CuO stabilized on magnetic decorated GO nanosheets efficiently promoted the one-pot synthesis of 3,4-dihydropyrimidine-2(1H)-one/thione and 1,4-dihydropyridine derivatives under green chemistry conditions

Mohammad Eslami 1,2

Mohammad G. Dekamin 2✉ Emailmdekamin@iust.ac.ir

Elham Mahdavi 2

1 Department of Chemistry Behbahan Khatam Alanbia University of Technology 63616-63973 Behbahan Iran

Pharmaceutical and Heterocyclic Compounds Research Laboratory, Department of Chemistry Iran University of Science and Technology 16846-13114 Tehran Iran

Mohammad Eslami,^a,b Mohammad G. Dekamin,*^b Elham Mahdavi^b

^a Department of Chemistry, Behbahan Khatam Alanbia University of Technology, Behbahan 63616–63973, Iran.

^b Pharmaceutical and Heterocyclic Compounds Research Laboratory, Department of Chemistry, Iran University of Science and Technology, Tehran, 16846 − 13114, Iran. E-mail: mdekamin@iust.ac.ir

Abstract

This study presents a green, efficient, and sustainable method for synthesizing biologically active 3,4-dihydropyrimidin-2(1H)-one/thione (3,4-DHPMs/3,4-DHPMTs) and 1,4-dihydropyridine (1,4-DHPs) heterocycles. The approach involves a one-pot, three-component condensation of aldehydes, 1,3-dicarbonyl compounds, and urea or ammonium carbonate, catalyzed by a magnetically separable CuO/mGO-TA-Me-BTA nanocomposite. The method adheres to green chemistry principles, offering advantages such as short reaction times, high yields, easy work-up, and the use of a recyclable, low-cost catalyst. The catalyst demonstrated remarkable stability and could be reused up to six times without significant loss of activity. The CuO/mGO-TA-Me-BTA nanocomposite was extensively characterized using Fourier transform infrared (FT-IR) spectroscopy, X-ray diffraction (XRD), field emission scanning electron microscopy (FESEM), energy-dispersive X-ray (EDX) spectrometry, elemental mapping, thermogravimetric analysis (TGA), atomic absorption spectroscopy (AAS), and vibrating sample magnetometry (VSM).

1. Introduction

Nanoscience opens up new frontiers across disciplines such as chemistry, biology, physics, and engineering by enabling precise control over matter at the atomic and molecular scale. A key breakthrough from nanoscience is the creation of nanocatalysts^1,2. Operating at the nanoscale, nanocatalysts offer enhanced catalytic performance, largely due to their increased surface area and modified electronic properties, resulting in faster, more efficient chemical reactions. These catalysts play a pivotal role in industrial processes, environmental protection, and energy technologies, helping to develop more sustainable production methods, reduce pollution, and improve energy conversion systems, such as in fuel cells and hydrogen production. The integration of nanoscience and nanocatalysts is revolutionizing industries, providing high-performance solutions that are both economical and environmentally responsible^3–6. On the other hands, graphene oxide (GO) is a highly effective nanocatalyst due to its large surface area, abundant oxygen-containing functional groups, good dispersion in polar solvents, moderate electron mobility, thermal and chemical stability, tunable surface properties, and environmental compatibility, making it valuable in green chemistry, energy production, and environmental remediation^7,8.

Nitrogen-containing heterocycles, especially 3,4-DHPM and 1,4-DHP have attracted considerable attention due to their versatile pharmacological activities^9–14. They serve as important scaffolds in drug design and discovery^15–17. Also, they have gained considerable attention due to their important role in the field of pharmaceuticals and drugs as well as their role in the synthesis of DNA and RNA^18,19. Their ability to inhibit calcium influx through L-type calcium channels in cardiac and smooth muscle cells, makes them valuable therapeutic agents for managing cardiovascular conditions. Several 3,4-DHPM/3,4-DHPMTs and 1,4-DHPs derivatives have been explored for their potential therapeutic applications, including as antihypertensive²⁰, antihyperglycemic²¹, anti-inflammatory agents²², antimicrobial agents²³, anticancer agents²⁴, analgesic²⁵, antibacterial²⁶, Calcium Channel Blockers (CCB)²⁷, antitubercular activity, and antiviral agents²⁸. Exploring the detailed structures of the 3,4-DHPMs/3,4-DHPMTs and 1,4-DHPs uncovers valuable insights into their essential contributions to the complex molecular designs of various medicinal compounds^9,29. As illustrated in Fig. 1, nitractin B, idoxuridine C, (R)-SQ 32926 D, emivirine E, 5-Fluorouracil F, (S)-monastrol G, fluorostrol, piperastrol I, (S)-L-771688 A, nifedipine, amlodipine, nimodipine, cilnidipine, and nicardipine, are widely recognized as significant members of the 3,4-DHPM/3,4-DHPMTs and 1,4-DHPs classes of pharmaceutical compounds.

