Functionalization of magnetic TMU-17-NH2 MOF with organic ligands for stabilization of copper species as an efficient heterogeneous catalyst for the Biginelli reaction and the synthesis of pyran derivatives

Roghayeh Vahedian; Heshmatollah Alinezhad; Ameneh Kiani

doi:10.1038/s41598-026-58019-7

. 2026 Jun 19;16:28117. doi: 10.1038/s41598-026-58019-7

Functionalization of magnetic TMU-17-NH₂ MOF with organic ligands for stabilization of copper species as an efficient heterogeneous catalyst for the Biginelli reaction and the synthesis of pyran derivatives

Roghayeh Vahedian ¹, Heshmatollah Alinezhad ^1,^✉, Ameneh Kiani ¹

PMCID: PMC13554157 PMID: 42321271

Abstract

A novel magnetic nanocatalyst, Cu@M-TMU-17-NH₂-Gly-Met, was successfully prepared through a multi-step post-synthetic modification strategy. Initially, the TMU-17-NH₂ framework was functionalized with glyoxal, followed by immobilization of metformin to introduce nitrogen-rich coordination sites for copper incorporation. The composition and structural integrity of the resulting nanocomposite were confirmed by FT-IR, TGA, XRD, FE-SEM, EDX, BET, ICP-MS, and VSM analyses. The catalytic performance of the prepared nanocomposite was evaluated in the synthesis of dihydropyrimidinone derivatives via the Biginelli reaction, as well as in the synthesis of 2-amino-4H-pyran derivatives through a multicomponent reaction strategy. The results demonstrated that the catalyst efficiently promoted both reactions under mild conditions, affording high yields (73–92% and 79–98%, respectively) within short reaction times. The catalyst exhibited excellent reusability and stability over several cycles with a gradual and acceptable decrease in yield (from 89% to 74% for the Biginelli reaction, and from 96% to 84% for the pyran synthesis) over seven consecutive cycles for model reaction The combination of high efficiency, ease of separation, and environmental compatibility highlights the potential of this nanocatalyst for practical applications in organic synthesis.

Supplementary Information

The online version contains supplementary material available at https://doi.org/10.1038/s41598-026-58019-7.

Keywords: Heterogeneous nanocatalyst, Metal–organic frameworks, Copper catalyst, Biginelli reaction, 2-amino-4H-pyran

Subject terms: Chemistry, Materials science

Introduction

Developing efficient synthetic methodologies remains one of the central goals of modern organic chemistry. Among these, the Biginelli reaction has received considerable attention for its ability to construct biologically significant dihydropyrimidinone (DHPM) frameworks through a one-pot, three-component process¹. First reported by Pietro Biginelli in 1893, this reaction involves the condensation of a β-ketoester, an aldehyde, and urea or thiourea. The resulting DHPM derivatives, which are six-membered nitrogen-containing heterocycles, exhibit a broad range of pharmacological activities such as antibacterial and anticancer effects².

These compounds are present in numerous biologically active molecules, including Monastrol (A), 5-fluorouracil (B), Emivirine (C), which exhibit diverse pharmacological properties such as antitumor, anticancer, anti-HIV, and antihypertensive activity. Additionally, riboflavin (vitamin B₂) (D) shares similar structural features, highlighting the Biginelli reaction’s importance in drug discovery and medicinal chemistry (Fig. 1)³.

Fig. 1 — Examples of biologically active dihydropyrimidines.

In parallel with DHPMs, 2-amino-4 H-pyran derivatives constitute another important class of oxygen-containing heterocycles with diverse biological and pharmaceutical applications, including anticancer, antimicrobial, anti-inflammatory, and antioxidant activities^4–6. These compounds are commonly synthesized through one-pot multicomponent reactions involving aldehydes, active methylene compounds, and cyclic 1,3-dicarbonyl compounds such as dimedone⁷. Owing to their atom economy, operational simplicity, and structural diversity, these multicomponent synthetic approaches are considered attractive strategies in green chemistry.

Despite the efficiency of these reactions, many reported catalytic systems—both for Biginelli and pyran syntheses—suffer from limitations such as harsh reaction conditions, long reaction times, low product yields, non-recyclable catalysts, and environmental concerns associated with toxic or corrosive reagents⁸. Homogeneous acid catalysts, such as strong mineral acids (e.g., HCl, H₂SO₄) and Lewis acids (e.g., FeCl₃, ZnCl₂), often exhibit high catalytic activity but are difficult to recover and reuse, limiting their applicability in sustainable and large-scale processes⁹.

To overcome these limitations, heterogeneous catalysts have emerged as promising alternatives because of their facile separation, improved stability, recyclability, and reduced metal leaching¹⁰. In this regard, porous materials have attracted increasing attention owing to their high surface area, tunable pore structures, and versatile surface functionalities, which can significantly enhance catalytic performance¹¹.

Among porous materials, metal–organic frameworks (MOFs) have emerged as an important class of crystalline hybrid materials composed of metal ions or clusters coordinated with organic linkers^12,13. Because of their exceptionally high surface area, tunable porosity, structural diversity, and adjustable functionality, MOFs have been extensively investigated in catalysis, gas storage and separation, sensing, drug delivery, and environmental remediation applications^14–17.

In particular, Zn-based MOFs are considered attractive candidates for heterogeneous catalysis and multicomponent organic transformations because of their low toxicity, facile synthesis, physicochemical stability, and accessible active sites^18,19.

Furthermore, the catalytic performance of Zn-based MOFs can be significantly improved through post-synthetic functionalization strategies. Among different functional groups, amino-functionalized Zn-based MOFs have received particular attention because the presence of free amine groups provides suitable sites for post-synthetic modification and immobilization of catalytically active species²⁰.

For example, ZnMOF-NH₂-glutaraldehyde@Pd has been successfully employed in Suzuki coupling reactions²¹, while Zn MOF-1-NH₂ has demonstrated efficient catalytic activity in sulfoxidation reactions²². In addition, Zn-MOF-NH₂-ZIF-8@Cu and Fe₃O₄@CFC-COOH@TMU-16@Cu have been utilized for the synthesis of propargylamine and tetrahydrobenzo[b]pyran^23,24.

