (2H, NH2, s), 7.09–7.27 (5H, H-Ar, m), 11.15 (1H, NH, s) ppm. 13C-NMR (100 MHz, DMSO-d6): δ = 13.40, 26.49, 59.32, 113.63, 117.81, 125.64, 128.72, 129.45, 135.71, 139.45, 163.20, 176.81 ppm.

6-Amino-4-(4-chlorophenyl)-3-methyl-2,4-dihydropyrano [2,3-c]pyrazole-5-carbonitrile (Table 3, entry 14)

1H-NMR (400 MHz, DMSO-d6) δ = 1.89 (3H, CH3, s), 4.98 (1H, CH-pyrano, s), 6.53 (2H, NH2, s), 7.32–7.44 (4H, H-Ar, d, d), 11.58 (1H, NH, s) ppm. 13C-NMR (100 MHz, DMSO-d6): δ = 14.02, 24.51, 59.34, 113.07, 117.19, 125.64, 129.51, 131.24, 134.79, 139.93, 164.11, 176.62 ppm.

6-Amino-4-(4-bromophenyl)-3-methyl-2,4-dihydro pyrano[2,3-c]pyrazole-5-carbonitrile (Table 3, entry 15)

1H-NMR (400 MHz, DMSO-d6) δ = 1.89 (3H, CH3, s), 5.12 (1H, CH-pyrano, s), 6.60 (2H, NH2, s), 7.32–7.84 (4H, H-Ar, d, d), 11.62 (1H, NH, s) ppm. 13C-NMR (100 MHz, DMSO-d6): δ = 12.78, 25.64, 59.89, 113.63, 116.99, 120.38, 132.24, 134.16, 140.85, 163.04, 176.28 ppm.

6-Amino-4-(4-hydroxyphenyl)-3-methyl-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile (Table 3, entry 16)

1H-NMR (400 MHz, DMSO-d6) δ = 1.88 (3H, CH3, s), 4.34 (1H, CH-pyrano, s), 6.79–6.84 (2H, H-Ar, d), 6.94 (2H, NH2, s), 7.05–7.08 (2H, H-Ar, d), 9.06 (1H, OH, s), 11.99 (1H, NH, s) ppm. 13C-NMR (100 MHz, DMSO-d6): δ = 13.50, 26.49, 59.34, 112.35, 116.25, 117.81, 127.03, 130.19, 138.90, 155.81, 162.81, 176.28 ppm.

6-Amino-4-(4-methoxyphenyl)-3-methyl-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile (Table 3, entry 17)

1H-NMR (400 MHz, DMSO-d6) δ = 1.92 (3H, CH3, s), 4.04 (1H, CH-pyrano, s), 6.78 (2H, NH2, s), 6.79–7.64 (4H, H-Ar, d, d), 11.67 (1H, NH, s) ppm. 13C-NMR (100 MHz, DMSO-d6): δ = 13.50, 26.49, 56.48, 58.36, 113.63, 114.30, 124.03, 127.03, 130.67, 140.56, 157.37, 163.49, 177.30 ppm.

6-Amino-3-methyl-4-(p-tolyl)-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile (Table 3, entry 18)

1H-NMR (400 MHz, DMSO-d6) δ = 1.93 (3H, CH3, s), 2.16 (3H, CH3, s), 4.64 (1H, CH-pyrano, s), 6.79 (2H, NH2, s), 7.05–7.49 (4H, H-Ar, d, d), 11.48 (1H, NH, s) ppm. 13C-NMR (100 MHz, DMSO-d6): δ = 14.59, 26.49, 59.89, 113.07, 117.81, 125.64, 128.72, 132.24, 135.19, 139.59, 162.81, 176.28 ppm.

6-Amino-4-(4-fluorophenyl)-3-methyl-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile (Table 3, entry 19)

1H-NMR (400 MHz, DMSO-d6) δ = 1.83 (3H, CH3, s), 5.19 (1H, CH-pyrano, s), 6.81 (2H, NH2, s), 7.13–8.50 (4H, H-Ar, d, d), 11.76 (1H, NH, s) ppm. 13C-NMR (100 MHz, DMSO-d6): δ = 13.50, 26.49, 59.32, 114.30, 115.23, 117.81, 131.24, 139.92, 159.20, 164.11, 178.10 ppm.

6-Amino-3-methyl-4-(4-nitrophenyl)-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile (Table 3, entry 20)

1H-NMR (400 MHz, DMSO-d6) δ = 1.97 (3H, CH3, s), 5.08 (1H, CH-pyrano, s), 6.52 (2H, NH2, s), 7.72–9.06 (4H, H-Ar, d, d), 11.58 (1H, NH, s) ppm. 13C-NMR (100 MHz, DMSO-d6): δ = 13.06, 25.77, 59.89, 114.22, 117.19, 123.53, 129.51, 139.59, 141.40, 146.78, 163.20, 176.28 ppm.

6-Amino-3-methyl-4-(3-nitrophenyl)-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile (Table 3, entry 21)

1H-NMR (400 MHz, DMSO-d6) δ = 2.17 (3H, CH3, s), 5.15 (1H, CH-pyrano, s), 6.53 (2H, NH2, s), 7.58–8.37 (4H, H-Ar, m), 11.53 (1H, NH, s) ppm. 13C-NMR (100 MHz, DMSO-d6): δ = 13.50, 25.64, 56.48, 113.69, 117.19, 120.38, 121.75, 133.29, 139.25, 139.59, 139.92, 147.60, 163.60, 177.07 ppm.

