A novel copper-based magnetic nano catalyst for the synthesis of hexahydroquinolines, aminocyanopyridines, and pyranopyrazoles

Abstract

A novel copper-based magnetic nanocatalyst, MNP@Im–Cu, was successfully synthesized via a six-step procedure. Its structural evolution, magnetic behavior, and thermal stability were systematically characterized using Fourier-transform infrared spectroscopy (FT-IR), field-emission scanning electron microscopy (FESEM), transmission electron microscopy (TEM), energy-dispersive X-ray spectroscopy (EDX), thermogravimetric analysis/differential thermal analysis (TGA/DTA), vibrating-sample magnetometry (VSM), inductively coupled plasma analysis (ICP), and X-ray diffraction (XRD). These analyses confirmed successful surface functionalization, uniform core–shell morphology, elemental homogeneity, magnetic properties, and thermal robustness. The catalytic efficiency of this multifunctional nanocatalyst was demonstrated in the one-pot, four-component synthesis of pharmaceutically relevant heterocycles: hexahydroquinolines (HHQs), 2-amino-3-cyanopyridines (ACPs), and pyranopyrazoles (PYPYs). Reactions proceeded under solvent-free conditions using readily available starting materials, affording the desired products in high to excellent yields with notably short reaction times. The catalyst exhibited excellent reusability and chemo-selectivity, underscoring its potential as a sustainable and efficient platform for multi-component heterocycle synthesis.

Supplementary Information

The online version contains supplementary material available at 10.1038/s41598-026-53404-8.

Introduction

Nitrogen-containing heterocycles are key scaffolds in medicinal chemistry due to their broad biological activities and extensive pharmaceutical applications^1–3. Among these, dihydropyridine (DHP) frameworks have attracted considerable attention for their ability to generate chemical diversity and refine structure–activity relationships^4–7. HHQs, a prominent subclass of DHPs, are typically synthesized via one-pot, four-component Hantzsch-type reactions involving dimedone, aromatic aldehydes, β-ketoesters, and ammonium acetate. Multicomponent reactions (MCRs), such as the Hantzsch reaction, represent a powerful synthetic strategy for constructing complex heterocyclic frameworks in a single operational step, offering high atom economy and structural diversity^8,9.Various catalysts have been explored for this transformation, including K₇[PW₁₁CoO₄₀]¹⁰, Fe₃O₄@(HSO₄)₂¹¹, BIL@ MNP¹², La₂O₃¹³, Bi(NO₃)₃·5H₂O¹⁴, as well as catalyst-free conditions¹⁵, yet there remains a need for more efficient, sustainable, and recyclable systems.

Following HHQs, ACPs have emerged as versatile building blocks, enabling the construction of diverse heterocyclic frameworks. The cyano group facilitates reactions with mono- and bidentate nucleophiles, while the amino group promotes substitution and condensation reactions, making ACPs highly valuable in synthetic chemistry^1,2. Several 2-amino-pyridines, such as piroxicam, sulfapyridine, tenoxicam, and tripelennamine, have been applied successfully in drug development³. Despite various catalytic systems reported, including Fe₃O₄ nanoparticles¹⁶, urea-based catalysts¹⁷, SrFe₁₂O₁₉ magnetic particles¹⁸, palladium hydroxide¹⁹, and copper(I) salts²⁰, there is still room for improvement in catalytic efficiency, sustainability, and recyclability.

Finally, 4H-pyran-based heterocycles have gained attention for their pharmacological properties. PYPYs, derived from these scaffolds, exhibit antimicrobial, anticancer, anti-inflammatory, analgesic, and antitumor activities^21–35. Numerous catalytic systems have been developed for PYPY synthesis, including Y₃Fe₅O₁₂³⁶, TEBA³⁷, TSA³⁸, Fe₃O₄@ SiO₂@PTS-DABA³⁹, NiFe₂O₄@SiO₂@H₁₄[NaP₅W₃₀O₁₁₀]⁴⁰, Fe₃O₄@HNTs–PEI⁴¹, and Fe₃O₄ @SiO₂–EP–NH–HPA⁴².The strategic use of MCRs in pyrano-pyrazole synthesis has enabled rapid access to bioactive compounds with minimal purification steps, aligning well with green chemistry principles⁴³.

Despite this diversity, a critical review of the literature indicates the need for a single, integrated catalytic system that combines high efficiency, magnetic recoverability, multi-functional cooperative groups, and copper-mediated reactivity to enable greener synthetic protocols. The MNP@Im-Cu catalyst was designed as a multifunctional, magnetically recoverable nano-composite integrating both organic and inorganic components in a hierarchical architecture. The Fe₃O₄ core provides strong magnetic properties, enabling easy recovery and reuse. The SiO₂ coating enhances the structural stability and prevents core oxidation while offering a large surface area for further modification. The APTES layer introduces amino groups that serve as anchor sites for cyanuric chloride, which acts as an efficient cross-linker to covalently attach imidazole functionalities. These imidazole moieties coordinate with Cu(II) ions, generating Lewis acidic active sites that promote carbonyl activation in multicomponent condensation reactions. Such an integrated structure combines stability, catalytic activity, and recyclability in a single platform, demonstrating a rational and sustainable design approach.