Despite these advantages, conventional MOF catalysts are often obtained as fine powders, making their separation and recovery from reaction media difficult and time-consuming. To address this issue, magnetic nanoparticles such as Fe₃O₄ have been incorporated into MOF structures to fabricate magnetically recoverable heterogeneous catalysts²⁵. Furthermore, magnetic porous nanocomposites combine the advantages of MOFs, including high surface area and tunable porosity, with the easy recoverability and reusability of magnetic nanoparticles, making them highly attractive platforms for sustainable and green catalytic applications^26–30.

In the present work, TMU-17-NH₂ was selected as an amino-functionalized Zn-based MOF platform because of the presence of free amine groups within its framework, which provide appropriate sites for post-synthetic modification and immobilization of catalytically active species. To enhance catalytic efficiency and introduce specific functional sites, we employed glyoxal as a bifunctional linker capable of forming imine bonds with surface amine groups. This allowed subsequent immobilization of metformin, a nitrogen-rich biguanide drug molecule with multiple coordination sites suitable for metal ions like copper. Copper can readily form stable and catalytically active complexes with nitrogen-containing ligands such as metformin because of its favorable redox properties and Lewis acidity. Incorporating copper into metformin-functionalized MOFs enhances the accessibility and reactivity of catalytic sites while maintaining the advantages of a heterogeneous system¹⁸.

Accordingly, a novel magnetically recoverable nanocatalyst, Cu@M-TMU-17-NH₂-Gly-Met, was successfully designed and synthesized. The catalytic performance of the prepared nanocomposite was investigated in the synthesis of biologically important dihydropyrimidinone (4a–n) and 2-amino-4H-pyran (7a–n) derivatives through one-pot multicomponent reactions under mild and recyclable conditions (Schemes 1 and 2). In addition to high catalytic efficiency and excellent product yields, the catalyst exhibited facile magnetic recovery, good stability, and remarkable reusability.

Scheme 1 — Synthesis of dihydropyrimidines using Cu@M-TMU-17-NH₂-Gly-Met.

Scheme 2 — Catalytic synthesis of pyranes catalyzed using Cu@M-TMU-17-NH₂-Gly-Met.

Experimental section

Materials and characterization

All reagents and solvents used in this study were purchased from Sigma-Aldrich and Merck and used without any further purification. The synthesized catalyst was characterized using several analytical techniques, including Fourier-transform infrared spectroscopy (FT-IR), X-ray diffraction (XRD), thermogravimetric analysis (TGA), field-emission scanning electron microscopy (FE-SEM), energy-dispersive X-ray spectroscopy (EDS mapping), Brunauer–Emmett–Teller (BET), vibrating sample magnetometer (VSM) and inductively coupled plasma mass spectrometry (ICP-MS). The progress of catalytic reactions was monitored using thin-layer chromatography (TLC) on silica gel F254 plates (0.2 mm thickness, 25–30 μm particle size).

Synthesis of Cu@M-TMU-17-NH₂-Gly-Met nanocatalyst

The ligand 4-bpdb was synthesized according to a previously reported procedure³¹. Subsequently, magnetic TMU-17-NH₂ was prepared through a solvothermal method using Zn(NO₃)₂·6 H₂O, 2-aminoterephthalic acid, Fe₃O₄ nanoparticles, and 4-bpdb in DMF medium³². The obtained M-TMU-17-NH₂ was functionalized with glyoxal to introduce aldehyde groups, followed by reaction with metformin to provide nitrogen-rich coordination sites for metal immobilization. Finally, copper species were immobilized onto the modified magnetic MOF through treatment with Cu(OAc)₂ and subsequent reduction using NaBH₄ under nitrogen atmosphere¹⁸, affording Cu@M-TMU-17-NH₂-Gly-Met (scheme 3). Detailed synthetic procedures and characterization data are provided in the Supporting Information.

Scheme 3 — The synthetic procedure of the production of Cu@TMU-17-NH₂-Gly-Met nanocatalyst.

General procedure for the Biginelli reaction

A mixture of aldehyde derivative (1 mmol), ethyl acetoacetate (1 mmol), urea (1.5 mmol), and Cu@M-TMU-17-NH₂-Gly-Met catalyst (10 mg) was stirred in ethanol under optimized conditions. The progress of the reaction was monitored by TLC. After completion, the catalyst was magnetically separated, and the product was isolated and purified by recrystallization. The obtained compounds were characterized by melting point, ¹H NMR, and ¹³C NMR spectroscopy. Detailed experimental procedures and spectral data are provided in the Supporting Information.

General procedure for the synthesis of 2-amino-4H-pyranes

A mixture of aldehyde derivative (1 mmol), malononitrile (1 mmol), dimedone (1 mmol), and Cu@M-TMU-17-NH₂-Gly-Met catalyst (10 mg) in ethanol was refluxed under optimized conditions. After completion of the reaction, the catalyst was separated using an external magnet, and the precipitated product was collected. The synthesized compounds were characterized by melting point, ¹H NMR, and ¹³C NMR spectroscopy. Detailed experimental procedures and spectral data are presented in the Supporting Information.

Results and discussion

In this study, a novel magnetic metal–organic framework, Cu@M-TMU-17-NH₂-Gly-Met, was successfully synthesized through a stepwise post-synthetic modification approach. Initially, the parent TMU-17-NH₂ framework was functionalized with glyoxal to introduce reactive aldehyde groups on its surface. Next, metformin molecules were covalently attached through Schiff-base linkages, forming M-TMU-17-NH₂-Gly-Met. Finally, copper ions were incorporated via coordination with the nitrogen and oxygen donor atoms of metformin, yielding the final Cu@M-TMU-17-NH₂-Gly-Met composite. A comprehensive suite of characterization techniques including FT-IR, TGA, FE-SEM, EDX, XRD, BET, and VSM analyses confirmed the successful functionalization steps, copper incorporation, and maintenance of structural integrity.