3,4-DHPM/3,4-DHPMTs and 1,4-DHPs derivatives were synthesized through multicomponent reactions, utilizing the Biginelli and Hantzsch named reactions, respectively. Due to the wide range of therapeutic properties, scientist have been attracted to developing synthetic methods for these types of molecules^29–31. In this context, multicomponent reactions (MCRs) have garnered significant attention for their ability to construct a diverse array of complex molecules with high efficiency, rapidity, step-economy, cost-effectiveness, and eco-friendliness^32–37. The literature review reveals that a range of novel synthetic routes, employing both heterogeneous and homogeneous catalysts, have been developed for the synthesis of 3,4-DHPM/3,4-DHPMTs and 1,4-DHPs derivatives. These approaches commonly revolve around a three-component reaction involving aldehydes, β-ketoesters, and urea/thiourea or ammonia.

Fig. 1

Illustrative of biologically active compounds known as 3,4-DHPM/3,4-DHPMTs and 1,4-DHPs.

Magnetic nanocatalysts have emerged as highly efficient agents in organic reactions^38,39, particularly in the Biginelli and Hantzsch reactions, showcasing remarkable catalytic performance, high conversion rates, selectivity, and recyclability. Their magnetic properties allow for easy separation and recovery using an external magnetic field, simplifying purification, reducing waste, and which enables multiple reuses without significant loss of activity, thus offering economic and environmental benefits^40–43. Collaborations among chemists, materials scientists, and engineers may further advance the integration of magnetic nanocatalysts into cutting-edge catalytic systems for broader applications in organic synthesis and beyond. Given the abundance of review reports that cover diverse catalysts utilized in the Biginelli and Hantzsch reactions, ranging from traditional Lewis acids to modern organocatalysts and innovative nanocatalytic systems, we will focus on providing a comprehensive overview of applied various catalysts^44–46.