To meet this challenge, we report the design and development of a novel multifunctional nanocatalyst, Fe₃O₄@SiO₂@APTES@CC@Im@Cu, hereafter referred to as MNP@Im-Cu. This catalyst features a superparamagnetic Fe₃O₄ core, a stabilizing silica layer, a function-alized linker with cooperative amino and imidazole groups, and active copper centers.

In line with green chemistry principles, solvent-free synthetic protocols were adopted, offering reduced environmental impact, shorter reaction times, higher yields, and simplified work-up. MNP@Im-Cu proved to be an efficient and magnetically recyclable catalyst for the one-pot multicomponent synthesis of HHQs, ACPs, and PYPYs, demonstrating excellent chemo-selectivity, robustness, and reusability, and outperforming previously reported systems in terms of yield, recyclability, and reaction efficiency.

Experimental

General remarks

All reagents and solvents were purchased from Merck and used as received without further purification. The catalyst was thoroughly characterized using various analytical techniques: Fourier-transform infrared (FT-IR) spectroscopy for functional group identification, field-emission scanning electron microscopy (FESEM) and transmission electron microscopy (TEM) for morphological and microstructural analysis, energy-dispersive X-ray (EDX) spectroscopy for elemental composition mapping, vibrating-sample magnetometry (VSM) for evaluating magnetic behavior, thermogravimetric/differential thermal analysis (TGA/DTA) for thermal stability assessment, inductively coupled plasma (ICP) analysis for metal content determination, and X-ray diffraction (XRD) for crystallographic structure and phase confirmation. The synthesized products were confirmed using standard techniques, including melting point determination, FT-IR spectroscopy, ¹H and ¹³C NMR spectroscopy, and mass spectrometry, ensuring their purity and structural integrity.

Synthesis of the MNP@Im-Cu catalyst

The MNP@Im-Cu nanocatalyst was synthesized via a six-step protocol involving magnetic core formation, surface functionalization, and metal coordination, as detailed below:

Step 1: synthesis of Fe₃O₄ magnetic nanoparticles (MNPs)

Fe₃O₄ nanoparticles were prepared using a co-precipitation method. FeCl₃·6H₂O (11.3 g) and FeCl₂·4H₂O (5.6 g) were dissolved in deionized water at 80 °C. Upon complete dissolution, 28 wt% NH₄OH (25 mL) was added dropwise under vigorous stirring. The mixture was stirred for 30 min at room temperature, followed by 2 h at 80 °C under a nitrogen atmosphere. The resulting black colloidal suspension was magnetically separated, washed repeatedly with deionized water and acetone, and dried at 60 °C to yield Fe₃O₄ powder⁴².

Step 2: coating with silica (Fe₃O₄@SiO₂)

Fe₃O₄ (1 g) was dispersed in an ethanol/water mixture (80:20 v/v) via ultrasonication for 15 min. Then, 28 wt% NH₄OH (2 mL) and tetramethyl orthosilicate (TMOS, 2 mL) were added dropwise. The mixture was stirred at 50 °C for 2 h. The obtained Fe₃O₄@SiO₂ particles were magnetically collected, washed thoroughly with water and ethanol, and dried overnight at 60 °C.

Step 3: amino functionalization (Fe₃O₄@SiO₂@APTES)

Fe₃O₄@SiO₂ (2 g) was dispersed in toluene via ultrasonication for 30 min. APTES (3-amino-propyltriethoxysilane, 2 mL) was added, and the mixture was refluxed at 110 °C for 24 h under nitrogen. The product was magnetically separated, washed with acetone, and dried at 60 °C.

Step 4: cyanuric chloride grafting (Fe₃O₄@SiO₂@APTES@CC)

Cyanuric chloride (0.5 g) was dissolved in THF (30 mL) and stirred at 0 °C for 3 h under nitrogen. Fe₃O₄@SiO₂@APTES (1 g) was added and ultrasonicated for 30 min, followed by stirring at room temperature for 24 h. The resulting product was magnetically separated, washed with ethanol and THF, and dried at 60 °C.

Step 5: imidazole functionalization (Fe₃O₄@SiO₂@APTES@CC@Im)

Fe₃O₄@SiO₂@APTES@CC (2 g) was dispersed in acetonitrile via ultrasonication for 15 min. Imidazole (2 g) was added, and the mixture was stirred at room temperature for 24 h. The solid was magnetically separated, washed with a 1:1 acetonitrile/ethanol mixture, and dried at 60 °C.