The FTIR spectra of TMU-17-NH₂ showed the two signal near 3466 and 3359 cm^–1 which were ascribed to NH₂ stretching vibrations. As such, this confirmed the presence of free amine groups in the pore cages of this MOF. Further, symmetric and asymmetric metal carboxylate stretching bands at 1381 and 1611 cm^–1 are also detected in the FTIR spectra of TMU-17-NH₂ (Fig. 2a)³³. In the FTIR spectra of Fe₃O₄, the signal at 540 cm^− 1 are observed, which is attributed to stretching vibration of the Fe- O-Fe (Fig. 2b)³⁴. This band confirms the presence of iron oxide in all magnetic samples (Fig. 2c, d, e, f). For confirmation magnetization of TMU-17-NH₂, we compared the results obtained from M-TMU-17-NH₂ (Fig. 2C) with the profile of TMU-17-NH₂ (Fig. 2a), and there were no notable variations in the FT-IR spectra of them, except for the the presence of iron oxide signal suggesting that the functional groups remained unaltered. In the FT-IR spectra of M-TMU-17-NH₂- Gly (Fig. 2d), the intense peaks centered at 1652 cm^− 1 and 1701 cm^− 1 were corresponding to C = N and C = O bonds, respectively, indicating that the formation of Schiff-base and introduced the C = O bond from glyoxal³⁵. It can be clearly confirmed that the modification of the Schiff base was carried out on M-TMU-17-NH₂. Afer the reaction of this structure with metformin, peaks in the area of 3092–3457 cm^− 1 indicates the NH group in the metformin moiety, was created (Fig. 2e). According to the FT-IR spectra Cu@TMU-17-NH2- Gly-Met after loading copper species onto the TMU-17-NH₂-Gly-Met (Fig. 2f), the shape of the spectrum did not change, and the structure of the metal–organic framework was well-preserved. The similarity in the spectra of M-TMU-17-NH₂, M-TMU-17-NH₂-Gly, M-TMU-17-NH₂-Gly-Met, and Cu@M-TMU-17-NH2-Gly-Met indicates that the MOF structure is preserved throughout all stages, and the main peaks are observable in each spectrum.

Fig. 2 — FT-IR spectra of (a) TMU-17-NH₂, (b) Fe₃O₄, (c) M-TMU-17-NH₂, (d) M-TMU-17-NH₂-Gly, (e) M-TMU-17-NH₂-Gly-Met and (f) Cu@M-TMU-17-NH₂-Gly-Met.

The XRD analysis was carried out to investigate the crystalline structure and phase retention throughout the synthesis steps. The successful preparation of TMU-17-NH₂ (Fig. 3a) was confirmed by the precise agreement between the diffraction peaks of the synthesized sample and the standard PXRD pattern reported for its single-crystal structure³³. The PXRD data also indicate that TMU-17-NH₂ possesses a three-dimensional cubic lattice. The XRD patterns of Fe₃O₄, M-TMU-17-NH₂-Gly-Met, and Cu@M-TMU-17-NH₂-Gly-Met (Fig. 3b–d) exhibit six characteristic reflections at 2θ = 30.2°, 35.4°, 43.2°, 53.1°, 57.2°, and 62.7°, which correspond to the spinel structure of magnetic Fe₃O₄³⁵.The persistence of these peaks confirms that the crystalline ferrite core remains intact after magnetization, glyoxal linkage, metformin functionalization, and subsequent copper loading. Moreover, after post-synthetic modification of TMU-17-NH₂ leading to the formation of M-TMU-17-NH₂-Gly-Met and Cu@M-TMU-17-NH₂-Gly-Met (Fig. 3c–d), no significant shifts or changes were observed in the MOF’s diffraction pattern. This indicates that the framework structure of TMU-17-NH₂ is preserved and remains stable during the surface functionalization and catalyst preparation steps.

Fig. 3 — XRD pattern of (a) TMU-17-NH₂, (b) Fe₃O₄, (c) M-TMU-17-NH₂-Gly-Met and (d) Cu@M-TMU-17-NH₂-Gly-Met.

Thermogravimetric analysis (TGA) was carried out to assess the thermal behavior of the Cu@M-TMU-17-NH₂-Gly-Met nanocomposite (Fig. 4). The profile displays a slight weight reduction below ~ 150 °C, which is associated with the release of physically adsorbed water and trapped solvent molecules within the material’s porous network. A more evident mass loss occurs in the range of 150–350 °C, originating from the decomposition of the grafted organic layers, including glyoxal-based linkages and metformin fragments (Metformin loading: 2.14 mmol/g) together with partial degradation of the MOF organic framework. At temperatures extending up to ~ 600 °C, a continued decline in mass is observed. In this high-temperature region, it is widely recognized that the “Zn–OH” moieties coordinated to the metal centers undergo dehydration, converting into “Zn═O” functionalities. Notably, the final residue in Cu@M-TMU-17-NH₂-Gly-Met is slightly higher compared to the other samples, which can be attributed to the presence of copper species, confirming their successful loading. Overall, the final residue (~ 39–40 wt%) confirms the substantial presence of inorganic components in the catalyst, consistent with the magnetic Fe₃O₄ core, Zn-MOF framework, and Cu-based species immobilized on the surface. The observed thermal stability, combined with the high inorganic content, verifies the structural robustness of the functionalized nanocatalyst under thermal conditions relevant to catalytic applications.

Field-emission scanning electron microscopy (FE-SEM) was employed to investigate the morphological features and surface evolution of the synthesized materials during the functionalization process. The FE-SEM images of TMU-17-NH₂ and Cu@M-TMU-17-NH₂-Gly-Met are presented in Fig. 5 (a, b), while the corresponding particle size distribution histogram is shown in Fig. 5 (c).

Fig. 5 — FE-SEM images of (a) TMU-17-NH₂, and (b) Cu@M-TMU-17-NH₂-Gly-Met, (c) histogram of the diameter distribution for the Cu@M-TMU-17-NH₂-Gly-Met.

The FE-SEM micrographs clearly reveal that, following functionalization and subsequent immobilization of copper species onto the TMU-17-NH₂ framework, the copper species are uniformly dispersed over the surface with a predominantly spherical morphology. Importantly, the porous structure of the framework remains well preserved after copper loading, indicating that the structural integrity of the support is maintained.