The investigations span the utilization of a variety of catalysts, encompassing N,O-bis(trimethylsilyl) acetamide (BSA)⁴⁷, Itaconic Acid⁴⁸, Acridine Yellow G⁴⁹, Zirconium(IV)tetrachloride⁵⁰, [C₃SO₃HDoim]HSO₄⁵¹, [Et₃NH][CH₃COO]⁵², [bmim(SO₃H)(OTf)]⁵³, [P4-VP]-Fe₃O₄-HSO₄ ionic liquid⁵⁴, COF-IM-SO₃H⁵⁵, coconut husk ash twisted graphene⁵⁶, [Btto][p-TS]⁵⁷, p-sulfonic acid calix[4]arene (CX₄)⁵⁸, silicasulfuric acid⁵⁹, H₁₄NaP₅W₂₉MoO₁₁₀ over SiO₂ (PASi)⁶⁰, Cd(ii)furan-2-thiocarobxylates⁶¹, PNVP/TiCl₄⁶², Ag₂O/GO/TiO₂⁶³, Nd-Ag@polyoxometalate⁶⁴, ZnO⁶⁵, Fe-ZnO⁶⁶, mixed-phase Nano-γ-Fe₂O₃-SO₃H⁶⁷, magnetic BiFeO₃⁶⁸_, BiVO4‐NP⁶⁹, MgFe₂O₄/cellulose/SO₃H⁷⁰, CNs@PCC⁷¹, Magnetic Boron Nitride⁷², Fe₃O₄@SiO₂@GP/Picolylamine-Cu(II)⁷³, Nano-γ-Al₂O₃/BF₃/Fe₃O₄⁷⁴, Nano-cellulose/BF₃/Fe₃O₄⁷⁵, Fe₃O₄@SiO₂/TES-Mo⁷⁶, Fe₃O₄@C@OSO₃H⁷⁷, Fe₃O₄@SiO₂/H₂PO₃⁷⁸, Fe₃O₄-morpholinum sulfate salt⁷⁶, Fe₃O₄@SiO₂-APTS-EDTA-As⁷⁹, Fe3O4@VS-APS brush solid acid⁸⁰, sulfosalicylic CuFe₂O₄⁸¹, MNPs-SiCoFe-SO₃H⁸², CuFe₂O₄@PEO-SO₃H⁸³, clay-graphene oxide⁸⁴, 1,3,5-tris(2-hydroxyethyl)isocyanurate functionalized graphene oxide⁸⁵, Zn coordination polymer⁸⁶, PIL-SB-Mn(III)⁸⁷, GQDs-based MNPs⁸⁸, isocyanurate-based periodic mesoporous organosilica⁸⁹, microporous catalytic vessel {[Zn₂(oxdia)(4,4′-bpy)₂]·8.5H₂O}_n⁹⁰, resin purolite CT275DR⁹¹ in the Biginelli reaction, as well as sulfanilic acid-functionalized boehmite⁹², sulfated polyborate⁹³, HgFe₂O₄⁹⁴, Fe/ZSM-5,, SBA-15-SO₃H⁹⁵, Fe₃O₄@cysteine⁹⁶, Fe₃O₄@SiO₂@PTS-APG⁹⁷, Fe₃O₄@MgO⁹⁸, Fe₃O₄@glutathione⁹⁹, n-Fe₃O₄@SiO₂-TA-SO₃H IL¹⁰⁰, CMC-g-poly(AA-co-AMPS)/Fe₃O₄¹⁰¹, MNP@BSAT@Cu(OAc)₂¹⁰², Fe₃O₄@Phen-Cu¹⁰³, Fe₃O₄-bibenzo[d]imidazole-Cu¹⁰⁴, manganese(III)-porphyrin complex¹⁰⁵, Fe₃O₄@benzo[d]oxazole@Mn¹⁰⁶, ZnO@SnO₂¹⁰⁷, NiO–ZrO_2, Ch-Rhomboclase-NCs¹⁰⁸, rGO-SO₃H¹⁰⁹, KIT6-NH₂/Schiff base Cu complex¹¹⁰, in the Hantzsch reaction.

Despite prior endeavors, chemists persistently innovate in the realm of organic reactions to tackle pressing challenges, unveil new synthetic pathways, and propel advancements in fields that span from pharmaceuticals to materials science. In line with our focus on crafting efficient magnetic nano catalysts, we designed a CuO-based CuO/mGO-TA-Me-BTA as non-toxic magnetic nanocatalyst for the synthesis of nitrogen-containing heterocyclic compounds via the Biginelli and Hantzsch reactions, all within the framework of green chemistry principles (Fig. 2)^111–121.

Fig. 2

Outline of the synthesis of 3,4-DHPM/3,4-DHPMTs and 1,4-DHPs derivatives employing the efficient CuO/mGO-TA-Me-BTA nanocatalyst under the green chemistry conditions.

2. Experimental

2.1. Materials: All starting materials, reagents and solvents are commercially available and were purchased from Merck or Aldrich and used without further purification, except for benzaldehyde, which was used as a fresh distilled sample. ¹H NMR spectra were recorded on a Bruker (Avance DRX-500) spectrometer using CDCl₃ as the solvent at room temperature. Chemical shifts (δ) are reported in parts per million (ppm) relative to tetramethylsilane as an internal standard. Fourier Transform infrared (FT-IR) spectra of the samples were measured using an ABB Bomem MB100 FTIR spectrophotometer. CHNS analysis was using LECO Truspec. Scanning electron microscopy (SEM) was performed on VEGA\\TESCAN-LMU. An energy dispersive detector (EDS) coupled to the microscope was used to identify chemical elements of the prepared catalyst. X-ray diffraction (XRD) pattern was recorded on APD 2000, using Cu Kα radiation (50 kV, 150 mA) in the range of 2θ = 10–120°.

2.2. Synthesis of Graphene Oxide (GO): The graphene oxide (GO) sheets were prepared by a modified Hummers´ method according to the method reported in the literature¹²⁶.