Step 6: copper coordination (MNP@Im-Cu)

Fe₃O₄@SiO₂@APTES@CC@Im (0.6 g) was dispersed in methanol (30 mL) via ultrasonication for 15 min. A solution of copper(II) acetate (1.4 g in 15 mL methanol) was added, and the mixture was refluxed at 60 °C for 24 h. The final MNP@Im-Cu nanocatalyst was magnetically separated, washed thoroughly with methanol, and dried at 60 °C to yield a brown powder.

General procedure for the synthesis of HHQs 8(a-o)

Dimedone (1 mmol, 0.140 g), Aldehyde (1 mmol), ethyl acetoacetate (1 mmol, 0.130 g, 0.12 mL), ammonium acetate (1 mmol, 0.077 g), and MNP@Im–Cu (0.05 g) were mixed and stirred at 70 °C. The reaction progress was monitored by thin-layer chromatography (TLC) using n-hexane/ ethyl acetate (8:2, v/v) as the eluent. Upon completion, the mixture was cooled to room temperature, and boiling ethyl acetate (20 mL) was added. Owing to its insolubility in ethyl acetate, the catalyst was magnetically separated. The filtrate was concentrated, and the obtained crude product was purified by recrystallization from ethyl acetate (Scheme 1).

Scheme 1.

General procedure for the synthesis of HHQs.

General procedure for the synthesis of ACPs 9(a–m)

A mixture of acetophenone (1 mmol, 0.120 g, 0.11 mL), aldehyde (1 mmol, 0.106 g), malononitrile (1 mmol, 0.066 g), ammonium acetate (1 mmol), and MNP@Im-Cu (0.04 g) was stirred at 60 °C. The progress of the reaction was monitored by TLC using n-hexane/ethyl acetate (7:3, v/v) as the eluent. After completion, the reaction mixture was cooled to room temperature, and boiling ethyl acetate (20 mL) was added. The magnetic catalyst was separated using an external magnet because it is insoluble in the solvent. The filtrate was concentrated, and the crude product was purified by recrystallization in ethyl acetate (Scheme 2).

Scheme 2.

General procedure for the synthesis of ACPs (9a–m).

General procedure for the synthesis of PYPYs 10(a–m)

A mixture of phenylhydrazine (1 mmol, 0.108 g, 0.10 mL), aldehyde (1 mmol), malononitrile (1 mmol, 0.066 g), ethyl acetoacetate (1 mmol, 0.130 g, 0.12 mL), and MNP@Im-Cu (0.03 g) was stirred at 60 °C. The reaction progress was monitored by TLC using n-hexane/ethyl acetate (8:2, v/v) as the eluent. After completion, the mixture was cooled to room temperature, and boiling ethyl acetate (20 mL) was added. The magnetic nanocatalyst was recovered easily using a magnet and reused after washing and drying. The resulting product was purified by recrystallization in ethyl acetate (Scheme 3).

Scheme 3.

General procedure for the synthesis of PYPYs 10(a–m).

Results and discussion

Synthesis of the catalyst

The synthesis route of the MNP@Im-Cu catalyst is presented in Scheme 4.

Scheme 4.

The proposed procedure for the synthesis of MNP@Im-Cu.

Characterization of the catalyst

The structural, morphological, and physicochemical characteristics of the synthesized catalyst (MNP@Im-Cu) were examined using various analytical techniques. FT-IR spectroscopy was employed to identify functional groups and confirm surface modification. The morphology and particle size were analyzed by field emission scanning electron microscopy (FESEM) and transmission electron microscopy (TEM). Elemental composition and distribution were investigated by energy-dispersive X-ray spectroscopy (EDX). Magnetic properties were measured by vibrating sample magnetometry (VSM), and thermal stability was evaluated by thermo-gravimetric/differential thermal analysis (TGA/DTA). Furthermore, inductively coupled plasma (ICP) analysis was performed to quantify the copper content in the catalyst, and X-ray diffraction (XRD) was utilized to determine the crystalline structure.

Characterization by FT-IR

The FT-IR spectra of each functionalization stage are presented in Fig. 1. In the spectrum of Fe₃O₄ (Fig. 1a), the characteristic absorption band at 575 cm⁻¹ corresponds to the Fe–O stretching vibration, confirming the formation of magnetite nanoparticles. After coating with silica (Fig. 1b), a strong peak at 1083 cm⁻¹ is attributed to the Si–O–Si stretching vibration of the silica shell, indicating successful deposition of SiO₂ on the magnetic core. The introduction of APTES onto the surface (Fig. 1c) is confirmed by a broad band around 3372 cm⁻¹, corresponding to the N–H stretching vibrations of the amine groups, verifying the presence of surface-bound amino functionalities. These amino groups act as reactive anchoring sites that covalently bond with cyanuric chloride through nucleophilic substitution and subsequently coordinate with imidazole and Cu(II) species, ensuring stable functionalization and providing active sites for catalytic reactions. Following the grafting of cyanuric chloride (Fig. 1d), a new peak at 1607 cm⁻¹, assigned to the C=N stretching vibration, confirms successful attachment of cyanuric chloride to the amino-functionalized surface. The subsequent reaction with imidazole (Fig. 1e) produces a peak at 1533 cm⁻¹ corresponding to the conjugated C=N bond, verifying the incorporation of imidazole moieties. Finally, in the spectrum of MNP@Im-Cu (Fig. 1f), the appearance of a distinct band at 1585 cm⁻¹ confirms the coordination of copper ions with the imidazole groups, completing the stepwise functionalization process. The progressive spectral changes observed at each stage collectively provide strong evidence for the successful surface modification and the formation of the MNP@Im-Cu nanocatalyst^44,45.