6-Amino-3-methyl-4-(2-nitrophenyl)-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile (Table 3, entry 22)

1H-NMR (400 MHz, DMSO-d6) δ = 2.11 (3H, CH3, s), 4.96 (1H, CH-pyrano, s), 6.79 (2H, NH2, s), 7.55–7.95 (4H, H-Ar, m), 11.48 (1H, NH, s) ppm. 13C-NMR (100 MHz, DMSO-d6): δ = 13.50, 20.83, 59.34, 113.63, 116.99, 125.64, 128.36, 129.51, 132.24, 134.79, 139.92, 149.72, 163.60, 176.02 ppm.

6-Amino-4-(2-chlorophenyl)-3-methyl-2,4-dihydropyrano [2,3-c] pyrazole-5-carbonitrile (Table 3, entry 23)

Off-white solid; IR (KBr): 3420 (NH2), 3200 (NH), 2192 (CN), 1635 (CN), 1600–1490 (CC), 1390 (C–N), 1054 (C–O) cm−1. 1H-NMR (400 MHz, DMSO-d6) δ = 2.084 (3H, CH3, t), 4.24 (1H, CH-pyrano, s), 6.37 (2H, NH2, s), 7.13–7.55 (5H, H-Ar, m), 11.01 (1H, NH, s) ppm. 13C-NMR (100 MHz, DMSO-d6): δ = 13.50, 20.09, 59.89, 113.07, 117.81, 126.23, 127.52, 128.36, 131.24, 140.85, 144.51, 162.81, 175.44 ppm.

6-Amino-4-(2-bromophenyl)-3-methyl-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile (Table 3, entry 24)

1H-NMR (400 MHz, DMSO-d6) δ = 1.88 (3H, CH3, s), 4.66 (1H, CH-pyrano, s), 6.07 (2H, NH2, s), 7.15–7.55 (4H, H-Ar, m), 11.26 (1H, NH, s) ppm. 13C-NMR (100 MHz, DMSO-d6): δ = 13.06, 25.64, 59.89, 113.07, 116.99, 123.53, 127.03, 131.24, 132.24, 139.92, 141.40, 164.11, 176.02 ppm.

Comparison of the catalyst

To investigate the catalytic activity of Fe3O4@NFC@Co(ii), we compared the results of the reaction of 4H-pyrane and the reaction of pyranopyrazole (Tables 4 and 5) with the previously reported. Table 4 lists the approaches in the catalyst literature. They each have their advantages, but some of them suffer from various demerits such as the use of an expensive catalyst, harsh reaction condition, toxic chemical and longer reaction time. Catalysts in the literature and their results are given in Table 5. Overall, the obtained catalyst showed better yield and higher TOF values in a shorter reaction time than other catalysts reported in the literature. Thus, the present protocol (Table 5, entry 10) has several advantages as a greener, economic, simple reaction set-up, and product isolation by simple magnet as compared to reported methods for the synthesis of 4H-pyran and pyranopyrazole derivatives.

Comparison of the present approach with literature reported method for 4H-pyrans synthesis

Entry	Catalyst (mol%)	Solvent	Time (min)	Temp. (°C)	Yield (%)	Ref.
1	KF–Al2O3	EtOH	180	r.t	77	64
2	Fe3O4@gC3N4	EtOH	190	60	80	65
3	Piperazine	H2O	7	90	96	66
4	Fe3O4@GA@isinglass	EtOH	50	Reflux	88	51
5	[2-aemim][PF6]	M.W	3	100	87	67
6	Fe 3 O 4 @NFC@Co( ii )	H 2 O	15 min	50	98	This work

Comparison of the present approach with literature reported method for pyranopyrazole synthesis

Entry	Catalyst (mol%)	Solvent	Time (h/min)	Temp. (°C)	Yield (%)	TOF	Ref.
1	Urea (10)	EtOH : H2O	8 h	r.t	86	1.075	68
2	Isonicotinic acid (10)	SF	10 min	89	90	56.25	69
3	Et3N (10)	EtOH	15 min	Reflux	65	26	70
4	l-Proline (10)	H2O	10 min	Reflux	90	56.25	71
5	γ-Alumina (30)	H2O	50 min	Reflux	80	3.19	72
6	β-Cyclodextrin (10)	EtOH : H2O	15 min	80	92	36.8	73
7	Piperidine (5)	H2O	10 min	r.t	83	66.4	74
8	HDBAC (30)	EtOH	45 min	Reflux	73	3.24	75
9	B(OH)3 (10)	SF	10 min	70	85	53.12	76
10	Fe 3 O 4 @NFC@Co( ii ) (0.9)	H 2 O	15 min	50	98	435.5	This work

Conclusion

In summary, this powerful multi-core catalyst Fe3O4@NFC@Co(ii) can be used as a novel, green, efficient, and reusable nanocatalyst for 4H-pyrane and pyranopyrazole reactions. This catalyst offers several advantages including high catalytic activity, excellent yields, short reaction time, and mild reaction conditions. Furthermore, the catalyst could be simply recovered from the reaction mixture using an external magnet and reused up to 5 times without a significant loss in activity.

Conflicts of interest

There are no conflicts to declare.