The homogeneous distribution of copper species suggests their effective anchoring onto the functionalized surface, which is crucial for enhancing catalytic activity. Furthermore, the particle size distribution analysis indicates an average particle size of approximately 75 nm, confirming the preservation of nanoscale characteristics without significant aggregation.

EDX and elemental mapping analysis is a good technique for characterizing the elemental composition of synthesized Cu@M-TMU-17-NH₂-Gly-Met (Figs. 6 and 7).The findings revealed that the EDX spectrum of Cu@M-TMU-17-NH₂-Gly-Met reveals the presence of key elements including C, N, O, Fe, and Zn which are attributed to the metal–organic framework structure. Moreover, the distinct signal of Copper (Cu) confirms its successful loading onto the functionalized MOF (Fig. 6). Also, the elemental mappings of Cu@M-TMU-17-NH₂-Gly are shown in Fig. 7. As clearly observed, all detected elements are uniformly distributed over the surface of the nanocatalyst, confirming the successful formation of the sample. Based on these results, it can be concluded that the synthesis of the final nanocatalyst was successful. Also, the precise quantity of Cu bound to the Schiff Base and amine group, determined by ICP-MS is 1.17 mmol/g.

Fig. 6 — EDX analysis of the Cu@M-TMU-17-NH₂-Gly-Met.

Fig. 7 — (a) SEM image of the exact selected region used for EDS of Cu@M-TMU-17-NH₂-Gly-Met (b) EDS mapping of the Cu@M-TMU-17-NH₂-Gly-Met.

It should be noted that XPS and HR-TEM analyses were not available in the current study; consequently, the precise oxidation state of copper and the exact nanoparticulate nature of the copper species cannot be unambiguously confirmed. Nevertheless, the combination of EDX analysis confirming Cu presence, the NaBH₄ reduction step employed during synthesis, and the FE-SEM morphological evidence collectively suggest that copper is incorporated as reduced species, most likely as Cu⁰ nanoparticles or a mixture of Cu-based species.

To evaluate the porosity and specific surface area of M-TMU-17-NH₂ and the final Cu@M-TMU-17-NH₂-Gly-Met nanocatalyst, N₂ adsorption–desorption isotherms (BET) was performed. The. The results indicate that the M-TMU-17-NH₂ exhibits a surface area of approximately was determined to be 84.68 m²/g, with a total pore volume of 0.039 cm³/g. In contrast, the Cu-loaded modified sample (Cu@M-TMU-17-NH₂-Gly-Met) shows a decrease in surface area to 21.67 m²/g with a total pore volume of 0.020 cm³/g, which may result from partial pore blocking due to the incorporation of copper species. Also in Fig. 8, the Cu@M-TMU-17-NH₂-Gly-Met nitrogen adsorption–desorption isotherms are type I isotherms, indicating that these materials are microporous.

Fig. 8 — (a) BET curves of Cu@M-TMU-17-NH₂-Gly-Met,; (b) tplot curves of Cu@M-TMU-17-NH₂-Gly-Met.

Figure 9 presents the magnetic hysteresis loops obtained from the VSM measurements for Fe₃O₄ and the Cu@M-TMU-17-NH₂-Gly-Met nanocomposite. The saturation magnetization values for Fe₃O₄ and Cu@M-TMU-17-NH₂-Gly-Met were determined to be 68.09 and 29.97 emu g⁻¹, respectively. The evidence clearly demonstrates that all synthesized samples exhibit superparamagnetic behavior. The significant decrease in magnetic properties, from 68.09 to 29.97 emu g⁻¹, is primarily associated with the successive surface modifications, including the presence of the TMU-17-NH₂ framework, organic functional groups (Glyoxal and Metformine), and the incorporation of copper species, which collectively reduce the magnetic contribution of the Fe₃O₄ core. Despite this reduction, the final nanocatalyst retains sufficient magnetic responsiveness to enable rapid and efficient magnetic separation from reaction media. Therefore, the prepared catalyst can be conveniently collected and reused simply by applying an external magnet.

Fig. 9 — VSM analysis of (a) Fe₃O₄ and (b) Cu@M-TMU-17-NH₂-Gly-Met.

Catalytic activity in the Biginelli reaction

After the catalyst characterization, the catalytic efficiency of Cu@M-TMU-17-NH₂-Gly-Met nanoparticles was assessed in the one-pot, three-component condensation of aromatic aldehydes (1a–p), ethyl acetoacetate (2), and urea (3). Initially, 4-cyanobenzaldehyde (1 mmol), urea (1.5 mmol), and ethyl acetoacetate (1 mmol) were used as a model system to optimize reaction (Table 1).

Table 1.

Optimization of reaction conditions for the synthesis dihydropyrimidines.

Entry	Catalyst (mg)	Solvent	Temperature (°C)	Time (min)	Yield %^{a, b}
1	-	EtOH	r.t	120	Trace
2	M-TMU-17-NH₂ (10)	EtOH	r.t	30	42
3	M-TMU-17-NH₂-Gly (10)	EtOH	r.t	30	46
4	M-TMU17-NH₂-Gly-Met (10)	EtOH	r.t	30	76
5	Cu@M-TMU-17-NH ₂ -Gly-Met (10)	EtOH	r.t	30	89
6	Cu@M-TMU-17-NH₂-Gl-Met (5)	EtOH	r.t	30	80
7	Cu@M-TMU-17-NH₂-Gly-Met (15)	EtOH	r.t	30	89
8	Cu@M-TMU-17-NH₂-Gly-Met (20)	EtOH	r.t	30	90
9	Cu@M-TMU-17-NH₂-Gly-Met (25)	EtOH	r.t	30	90
10	Cu@M-TMU-17-NH₂-Gly-Met (30)	EtOH	r.t	30	91
11	Cu@M-TMU-17-NH₂-Gly-Met (10)	DMF	r.t	30	79
12	Cu@M-TMU-17-NH₂-Gly-Met (10)	H₂O	r.t	30	59
13	Cu@M-TMU-17-NH₂-Gly-Met (10)	EtOH : H₂O	r.t	30	78
14	Cu@M-TMU-17-NH₂-Gly-Met (10)	MetOH	r.t	30	76
15	Cu@M-TMU-17-NH₂-Gly-Met (10)	CH₃CN	r.t	30	67
16	Cu@M-TMU-17-NH₂-Gly-Met (10)	CHCl₃	r.t	30	47
17	Cu@M-TMU-17-NH₂-Gly-Met (10)	(C₂H₅)₂O	r.t	30	44
18	Cu@M-TMU-17-NH₂-Gly-Met (10)	n-Hexane	r.t	30	41
19	Cu@M-TMU-17-NH₂-Gly-Met (10)	EtOH	50	30	89
20	Cu@M-TMU-17-NH₂-Gly-Met (10)	EtOH	reflux	30	90
21	4-bdp	EtOH	r.t	30	48
22	Fe₃O₄	EtOH	r.t	30	28
23	Zn(NO3)₂	EtOH	r.t	30	30
24	Cu(OAc)₂	EtOH	r.t	30	35
25	Cu-metformin complex (10 mol%)	EtOH	r.t	30	60