Synthesis of Benzotriazole (BTA)

5.4 g of o-phenylenediamine was dissolved in a mixture containing 6.0 mL of glacial acetic acid and 20 mL of water. The solution was then cooled to 15°C. A separate solution of 3.0 g of sodium nitrite dissolved in 7 mL of water, was then gradually introduced into the reaction mixture. Upon addition, a noticeable color change from deep red to pale brown was observed. The reaction mixture was further cooled in an ice bath for 30 minutes. The resulting benzotriazole product was isolated through filtration and subsequently washed with cold water to ensure its purity.

2.3. Synthesis of 1-(prop-2-yn-1-yl)-1H-benzo[ d ][1,2,3]triazole: In the subsequent step, 2.0 mmol of the synthesized benzotriazole, 2.2 mmol of propargyl bromide, 4.0 mmol of potassium carbonate, and 5 mL of DMF were introduced into a reaction flask. The mixture was stirred at 45°C for 12 hours. Reaction progress was monitored via thin-layer chromatography using a solvent system of ethyl acetate (1:3). Upon completion, the product, 1-(prop-2-yn-1-yl)-1H-benzo[d][1,2,3]triazole, was isolated through extraction with ethyl acetoacetate and then dried in an oven to obtain the final product.

2.4. Synthesis of 1-((1 H -1,2,3-triazol-5-yl)methyl)-1 H -benzo[ d ][1,2,3]triazole: The grafting of 1-(prop-2-yn-1-yl)-1H-benzo[d][1,2,3]triazole onto magnetic graphene oxide was carried out via a click reaction. Initially, 300.0 mg of graphene oxide was dispersed in 80 mL of deionized water via ultrasonication. To this dispersion, 10.0 mmol of 1-(prop-2-yn-1-yl)-1H-benzo[d][1,2,3]triazole, 15.0 mmol sodium azide, 20 mol% of sodium ascorbate, 0.5 mmol of copper sulfate, and 20 mL of tert-butyl alcohol were added. The reaction mixture was stirred at 60°C for 24 hours. Upon completion, the nanocomposite was isolated using an external magnetic field and thoroughly washed with distilled water (3×10 mL) and ethanol (1×10 mL), then dried at 50°C.

2.5. Synthesis of CuO/mGO-TA-Me-BTA nano-catalyst: In a 250 mL reaction vessel, 1.0 g of a magnetic graphene oxide nanocomposite grafted with benzotriazole (CuO/mGO-TA-Me-BTA) was dispersed in 100 mL of deionized water through ultrasonication. To this dispersion, 3.0 mmol of copper(II) sulfate dissolved in 25 mL of deionized water, was added, and the mixture was stirred at room temperature for 24 hours. Afterward, the nanocomposite was isolated using an external magnetic field, washed with distilled water, and dried in a vacuum. The structure of the synthesized nanocomposite (CuO/mGO-TA-Me-BTA) was characterized by FT-IR, XRD, SEM, EDX, elemental mapping, TGA, VSM, and AAS analyses.

2.6. One-pot, three-component synthesis of the 3,4-dihydropyrimidin-2-one/thion derivatives in the presence of the CuO/mGO-TA-Me-BTA magnetic nanoparticles (4a-w): For the synthesis of 3,4-dihydropyrimidinone derivatives, a mixture of 1.0 mmol aldehyde, 1.1 mmol urea (or thiourea), 1.0 mmol ethyl acetoacetate, and 10.0 mg of the CuO/mGO-TA-Me-BTA nanocomposite as a catalyst was added to a 5 mL round-bottom flask along with 1.5 mL distilled water and 0.5 mL of ethanol. The reaction mixture was stirred using a magnetic stirrer and heated under reflux in an oil bath for the required time, as indicated in Table 2. The progress of the reaction was monitored by thin-layer chromatography (TLC) using a solvent system of 1:3 n-hexane:acetate. Upon completion of the reaction, the magnetic nanocatalyst was separated using an external magnetic field, and the 3,4-dihydropyrimidinone product was isolated by extraction with ethyl acetate. If necessary, the products were crystallized from a mixture of ethyl acetate-n-hexane or ethanol. The final structures of the synthesized compounds were identified and confirmed by M.P (Melting Point), ¹H NMR, and FT-IR analyses.