Fig. 1.

FT-IR spectra of (a): Fe₃O₄ (b): Fe₃O₄@SiO₂ (c): Fe₃O₄@SiO₂@APTES (d): Fe₃O₄@SiO₂@ APTES@CC (e): Fe₃O₄@SiO₂@APTES@CC@Im (f): MNP@Im-Cu.

Characterization by FESEM and TEM

The morphology and internal structure of the MNP@Im-Cu catalyst were examined using FESEM and TEM techniques. As shown in Fig. 2, FESEM images of the fresh catalyst indicate that the nanoparticles possess a predominantly spherical morphology with a relatively uniform size distribution. A particle size distribution histogram of the fresh catalyst (Fig. 3) shows an average particle size of 31.7 nm. FESEM images of the recovered catalyst (Fig. 4) show that the morphology is preserved, and its particle size distribution histogram (Fig. 5) shows an average particle size of 36.8 nm, confirming the structural stability and reusability of the MNP@Im-Cu nanoparticles. TEM analysis of the fresh catalyst (Fig. 6) provides further insight, confirming the formation of a well-defined core–shell structure. This clearly defined core–shell architecture demonstrates the successful synthesis of the catalyst, with a distinct magnetic core enveloped by a functionalized shell, which is expected to enhance its catalytic performance^46.

Fig. 2.

The FESEM image of MNP@Im-Cu.

Fig. 3.

Particle size distribution histogram of the fresh MNP@Im-Cu catalyst.

Fig. 4.

The FESEM image of the recovered MNP@Im-Cu catalyst.

Fig. 5.

Particle size distribution histogram of the recovered MNP@Im-Cu catalyst.

Fig. 6.

TEM images of MNP@Im-Cu.

Characterization by EDX

Energy-dispersive X-ray spectroscopy (EDX) was employed to determine the elemental composition of the synthesized nanoparticles. The EDX spectrum presented in Fig. 7 confirms the presence of Fe, Si, O, N, C, and Cu as the main elements comprising the catalyst.

Fig. 7.

EDX of MNP@Im-Cu.

Characterization by TGA

Thermogravimetric analysis (TGA) was performed from 25 to 800 °C under a nitrogen atmosphere to evaluate the thermal stability and confirm successful stepwise surface functionalization of the MNP@Im-Cu catalyst. As seen in Fig. 8, the bare Fe₃O₄ (a) nanoparticles exhibit a weight loss of ~ 7%, mainly due to adsorbed moisture. Silica-coated Fe₃O₄@SiO₂ (b) shows a higher weight loss of ~ 12%, attributed to the elimination of surface hydroxyl groups. Functionalization with APTES (c) results in a further increase to ~ 22%, confirming successful grafting of the organic layer. Interestingly, after cyanuric chloride (CC) coupling (d) and imidazole functionalization (e), the weight loss decreases to ~ 19% and ~ 15%, respectively. This trend reflects the formation of thermally stable planar heterocyclic ligands, which resist decomposition better than the previous amine layer. Finally, complexation with copper(II) ions to form MNP@Im-Cu (f) slightly increases weight loss to ~ 18%, likely due to minor moisture adsorption, surface rearrangement, or initial degradation of the metal–ligand complex, confirming successful copper coordination.

Fig. 8.

TGA of (a) Fe₃O₄, (b) Fe₃O₄@SiO₂, (c) Fe₃O₄@SiO₂@APTES, (d) Fe₃O₄@SiO₂@APTES@CC, (e) Fe₃O₄@SiO₂@APTES@CC@Im, and (f) the final MNP@Im-Cu catalyst.

Overall, the TGA profiles demonstrate that the catalyst possesses adequate thermal stability for common reaction conditions and confirm the successful multi-step synthesis, including the formation of a stable heterocyclic ligand shell.

Characterization by VSM

The magnetic properties of bare (A): Fe₃O₄ and the final (B): MNP@Im-Cu catalyst were measured using VSM (Fig. 9). The saturation magnetization decreased from 58 emu/g for pristine Fe₃O₄ to 45 emu/g for the functionalized catalyst, indicating the successful deposition of non-magnetic layers, including SiO₂ and organic moieties. Despite this reduction, the catalyst retains strong magnetic behavior, allowing rapid separation from the reaction mixture using an external magnet, which is essential for its recyclability.

Fig. 9.

VSM curves of (A): Fe₃O₄ and (B): MNP@Im-Cu.