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^a Reaction conditions: 4-cyanobenzaldehyde (1 mmol), ethyl acetoacetate (1 mmol), and urea (1.5 mmol) were used as the reactants in a solvent of 10 mL containing the catalyst. ^b Yields isolated.

A series of control experiments demonstrated the significant role of each modification step. The reaction yield was negligible without a catalyst and moderate when using M-TMU-17-NH₂. The introduction of glyoxal improved the yield to 46%, while metformin modification further increased it to 76%. Remarkably, the full composite Cu@M-TMU-17-NH₂-Gly-Met achieved an 89% yield, confirming the synergistic interaction between copper species and the functionalized MOF framework (entries 1–5).

Optimization studies revealed that using 10 mg of catalyst was sufficient, as larger quantities did not significantly enhance the yield (entries 6–10). Among various solvents tested including Ethanol, Methanol, Water, DMF, CH₃CN, CHCl₃, Diethyl ether, and n-Hexane (entries 11–18). Ethanol provided the highest catalytic performance, followed by DMF and water/ethanol mixtures. In contrast, aprotic solvents like CHCl₃ and n-hexane yielded significantly lower conversions. The superior activity in polar solvents can be attributed to their ability to activate the carbonyl group, thereby promoting the reaction. Temperature variations had minimal impact, and the reaction proceeded efficiently at room temperature (entries 19 and 20).

Control experiments using 4-bdp, Fe₃O₄, Zn(NO₃)₂, Cu(OAc)₂, and unsupported Cu–metformin complexes resulted in lower yields (48%, 28%, 30%, 35%, and 60%, respectively), further emphasizing the importance of the cooperative interaction between copper and the MOF matrix (entries 21–25).

Under optimized conditions, a wide range of aromatic aldehydes containing both electron-donating and electron-withdrawing substituents were successfully converted into dihydropyrimidinone derivatives (4a–p) in high yields (73–92%) and short reaction times (30 min) (Table 2). All products were characterized by melting point, ¹H NMR, and ¹³C NMR spectra, which matched previously reported data.

Table 2.

Synthesis of various dihydropyrimidines catalyzed by Cu@M-TMU 17 NH2 Gly Met (10mg) under optimized conditionsa.


Entry	Product	Ar	Structures	TOF (h^− 1)	TON	Mp ^OC^[Ref]	Yield ^b
1	4a	C₆H₅		142	71	211–213³⁶	83
2	4b	4-OMe C₆H₄		136	68	200–202³⁷	79
3	4c	4-N(Me)₂ C₆H₄		124	62	257–259³⁸	73
4	4d	4-Cl C₆H₄		148	74	210–212³⁶	86
5	4e	4-Me C₆H₄		132	66	216–218³⁹	78
6	4f	4-CN C₆H₄		152	76	222–224⁴⁰	89
7	4 g	4-NO₂ C₆H₄		158	79	208–210⁴¹	92
8	4 h	4-Br C₆H₄		148	74	199–201⁴²	86
9	4i	4-OH C₆H₄		136	68	239–241⁴³	80
10	4j	3-NO₂ C₆H₄		152	76	228–230⁴⁴	89
11	4k	2-OH C₆H₄		128	64	200–202⁴⁵	76
12	4 L	2-Cl C₆H₄		138	69	209–211⁴⁵	81
13	4 m	2,4-diCl C₆H₃		146	73	248–250³⁶	86
14	4n	3-Br C₆H₄		148	74	184–186⁴⁶	87

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a Reaction conditions: aldehydes (1 mmol), ethyl acetoacetate (1 mmol), and urea (1.5 mmol), in the presence of the Cu@M-TMU-17-NH2-Gly-Met (10 mg) in a 10 mL EtOH. b Isolated yield.

Comparison with reported catalysts

To evaluate the efficiency of the synthesized catalyst, its performance was compared with several reported systems for the model Biginelli reaction (4f) (Table 3). Catalysts such as Fe₃O₄@SiO₂–SO₃H (entry 1), K₂S₂O₈, Eosin Y, AgNO₃ (entry 2), Zn–MOF–NH₂ (entry 3), Bi(OTf)₃ (entry 4), and TiO₂@SBA-15 catalyst (entry 5), have been previously utilized for similar transformations. However, most of these catalysts required elevated temperatures (60–90 °C), longer reaction times (1–48 h), or less eco-friendly solvents like DMF, yielding 68–78%.

Table 3.

Comparison of catalytic activity between Cu@M-TMU-17-NH₂-Gly-Met and literature-reported catalysts in the synthesis of compound 4f.

Entry	Catalyst	Conditions	Time	Yield (%) ^[Ref]
1	Fe₃O₄@SiO₂-SO₃H	EtOH/reflux	2 h	78⁴⁷
2	K₂S₂O₈, Eosin Y, AgNO₃	CH₃CN: H₂O	48 h	75⁴⁸
3	Zn-MOF-NH₂	DMF/80 °C	90 min	75⁴⁹
4	Bi(OTf)₃	Solvent-free/120 °C	1 h	70⁵⁰
5	TiO₂@SBA-15	CH₃CN/85 °C	3 h	68⁵¹
6	Cu@M-TMU-17-NH ₂ -Gly-Met	EtOH/25 ^oC	30 min	89 ^a

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a This work.