2.7. One-pot, three-component synthesis of the 1,4-Dihydropyridine derivatives in the presence of the CuO/mGO-TA-Me-BTA magnetic nanoparticles (6a-m): For the synthesis of 1,4-dihydropyridine derivatives, a 5 mL round-bottom flask was filled with a mixture of 1.0 mmol of aldehyde, 2.0 mmol of ethyl acetoacetate, 1.5 mmol of ammonium acetate, 10 mg of CuO/mGO-TA-Me-BTA nanocomposite, used as the catalyst, 1.5 mL distilled water, and 0.5 mL ethanol as the solvent. The reaction mixture was stirred with a magnetic stirrer and heated under reflux in an oil bath for the duration specified in Table 3. Reaction progress was monitored by thin-layer chromatography (TLC) using a 1:3 n-hexane:ethylacetate solvent system. After the reaction was complete, the magnetic nanocatalyst was separated using an external magnetic field, and the 1,4-dihydropyridine product was extracted with ethyl acetate. If needed, the products were crystallized from a mixture of ethyl acetate and n-hexane or ethanol. The final structures of the synthesized compounds were confirmed by melting point (M.P) determination, ¹H NMR, and FT-IR spectroscopy.

2.8. Spectroscopic characterization of the products 4e, 4m, 4n, 4t, 4u, 6c, 6h, and 6l.

Ethy l-4-(2-chlorophenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (4e, entry 5, Table 2); White solid; M.P: 206–207 ^oC, ¹H NMR (500 MHz, DMSO-d₆, δ = ppm) δ: 9.3 (s, 1H, NH), 7.68 (s, 1H, NH), 7.39 (d, 1H, J = 7.5 Hz, ArH), 7.26–7.30 (m, 3H, ArH), 5.6 (s, 1H, CH), 3.89 (q, J = 7.1 Hz, 2H, CH₂), 2.29 (s, 3H, CH₃), 0.98 (t, J = 6.5, 3H, CH₃); FT-IR (KBr, disk) ν (cm^− 1): 3354 (NH stretch for amide), 3229(NH stretch for amide), 3111 (Ar-H stretch), 2972 (CH₂CH₃, CH₃ stretch), 2869 (CH₂ stretch), 1695 (C = C-CO-OR, C = O stretch), 1642 (RCONHR`, C = O stretch), 1593 (C = C stretch), 1445 (Ar C-C stretch), 1370 (RCH₂CH₃, CH₂), 1322 (CH₃), 1225 (RCOOR`, C-O stretch), 1092 (RCONHR`, C-O stretch), 1027 (C-N stretch),745 (C-Cl stretch).

Ethyl 4-(4-hydroxyphenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (4m, entry 13, Table 2); White solid; M.P: 232–233 ^oC, ¹H NMR (500 MHz, DMSO-d₆, δ = ppm) δ: 12.89 (1H, br, OH), 9.25 (s, 1H, NH), 7.90 (d, 2H, J = 8.0 Hz, ArH), 7.80 (s, br, 1H, NH), 7.34 (d, 2H, J = 8.0 Hz, ArH), 5.20 (s, 1H, CH), 3.98 (q, J = 7.0 Hz, 2H, CH₂), 2.25 (s, 3H, CH₃), 1.08 (t, J = 7.0, 3H, CH₃); FT-IR (KBr, disk) ν (cm^− 1): 3510 (OH stretch), 3359 (NH stretch for amide), 3232 (NH stretch for amide), 3122 (Ar-H stretch), 2997 (CH₂CH₃, CH₃ stretch), 2821 (CH₂ stretch), 1689 (C = C-CO-OR, C = O stretch), 1643 (RCONHR`, C = O stretch), 1481 (C = C stretch), 1460 (Ar C-C stretch), 1377 (RCH₂CH₃, CH₂), 1300 (CH₃), 1238 (RCOOR`, C-O stretch), 1087 (RCONHR`, C-O stretch), 1008 (C-N stretch).