Characterization by ICP

ICP-OES analysis (Table 1) confirmed the successful synthesis of the MNP@Im-Cu nano-catalyst, revealing high concentrations of Fe (355,327 ppm) and Cu (26,429 ppm), consistent with the magnetite core and surface-coordinated copper species. After catalytic recycling, the catalyst retained approximately 91% of both metals (Fe: 322,552 ppm; Cu: 23,991 ppm), indicating excellent structural integrity and minimal metal leaching. These results validate the robustness of the catalyst architecture, the stability of Im-Cu coordination under reaction conditions, and the potential of MNP@Im-Cu for efficient, reusable, and sustainable catalytic applications.

Table 1.

ICP of MNP@Im-Cu.

Compound	Catalyst (ppm)	Recycled catalyst (ppm)
Cu	26,428.57	23,990.72
Fe	355,327.38	322,551.55

Characterization by XRD

As shown in Fig. 10, the powder X-ray diffraction (XRD) pattern of the MNP@Im-Cu catalyst exhibits a series of well-defined peaks at 2θ values of 30.40, 35.75, 37.45, 44.65, 54.10, 57.45, 62.70, and 71.30°. These reflections correspond to the (220), (311), (222), (400), (422), (511), (440), and (620) lattice planes, respectively, confirming the presence of a crystalline spinel-type Fe₃O₄ structure. The sharp and symmetrical peaks indicate that the magnetite core retains its crystallinity and structural integrity after successive surface functionalizations. The absence of additional diffraction peaks related to copper oxide or other crystalline impurities suggests that the Cu(II) species are highly dispersed and immobilized on the amorphous functional shell. Overall, the XRD results provide strong structural evidence for the stability and phase purity of the MNP@Im-Cu nanocatalyst^47,48.

Fig. 10.

XRD pattern of MNP@Im-Cu catalyst.

Synthesis of HHQs by MNP@Im-Cu

Optimization of the reaction condition

To investigate the effects of solvent, catalyst amount, and temperature on the reaction time and yield, the reaction of benzaldehyde, dimedone (or 5,5-dimethylcyclohexane-1,3-dione), ethyl acetoacetate, and ammonium acetate was performed at different temperatures, catalyst amounts, and using various solvents such as ethyl acetate, acetonitrile, water, n-hexane, ethanol, and under solvent-free conditions. The optimal conditions for the reaction were found to be 0.05 g of catalyst, a temperature of 70 °C, and solvent-free conditions (Table 2).

Table 2.

Optimization of the reaction condition in the synthesis of HHQs by MNP@Im-Cu.

Entrya	Catal. amount (g)	Yield %b	Temp. °C	Yield %b	Solvent	Yield %b
1	0.01	82	50	89	Solvent-free	95
2	0.02	86	60	92	EtOAc	90
3	0.03	89	70	94	CH3CN	88
4	0.04	90	80	91	H2O	75
5	0.05	95	90	86	n-hexane	73
6	0.06c	92	100	87	EtOH	88

^aReaction conditions: benzaldehyde (1 mmol), dimedone (1 mmol), ethyl acetoacetate (1 mmol), and NH₄OAc (1 mmol).

^bIsolated yield.

^cThe slight decrease in yield at higher catalyst loadings (e.g., Entry 6) may be attributed to nanoparticle aggregation or potential side reactions.

Significant values are in bold.

Synthesis of the HHQs at optimum conditions

Based on the optimal reaction conditions, various HHQs were synthesized from the reaction of dimedone, ethyl acetoacetate, ammonium acetate, and aryl aldehydes by MNP@Im-Cu in high yields and short reaction times (Table 3).

Table 3.

Synthesis of various HHQs 8(a–o) at the optimum reaction condition.

Entrya	Product	Time (min)	Yield (%)b	M.P. °C Found	M.P. °C literature	TONc	TOFd
1		3	95	220–222	219–22249	45.6	15.22
2		5	67	256–259	256–25950	32.19	6.44
3		3	81	183–187	193–19551	38.92	12.97
4		10	87	209–211	211–21350	41.79	4.18
5		7	92	240–244	243–24550	44.21	6.32
6	8f.	10	80	239–241	242–24552	38.43	3.84
7		3	90	209–211	204–20651	43.25	14.42
8		7	83	230–234	235–23750	39.88	5.70
9		8	73	243–246	244–24650	35.08	4.39
10		5	95	257–261	256–25850	45.65	9.13
11		5	73	207–210	202–20552	35.08	7.02
12		3	88	263–265	259–26350	42.29	14.10
13		5	56	235–237	248–24953	26.91	5.38
14		7	91	240–243	244–24654	43.73	6.25
15		10	87	241–245	242–24349	41.79	4.18

^aReaction conditions: benzaldehyde (1 mmol), dimedone (1 mmol), ethyl acetoacetate (1 mmol) and NH₄OAc (1 mmol), MNP@Im-Cu (0.05 g, ~ 2.1 mol% Cu), temperature (70 °C), and solvent-free.