In contrast, the Cu@M-TMU-17-NH₂-Gly-Met catalyst efficiently promoted the reaction at room temperature (25 °C) using ethanol as a low-toxicity solvent, achieving 89% yield within 30 min with only a small catalyst amount (10 mg). This superior activity can be attributed to the synergistic combination of copper species and metformin functionalities on the TMU-17-NH₂ framework, providing high surface area, uniform metal dispersion, and enhanced accessibility of active sites.

These results demonstrate that the Cu@M-TMU-17-NH₂-Gly-Met nanocatalyst acts as an efficient and recyclable heterogeneous catalytic system for the rapid synthesis of dihydropyrimidinone derivatives under relatively mild reaction conditions.

For the synthesis of dihydropyrimidinone derivatives, a plausible proposed mechanism, based on literature precedents and the observed control experiment trends, is presented in Scheme 4. Initially, the carbonyl group of the aromatic aldehyde (1) may be activated through interaction with the Cu@M-TMU-17-NH₂-Gly-Met nanocatalyst. Such activation could enhance the electrophilicity of the carbonyl carbon, thereby facilitating nucleophilic attack by urea (3) to generate the corresponding addition intermediate (a). Subsequently, ethyl acetoacetate may undergo keto–enol tautomerization under the catalytic conditions, affording the reactive enol form (b). The enol intermediate could then participate in nucleophilic addition to intermediate (a), leading to intermediate (c). Finally, intramolecular cyclization followed by dehydration is proposed to afford the desired dihydropyrimidinone product (4)⁵².

Scheme 4 — A plausible proposed mechanism of the Biginelli reaction catalyzed by Cu@M-TMU-17-NH₂**-Gly-Met**.

Catalytic activity in the synthesis of 2-amino-4H-pyranes

Another transformation employed to evaluate the catalytic performance of Cu@M-TMU-17-NH₂-Gly-Met was the one-pot three-component synthesis of 2-amino-4 H-pyranes through the reaction of aromatic aldehydes (1a–n), malononitrile (5), and dimedone (6). For optimization purposes, the condensation of 1 mmol dimedone, malononitrile, and 4-cyanobenzaldehyde (1f) in ethanol (10 mL) was selected as a representative model reaction.

As summarized in Table 4, the model reaction was initially carried out under different catalytic conditions, including M-TMU-17-NH₂, M-TMU-17-NH₂-Gly, M-TMU-17-NH₂-Gly-Met, Cu@M-TMU-17-NH₂-Gly-Met, as well as in the absence of any catalyst (entries 1–5). In the absence of any catalyst, product 7f was formed only to a negligible extent, while the use of M-TMU-17-NH₂ afforded a moderate yield. Subsequent modification with glyoxal led to an improvement in product 7f formation, giving a yield of 40%. Further functionalization with metformin resulted in a substantial enhancement of catalytic activity, increasing the yield to 76%. Notably, the fully assembled catalyst, Cu@M-TMU-17-NH₂-Gly-Met, delivered product 7f the highest efficiency with an 96% yield, highlighting the synergistic effect between copper species and the functionalized MOF architecture (entries 1–5).

Table 4.

Optimization of reaction conditions for the synthesis 2-amino-4H-pyranes.

Entry	Catalyst (mg)	Solvent	Temperature (°C)	Time (min)	Yield %^{a, b}
1	-	EtOH	reflux	120	Trace
2	M-TMU-17-NH₂ (10)	EtOH	reflux	5	33
3	M-TMU-17-NH₂-Gly (10)	EtOH	reflux	5	40
4	M-TMU17-NH₂-Gly-Met (10)	EtOH	reflux	5	68
5	Cu@M-TMU-17-NH₂ -Gly-Met (10)	EtOH	reflux	5	96
6	Cu@M-TMU-17-NH₂-Gl-Met (5)	EtOH	reflux	5	78
7	Cu@M-TMU-17-NH₂-Gly-Met (15)	EtOH	reflux	5	97
8	Cu@M-TMU-17-NH₂-Gly-Met (20)	EtOH	reflux	5	97
9	Cu@M-TMU-17-NH₂-Gly-Met (25)	EtOH	reflux	5	98
10	Cu@M-TMU-17-NH₂-Gly-Met (30)	EtOH	reflux	5	98
11	Cu@M-TMU-17-NH₂-Gly-Met (10)	DMF	reflux	5	67
12	Cu@M-TMU-17-NH₂-Gly-Met (10)	H₂O	reflux	5	55
13	Cu@M-TMU-17-NH₂-Gly-Met (10)	EtOH : H₂O	reflux	5	70
14	Cu@M-TMU-17-NH₂-Gly-Met (10)	MeOH	reflux	5	76
15	Cu@M-TMU-17-NH₂-Gly-Met (10)	CH₃CN	reflux	5	55
16	Cu@M-TMU-17-NH₂-Gly-Met (10)	CHCl₃	reflux	5	55
17	Cu@M-TMU-17-NH₂-Gly-Met (10)	(C₂H₅)₂O	reflux	5	40
18	Cu@M-TMU-17-NH₂-Gly-Met (10)	n-Hexane	reflux	5	38
19	Cu@M-TMU-17-NH₂-Gly-Met (10)	EtOH	r.t	5	88
20	Cu@M-TMU-17-NH₂-Gly-Met (10)	EtOH	50	5	90
21	4-bdp	EtOH	reflux	5	44
22	Fe₃O₄	EtOH	reflux	5	Trace
23	Zn(NO3)₂	EtOH	reflux	5	22
24	Cu(OAc)₂	EtOH	reflux	5	35
25	Cu-metformin complex (10 mol%)	EtOH	reflux	5	50

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a Reaction conditions: 4-cyanobenzaldehyde (1 mmol), malononitrile (1 mmol), and dimedone (1 mmol) were used as the reactants in a solvent of 10 mL containing the catalyst. b Yields isolated.