Ethyl 4-(2-hydroxy-3-methoxyphenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (4n, entry 14, Table 2); White solid; M.P: 238 ^oC, ¹H NMR (500 MHz, DMSO-d₆, δ = ppm) δ: 9.08 (s, 1H, NH), 8.73 (s, 1H, OH), 7.06 (1H, br, OH), 6.74 (d, 1H, J = 7.0 Hz, ArH), 6.69 (t, 1H, J = 8.0 Hz, ArH), 6.61 (d, 1H, J = 7.5 Hz, ArH), 5.54 (d, J = 2.5 Hz, 1H, CH), 3.92 (d of q, J = 9.0 Hz, 2H, CH₂), 3.77 (s, 3H, OCH₃), 2.96 (s, 3H, CH₃), 1.03 (t, J = 7.0, 3H, CH₃); FT-IR (KBr, disk) ν (cm^− 1): 3507 (OH stretch for amide), 3353 (NH stretch for amide), 3225 (NH stretch for amide), 3117 (Ar-H stretch), 2960 (CH₂CH₃, CH₃ stretch), 2840 (CH₂ stretch), 1686 (C = C-CO-OR, C = O stretch), 1640 (RCONHR`, C = O stretch), 1594 (C = C stretch), 1490 (Ar C-C stretch), 1370 (RCH₂CH₃, CH₂), 1340 (CH₃), 1281 (RCOOR`, C-O stretch), 1224 (Ar-O-R, C-O stretch), 1071 (RCONHR`, C-O stretch), 1025 (C-N stretch).

Ethyl 4-(4-chlorophenyl)-6-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (4t, entry 20, Table 2); White solid; M.P: 188–190 ^oC, ¹H NMR (500 MHz, DMSO-d₆, δ = ppm) δ: 10.33 (s, 1H, NH), 9.62 (s, br, 1H, NH), 7.36 (d, 2H, J = 8.0 Hz, ArH), 7.16 (d, 1H, J = 8.0 Hz, ArH), 5.09 (s, 1H, CH), 3.94 (q, J = 7.0 Hz, 2H, CH₂), 2.23 (s, 3H, CH₃), 1.03 (t, J = 7.0, 3H, CH₃); FT-IR (KBr, disk) ν (cm^− 1): 3325 (NH stretch for thioamide), 3172 (NH stretch for thioamide), 3097 (Ar-H stretch), 2997 (CH₂CH₃, CH₃ stretch), 2893 (CH₂ stretch), 1670 (C = C-CO-OR, C = O stretch), 1573 (RCSNHR`, C = S stretch), 1463 (Ar C-C stretch), 1381 (RCH₂CH₃, CH₂), 1328 (CH₃), 1284 (RCOOR`, C-O stretch), 1195 (C-S stretch), 1116 (RCONHR`, C-O stretch), 1014 (C-N stretch), 752 (C-Cl stretch).

Ethyl 6-methyl-4-phenyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (4u, entry 21, Table 2); White solid; M.P: 207–208 ^oC, ¹H NMR (500 MHz, DMSO-d₆, δ = ppm) δ: 10.29 (s, 1H, NH), 9.60 (s, br, 1H, NH), 7.28 (t, 2H, J = 7.0 Hz, ArH), 7.21 (t, 1H, J = 7.0 Hz, ArH), 7.15 (d, 2H, J = 7.0 Hz, ArH), 5.11 (d, J = 3.5 Hz, 1H, CH), 3.95 (q, J = 6.5 Hz, 2H, CH₂), 2.23 (s, 3H, CH₃), 1.04 (t, J = 7.0, 3H, CH₃); FT-IR (KBr, disk) ν (cm^− 1): 3327 (NH stretch for thioamide), 3170 (NH stretch for thioamide), 3101 (Ar-H stretch), 2981 (CH₂CH₃, CH₃ stretch), 2895 (CH₂ stretch), 1670 (C = C-CO-OR, C = O stretch), 1573 (RCSNHR`, C = S stretch), 1462 (Ar C-C stretch), 1375 (RCH₂CH₃, CH₂), 1328 (CH₃), 1282 (RCOOR`, C-O stretch), 1197 (C-S stretch), 1114 (RCONHR`, C-O stretch), 1026 (C-N stretch).