^bIsolated yield.

^cTurnover number (TON): TON = (moles of product)/(moles of Cu). Cu loading (2.64 wt%) was determined by ICP-OES.

^dTurnover frequency (TOF): TOF = TON/(reaction time, min).

Proposed mechanism

The proposed mechanism for the synthesis of hexahydroquinolines involves a multistep cascade catalyzed by MNP@Im–Cu. Initially, the aldehyde carbonyl is activated by the Lewis acidic Cu²⁺ centers, increasing its susceptibility to nucleophilic attack. Concurrently, the enol form of dimedone, also activated by the catalyst, reacts with the aldehyde to form the Knoevenagel intermediate (I). Ammonium acetate undergoes acid–base equilibrium to generate ammonia in situ, which then reacts with ethyl acetoacetate to yield the enamine intermediate (II). A subsequent 1,4-conjugate addition between intermediates (I) and (II), facilitated by surface acidic sites, produces intermediate (III). Finally, intramolecular cyclization and dehydration, both catalyzed by MNP@Im–Cu, afford the final hexahydroquinoline product (Scheme 5).

Scheme 5.

The plausible proposed mechanism for the synthesis of HHQs by MNP@Im-Cu.

Synthesis of ACPs by MNP@Im-Cu

Optimization of the reaction condition

To investigate the effect of solvent, catalyst amount, and temperature on the reaction time and yield, the condensation reaction of benzaldehydes, malononitrile, acetophenone, and ammonium acetate was carried out under various conditions, including different solvents (ethyl acetate, acetonitrile, water, n-hexane, ethanol, and solvent-free), catalyst amounts, and temperatures. The optimal conditions were found to be 0.04 g of catalyst at 60 °C under solvent-free conditions (Table 4).

Table 4.

Effect of the catalyst amount and temperatures on the reaction times and yields.

Entrya	Catal. amount (g)	Yield %b	Temp. °C	Yield %b	Solvent	Yield %b
1	0.01	75	50	85	Solvent-free	87
2	0.02	79	60	89	EtOAc	75
3	0.03	84	70	85	CH3CN	80
4	0.04	87	80	83	H2O	75
5	0.05	85	90	81	n-hexane	80
6	0.06c	83	100	78	EtOH	81

^aReaction conditions: benzaldehyde (1 mmol), malononitrile (1 mmol), acetophenone (1 mmol), and NH₄OAc (1 mmol).

^bIsolated yield.

^cThe slight decrease in yield at higher catalyst loadings (e.g., Entry 6) may be attributed to nanoparticle aggregation or potential side reactions.

Significant values are in bold.

Synthesis of ACPs at optimum conditions

ACPs synthesized using this method are given in Table 5. Short reaction time is one of the important features of this method and the catalyst.

Table 5.

Synthesis of various ACPs at the optimum reaction condition.

Entrya	Product	Time (min)	Yield (%)b	M.P. °C Found	M.P. °C literature	TONc	TOFd
1		5	87	183–185	187–18854	52.25	10.45
2		10	71	155–157	148–15054	42.64	4.26
3		15	86	165–168	155–15755	51.65	3.44
4		10	80	240–245	231–23355	48.05	4.81
5		15	87	183–189	17755	52.25	3.48
6		10	88	194–197	18155	52.85	5.29
7		10	66	199–202	198–20055	39.64	3.96
8		10	80	238–240	238–24054	48.05	4.81
9		10	80	180–185	177–17954	48.05	4.81
10		10	89	193–197	188–19056	53.45	5.35
11		10	74	185–187	182–18355	44.44	4.44
12		10	82	275–279	270–27353	49.25	4.93
13		7	68	211–218	201–20357	40.84	5.83

^aReaction conditions: benzaldehyde (1 mmol), malononitrile (1 mmol), acetophenone (1 mmol), and NH₄OAc (1 mmol), MNP@Im-Cu (0.04 g ~ 1.7 mol%), temperature (60 °C), and solvent-free.

^bIsolated yield.

^cTurnover number (TON): TON = (moles of product)/(moles of Cu). Cu loading (2.64 wt%) was determined by ICP-OES.

^dTurnover frequency (TOF): TOF = TON/(reaction time, min).

Proposed mechanism

The proposed mechanism of the reaction, illustrated in Scheme 6, proceeds via a multistep sequence catalyzed by MNP@Im–Cu. Initially, the aldehyde reacts with malononitrile in the presence of the catalyst to form intermediate (I). Concurrently, acetophenone reacts with ammonium acetate, generating the enamine species intermediate (II). These two intermediates then undergo a nucleophilic addition and subsequent cyclization, yielding intermediate (III). Finally, intermediate (III) undergoes intramolecular cyclization to produce the target 2-amino-3-cyano-pyridine product (IV). This sequence demonstrates the catalyst’s dual role in activating both carbonyl and nucleophilic species, ensuring an efficient and straightforward formation of the heterocyclic product.

Scheme 6.