The influence of catalyst loading was subsequently examined, revealing that 10 mg of Cu@M-TMU-17-NH₂-Gly-Met represents the optimal amount, as increasing the catalyst dosage did not lead to significant further improvement in yield (entries 6–10). Additionally, the effect of solvent on the reaction outcome was investigated using different solvents, among which ethanol proved to be the most effective, providing the highest yield (entries 11–18). Increasing the temperature from 25 to 80 °C leads to an improvement in the reaction efficiency for synthesis of product 7f, so the optimal temperature for this reaction was chosen to be the reflux temperature (entries 5, 19 and 20). Furthermore, control experiments performed using 4-bdp, Fe₃O₄, Zn(NO₃)₂, Cu(OAc)₂, and the Cu-met complex (Cu(OAc)₂-Met) in the absence of M-TMU-17-NH₂-support resulted in yields of 44%, trace, 22%, 35% and 50%, respectively (entries 21–25), highlighting the beneficial role of the supported catalytic system.

Under the optimized conditions established in Table 4, the general applicability of this protocol was evaluated using a variety of aromatic aldehydes, malononitrile, and dimedone in a three-component reaction. As presented in Table 5, aldehydes bearing either electron-donating or electron-withdrawing substituents smoothly participated in the reaction, delivering the desired pyran derivatives (7a–7n) in good to excellent yields in short reaction times (5 min). The structures of the synthesized products were confirmed by comparison of their physical properties and NMR spectral data with those reported in the literature.

Table 5.

Synthesis of various 2-amino-4H-pyranes catalyzed by Cu@ M-TMU 17 NH2 Gly Met (10mg) under optimized conditionsa


Entry	Product	Ar	Structure	TOF(h⁻¹)	TON	Mp ^OC^[Ref]	Yield%
1	7a	C₆H₅		864	72	236–238 ^[53]	85
2	7b	4-OMe C₆H₄		852	71	209–211 ^[54]	83
3	7c	4-N(Me)₂ C₆H₄		816	68	250–252 ^[55]	79
4	7d	4-Cl C₆H₄		925	77	208–210^[56]	91
5	7e	4-Me C₆H₄		852	71	210–212^[57]	82
6	7f	4-CN C₆H₄		984	82	234–236^[58]	96
7	7g	4-NO₂ C₆H₄		1008	84	185–187 ^[59]	98
8	7h	4-Br C₆H₄		900	75	209–211^[60]	88
9	7i	4-OH C₆H₄		852	71	205–207^[61]	83
10	7j	3-NO₂ C₆H₄		972	81	210–212^[62]	95
11	7k	2-OH C₆H₄		852	71	215–217^[63]	82
12	7l	2-Cl C₆H₄		900	75	211–213^[64]	88
13	7m	2,4-diCl C₆H₃		924	77	122–124 ^[65]	90
14	7n	3-Br C₆H₄		948	79	234–236 ^[66]	92

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^a Reaction conditions: aldehydes (1 mmol), malononitrile (1 mmol), and dimedone (1 mmol), in the presence of the Cu@M-TMU‑17‑NH₂‑Gly‑Met (10 mg) in a 10 mL EtOH. ^b Isolated yield.

The synthesis of the 2-amino-4H-pyran derivative (7f) in the presence of various nanocatalysts has been reported, and the corresponding results are summarized in Table 6. As shown in Table 6, the use of many previously reported catalytic systems suffers from certain drawbacks, including lower product yields and longer reaction times. In contrast, the nanocatalyst Cu@M-TMU-17-NH₂-Gly-Met employed in this study enabled the synthesis of 2-amino-4 H-pyran derivatives in a very short reaction time and in ethanol as a low-toxicity solvent, affording excellent yields. Therefore, compared with previously reported catalysts, the Cu@M-TMU-17-NH₂-Gly-Met nanocatalyst provides an efficient and reusable catalytic protocol, allowing the reaction to proceed within a shorter time while delivering the desired products in high yields.

Table 6.

Comparison of catalytic activity between Cu@M-TMU-17-NH₂-Gly-Met and literature-reported catalysts in the synthesis of compound 7f.

Entry	Catalyst	Conditions	Time	Yield (%) ^[Ref]
1	silica sulfuric acid	H₂O/80 °C	4 h	90⁶⁷
2	Er-MOF	EtOH/reflux	8 h	90⁶⁸
3	Triazine-based functionalized HY zeolite	EtOH/reflux	30 min	85⁶⁹
4	diammonium phosphate	H₂O/25 °C	30 min	82⁷⁰
5	Cu nanoparticles on ZPD	EtOH/reflux	30 min	85⁴
6	2-amino-2-hydroxymethyl-1,3-propanedio	H₂O/EtOH/25 °C	1.5 h	91⁷¹
7	NSB-DBU	H₂O/25 °C	30 min	88⁷²
8	Cu@M-TMU-17-NH ₂ -Gly-Met	EtOH/25 ^oC	5 min	96 ^a

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a This work.

Based on experimental observations and previously reported studies, a plausible reaction pathway for the synthesis of 2-amino-4 H-pyran derivatives in the presence of Cu@M-TMU-17-NH₂-Gly-Met nanocatalyst is proposed in Scheme 5.

Scheme 5 — A plausible proposed mechanism for the synthesis of 2-amino-4H-pyran catalyzed by Cu@M-TMU-17-NH₂-Gly-Met.

In the first step, a Knoevenagel condensation between the aromatic aldehyde (1) and malononitrile (5) may occur under the catalytic conditions, generating the α,β-unsaturated intermediate (I). The nanocatalyst is proposed to facilitate this transformation through activation of the carbonyl group and stabilization of the developing charges. Subsequently, dimedone (6) may undergo enolization to produce a nucleophilic enolate species, which could participate in a Michael addition to intermediate (I), affording intermediate (II).

Intermediate (II) is then proposed to undergo tautomerization to form the more stable intermediate (III). Finally, intramolecular cyclization is believed to furnish the 2-amino-4H-pyran scaffold (7)⁷³.

The recyclability and repeated usability of catalysts are among the most important parameters in industrial applications and recyclable catalytic processes. Therefore, the reusability of the Cu@M-TMU-17-NH₂-Gly-Met nanocatalyst was systematically investigated in model reactions (Fig. 3). After completion of each reaction, the nanocatalyst was isolated using an external magnetic field, thoroughly washed several times with ethanol and water, and subsequently dried overnight at 80 °C. In the Biginelli reaction, the nanocatalyst retained substantial catalytic activity over seven consecutive cycles, with the yield gradually decreasing from 89% to 74% (Fig. 10a). A similar trend was observed for the synthesis of 2-amino-4H-pyran derivatives, where the reaction yield declined from 96% to 84% after seven cycles (Fig. 10b). In addition, the catalyst mass was monitored after each cycle. For instance, the initial mass of 10.0 mg of Cu@M-TMU-17-NH₂-Gly-Met nanocatalyst decreased to 7.85 and 7.96 mg after seven consecutive runs in the synthesis of compounds 4f and 7f, respectively (highlighted in Purple in Fig. 9). Although a gradual decrease in yield was observed over seven cycles (89% to 74% for compound 4f, and 96% to 84% for compound 7f), the catalyst retained sufficient activity throughout, demonstrating acceptable recyclability. This moderate yield decrease may be attributed to minor catalyst mass loss and partial blockage of active sites upon repeated use, which demonstrates the practical recyclability and stability of the catalytic system during repeated use.

Fig. 10 — Recyclability of the multifunctional Cu@M-TMU-17-NH₂-Gly-Met nanocatalyst during consecutive cycles for the synthesis of compounds (a) Biginelli reaction (4f) and (b) 2-amino-4H-pyran (7f) under optimized conditions. The Purple -marked values indicate the exact recovered mass of the nanocatalyst after each cycle.

Reusability and stability of Cu@M-TMU-17-NH₂-Gly-Met nanocatalyst Furthermore, FT-IR spectra (Fig. 11), SEM images (Fig. 12) and XRD patterns (Fig. 13), of the recovered catalyst after seven cycles showed no noticeable differences compared to those of the fresh catalyst, indicating that the structural integrity and morphology of the Cu@M-TMU-17-NH₂-Gly-Met nanocatalyst remained essentially unchanged during repeated use.

Fig. 13 — XRD patterns of the (a): fresh Cu@M-TMU-17-NH₂-Gly-Met and (b): reused Cu@M-TMU-17-NH₂-Gly-Met after seven cycles.

To further evaluate the stability of the catalyst, additional experiments were conducted in which the Cu@M-TMU-17-NH₂-Gly-Met nanocatalyst was removed before completion of the reaction, while the reaction mixture was allowed to proceed under identical conditions for an additional period of time (hot-filtration test). As illustrated in Fig. 14, no considerable increase in product yield was observed after catalyst removal. These results confirm the absence of significant catalyst leaching into the reaction medium and verify the heterogeneous nature and structural stability of the nanocatalyst under the reaction conditions.

Fig. 14 — The time-conversion curves obtained from the hot-filtration test for the synthesis of (a) 4f and (b) 7f before and after separation of the Cu@M-TMU-17-NH₂-Gly-Met nanocatalyst.

In addition, a leaching experiment was performed alongside the hot-filtration test. The amounts of metal species remaining in the recovered catalyst were quantified using ICP-MS analysis. The recycled catalyst contained 1.15 mmol/g of Cu, 2.90 mmol/g of Zn, and 6.86 mmol/g of Fe per equivalent catalyst mass, whereas the fresh catalyst initially contained 1.17 mmol/g Cu, 2.94 mmol/g Zn, and 6.93 mmol/g mmol Fe. These findings indicate that only negligible metal leaching occurred during the catalytic process, further confirming the excellent structural stability of the nanocatalyst.

Conclusion

In summary, a novel magnetic nanocatalyst, Cu@M-TMU-17-NH₂-Gly-Met, was successfully synthesized and applied in the efficient synthesis of dihydropyrimidinone and pyran derivatives. The catalyst exhibited excellent activity, high yields, and good reusability under mild reaction conditions. The structural stability, ease of recovery, and easy magnetic recovery, catalyst recyclability, and mild reaction conditions make it a promising candidate for practical organic synthesis applications. These findings highlight the potential of functionalized MOF-based nanocatalysts in advanced catalytic applications.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary Material 1^{(560.3KB, docx)}

Acknowledgements

We gratefully acknowledge the support of the Research Council of the University of Mazandaran.

Author contributions

Author contributions: RV supported the expenses, including the preparation of materials and analysis inthe article. HA and AK conceived the presented idea and contributed to the data curation, methodology, and validation. RV experimented. All authors reviewed the results and approved the finalversion of the manuscript.

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.

Footnotes

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplementary Material 1^{(560.3KB, docx)}

Data Availability Statement

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

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PERMALINK

Functionalization of magnetic TMU-17-NH2 MOF with organic ligands for stabilization of copper species as an efficient heterogeneous catalyst for the Biginelli reaction and the synthesis of pyran derivatives

Roghayeh Vahedian

Heshmatollah Alinezhad

Ameneh Kiani

Abstract

Supplementary Information

Introduction

Fig. 1.

Scheme 1.

Scheme 2.

Experimental section

Materials and characterization

Synthesis of Cu@M-TMU-17-NH₂-Gly-Met nanocatalyst

Scheme 3.

General procedure for the Biginelli reaction

General procedure for the synthesis of 2-amino-4H-pyranes

Results and discussion

Fig. 2.

Fig. 3.

Fig. 4.

Fig. 5.

Fig. 6.

Fig. 7.

Fig. 8.

Fig. 9.

Catalytic activity in the Biginelli reaction

Table 1.

Table 2.

Comparison with reported catalysts

Table 3.

Scheme 4.

Catalytic activity in the synthesis of 2-amino-4H-pyranes

Table 4.

Table 5.

Table 6.

Scheme 5.

Fig. 10.

Fig. 11.

Fig. 12.

Fig. 13.

Fig. 14.

Conclusion

Supplementary Information

Acknowledgements

Author contributions

Data availability

Declarations

Competing interests

Footnotes

References

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

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Functionalization of magnetic TMU-17-NH₂ MOF with organic ligands for stabilization of copper species as an efficient heterogeneous catalyst for the Biginelli reaction and the synthesis of pyran derivatives