The plausible mechanism for the synthesis of ACPs by MNP@Im-Cu.

Synthesis of PYPYs by MNP@Im-Cu

Optimization of the reaction condition

To evaluate the influence of solvent, catalyst loading, and temperature on the reaction efficiency, the condensation of benzaldehyde, malononitrile, phenylhydrazine, and ethyl acetoacetate was performed under various conditions, including different solvents (ethyl acetate, acetonitrile, water, n-hexane, ethanol, and solvent-free medium), catalyst amounts, and reaction temperatures. The optimal results were obtained using 0.03 g of catalyst at 60 °C under solvent-free conditions (Table 6).

Table 6.

Effect of catalyst amount and temperature on reaction time and yield.

Entrya	Catal. amount (g)	Yield %b	Temp. °C	Yield %b	Solvent	Yield %b
1	0.01	86	50	85	Solvent-free	90
2	0.02	89	60	90	EtOAc	85
3	0.03	91	70	89	CH3CN	75
4	0.04	88	80	82	H2O	80
5	0.05	87	90	81	n-hexane	88
6	0.06c	85	100	80	EtOH	69

^aReaction conditions: benzaldehyde (1 mmol), malononitrile (1 mmol), phenylhydrazine (1 mmol), and ethyl acetoacetate (1 mmol).

^bIsolated yield.

^cThe slight decrease in yield at higher catalyst loadings (e.g., Entry 6) may be attributed to nanoparticle aggregation or potential side reactions.

Significant values are in bold.

Synthesis of the PYPYs 10(a–m) at optimum conditions

Various 10(a–m) were synthesized based on the optimal reaction conditions (Table 7).

Table 7.

Synthesis of various PYPYs at the optimum reaction condition.

Entrya	Product	Time (min)	Yield (%)b	M.P. °C Found	M.P. °C literature	TONc	TOFd
1		5	90	179–181	176–17758	72.06	14.41
2		15	73	185–188	176–17858	58.45	3.90
3		20	70	173–175	186–18958	56.04	2.80
4		7	79	218–221	225–22759	63.25	9.04
5		10	82	169–171	168–17059	65.65	6.57
6		15	87	179–182	173–17558	69.66	4.64
7		25	70	176–179	178–18059	56.04	2.24
8		15	89	200–206	197–19959	71.26	4.75
9		15	68	183–189	176–17858	54.44	3.63
10		7	74	189–193	208–21058	59.25	8.46
11		15	77	206–210	197–19858	61.65	4.11
12		15	82	171–173	163–16558	65.65	4.38
13		20	75	153–156	145–14860	60.05	3.00

^aReaction conditions: benzaldehyde (1 mmol), malononitrile (1 mmol), phenylhydrazine (1 mmol), and ethyl acetoacetate (1 mmol), MNP@Im-Cu (0.03 g ~ 1.3 mol%), temperature (60 °C), and solvent-free.

^bIsolated yield.

^cTurnover number (TON): TON = (moles of product)/(moles of Cu). Cu loading (2.64 wt%) was determined by ICP-OES.

^dTurnover frequency (TOF): TOF = TON/(reaction time, min).

Proposed mechanism

The proposed mechanism for the reaction is illustrated in Scheme 7. Initially, phenylhydrazine reacts with the activated keto ester to form intermediate (I). Simultaneously, the activated aromatic aldehyde condenses with malononitrile to afford intermediate (II). Subsequently, intermediate (II) undergoes an addition reaction with intermediate (I), leading to the formation of intermediate (III). This intermediate then undergoes intramolecular cyclization to generate intermediate (IV), which finally tautomerizes to furnish the desired pyranopyrazole product.

Scheme 7.

The plausible mechanism for the synthesis of PYPYs by MNP@Im-Cu.

Hot filtration test

A hot filtration test was carried out to verify the heterogeneity of the MNP@Im-Cu catalyst using 6-amino-4-(4-chlorophenyl)-3-methyl-1-phenyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile (10c) as a model substrate. For this test, the reaction was stopped at 10 min, giving a 44% yield. The catalyst was then removed with a magnet, and the reaction mixture was allowed to continue under the same conditions for an additional 10 min. After purification, the yield increased only slightly to 46%, indicating that the reaction barely proceeded without the catalyst. These results confirm that the MNP@Im-Cu catalyst is truly heterogeneous and does not leach into the solution (Fig. 11).

Fig. 11.

Heterogeneity Test of MNP@Im-Cu Catalyst via Hot Filtration.

Recyclability of MNP@Im-Cu

The reusability of the MNP@Im-Cu catalyst was evaluated for the three synthetic routes, namely the synthesis of HHQs, ACPs, and PYPYs, under their respective optimized conditions. After each reaction, the catalyst was magnetically separated, washed with ethanol, dried, and reused in six consecutive cycles. The product yields for each cycle are summarized in Fig. 12.

Fig. 12.

Reusability of MNP@Im-Cu in three synthetic routes.

MNP@Im-Cu maintained high catalytic activity over six consecutive cycles for all three reactions, confirming its excellent stability and reusability. Minor decreases in yield can be attributed to a slight loss of catalyst during magnetic separation and washing. Overall, these results demonstrate that MNP@Im-Cu is a robust and recyclable nanocatalyst suitable for multi-component heterocycle synthesis.

Also, the FT-IR spectrum of the recovered MNP@IM-Cu catalyst was recorded after the catalytic reaction to assess its structural stability. The preservation of all major absorption bands compared to the fresh catalyst confirms that no significant structural degradation occurred, demonstrating the excellent recyclability and stability of the catalyst (Fig. 13).

Fig. 13.

The FT-IR spectrum of the recovered MNP@Im-Cu.

Catalytic performance comparison

The catalytic performance of MNP@Im-Cu was compared with recently reported catalysts for the synthesis of HHQs, ACPs, and PYPYs (Tables 3, 5, and 7). As shown, MNP@Im-Cu exhibits excellent catalytic efficiency, providing high yields in short reaction times under mild, solvent-free conditions. These results highlight the effectiveness of MNP@Im-Cu compared to other reported catalysts, demonstrating its potential as a fast, efficient, and reusable nanocatalyst (Table 8).

Table 8.

Comparison of MNP@Im-Cu with other catalysts.

Entry	Catalyst	cat	Reaction	Condition	Time (min)	Yield (%)	References
1	[CPySO3H]+Cl-	0.05 g	HHQs	EtOH, 70 °C	30	85	44
2	[Pyridine-SO3H]Cl	3% mmol	HHQs	SF, 50 °C	21	82	50
3	ZrOCl2.8H2O	0.015% mmol	HHQs	SF, 85 °C	5	96	49
4	Silica sulfuric acid3	0.1 g	HHQs	50 °C	255	89	61
5	t-BuOK	0.05 g	HHQs	SF, 60 °C	120	92	55
6	This work MNP@Im-Cu	0.05 g	HHQs	SF, 70 °C	5	93	Present work
7	Cu@imineZCMNs	0.01 g	ACPs	SF, 80 °C	17	92	62
8	Urease	0.01 g	ACPs	H2O, 70 °C	85	81	17
9	Cu/C	2% mmol	ACPs	CH3CN, reflux	7	86	58
10	Graphene oxide	5% mmol	ACPs	H2O, 80 °C	300	90	63
11	Cu(I)	20 mmol	ACPs	Toluene, 120 °C	600	50	20
12	α-zirconium phosphate	0.015 g	ACPs	SF, 60 °C	54	85	64
13	Nicotin. methane sulfonate	5% mmol	ACPs	SF, 80 °C	40	92	65
14	TBBDA	0.05 g	ACPs	SF, 100 °C	22	85	55
15	This work (MNP@Im-Cu)	0.04 g	ACPs	SF, 65 °C	10	78	Present work
16	Fe3O4@SiO2-EP-NH-HPA	0.02 g	PYPYs	H2O, R.T	7	94	42
17	Trityl chloride	10% mol	PYPYs	SF, 60 °C	50	82	66
18	Ionic liquid	10% mmol	PYPYs	H2O‏, 60	25	80	67
19	Fe3O4@SiO2@CoSB	0.008 g	PYPYs	EtOH, R.T	20	91	68
20	Fe3O4@SiO2@PTS-DABA	0.005 g	PYPYs	EtOH, ‏reflux	25	89	39
21	This work (nano-catalyst)	0.03 g	PYPYs	SF, 65 °C	15	76	Present work

¹Solvent-free, R.T. = room temperature.

Conclusion

In summary, the MNP@Im-Cu catalyst demonstrated outstanding catalytic performance in the synthesis of HHQs, ACPs, and PYPYs, achieving excellent isolated yields (up to 92%) within short reaction times (10–70 min, depending on the substrate). The presence of strong Lewis acidic Cu²⁺ sites on the catalyst surface effectively promoted multi-component condensation reactions under mild, solvent-free conditions. Structural characterization confirmed that the catalyst retained its core–shell morphology, high crystallinity, and surface functionalization even after several recycling runs. ICP-OES analysis indicated that approximately 91% of the active metals (Fe and Cu) were preserved after repeated use, consistent with the observed high recyclability. The developed catalyst offers several notable advantages, including simple magnetic separation, high thermal and chemical stability, rapid reaction rates, and minimal loss of activity across multiple cycles. These features collectively highlight the efficiency, robustness, and sustainability of MNP@Im-Cu as a green and reusable catalytic system. Overall, this study provides valuable insight into the design, characterization, and application of magnetically recoverable copper-based catalysts for environmentally benign organic transformations.

Author contributions

Arezo Monem did the lab experiment. Davood Habibi contributed as a co-author.

Funding

The authors declare that there was no funding for this research project.

Data availability

All data generated or analyzed during this study are included in this published article and its supplementary information files.

Declarations

Competing interests

The authors declare no competing interests.