Diethy l2,6-dimethyl-4-(4-colorophenyl)-1,4-dihydropyridine-3,5-dicarboxylate (6c, entry 3, Table 3); White solid, M.P: 142 ^oC, ¹H NMR (500 MHz, CDCl₃, δ = ppm) δ: 7.20 (d, J = 8.5 Hz, 2H, Ar-H), 7.14 (d, J = 8.4 Hz, 2H, Ar-H), 5.74 (s, 1H, NH), 4.8 (s, 1H, CH), 4.1 (m, 4H, CH₂), 2.28 (s, 6H, CH₃), 1.2 (t, J = 7.1 Hz, 6H, CH₃); FT-IR (KBr, disk) ν (cm^− 1) : 3361 (NH stretch for amine), 3096 (Ar-H stretch), 2989 ( RCH₂CH₃, CH₃ stretch), 2928 (CH₂ stretch), 1697 (C = C-CO-OR, C = O stretch), 1654 (C = C-CO-OR, C = O stretch), 1636 (C = C stretch), 1489 (Ar C-C stretch), 1372 (RCH₂CH₃, CH₂ and CH₃), 1334 ( CH₃), 1215 (RCOOR`, C-O stretch), 1119 (RCOOR`, C-O stretch), 1082 (C-N stretch), 785 (C-Cl stretch).

Diethyl 4-(3,4-dimethoxyphenyl)-2,6-dimethyl-1,4-dihydropyridine3,5-dicarboxylate (6h, entry 8, Table 3); White solid, M.P: 147–148 ^oC, ¹H NMR (500 MHz, CDCl₃, δ = ppm) δ: 6.87 (d, J = 2 Hz, 1H, ArH), 6.78 (dd, J = 2 Hz, 1H, ArH), 6.70 (d, J = 8.2 Hz, Ar-H), 5.95 (s, 1H, NH), 4.92 (s, 1H, CH), 4.08 (m, 4H, CH₂), 3.81 (s, 6H, CH₃O), 3.79 (s, 6H, CH₃O), 2.30 (s, 6H, CH₃),1.22 (t, J = 7.1 Hz, 6H, CH₃); FT-IR (KBr, disk) ν (cm^− 1): 3345 (NH stretch for amine), 3094 (Ar-H stretch), 2983 ( RCH₂CH₃, CH₃ stretch), 2928 (CH₂ stretch), 1688 (C = C-CO-OR, C = O stretch), 1653(C = C-CO-OR, C = O stretch), 1619 (C = C stretch), 1485 (Ar C-C stretch), 1368 (RCH₂CH₃, CH₂ and CH₃), 1322 (CH₃), 1257 (Ar-O-R, C-O stretch), 1227 (Ar-O-R, C-O), 1209 (RCOOR`, C-O stretch), 1138 (RCOOR`, C-O stretch), 1028 (C-N stretch).

Diethyl2,6-dimethyl-4-(thiophen-2-yl)-1,4-dihydropyridine-3,5-dicarboxylate (6l, entry 12, Table 3); White solid, M.P: 170–171 ^oC, ¹H NMR (500 MHz, CDCl3, δ = ppm) δ: 5.8 (s, 1H, NH), 7.20 (t, J = 1.0 Hz, 1H, Het-Ar-H), 6.20 (dd, J = 2 Hz, 2H, Het-Ar-H), 5.94 (d, J = 3.0 Hz, 1H, Het-Ar-H), 5.82 (s, br, 1H, NH), 5.19 (s, 1H, CH), 4.15 (m, 4H, CH₂), 2.32 (s, 6H, CH₃), 1.24 (t, J = 7.31 Hz, 6H, CH₃); FT-IR (KBr, disk) ν(cm^− 1): 3348 (NH stretch for amine), 3098 (Het-Ar-H stretch), 2985 (RCH₂CH₃, CH₃ stretch), 2903 (CH₂ stretch, CH₂ and CH₃), 1335 (CH₃), 1209 (RCOOR`, C-O stretch), 1121 (RCOOR`, C-O stretch), 1091 (C-N stretch), 807 (C-S stretch).

3. Results and discussion

As shown in Fig. 3 and based on our previous experience, the synthesis pathway for the Cu(II) stabilized magnetic benzotriazole-grafted graphene oxide (GO) nano-structured catalyst (CuO/mGO-TA-Me-BTA) involves a series of sequential steps. Graphene oxide nanosheets have been generated by oxidizing graphite using a modified Hummers' method^122–124. These nanosheets have subsequently been enveloped with magnetic Fe₃O₄, leading to the formation of mGO. N-propargyl benzotriazole has been attached onto the pre-treated mGO, followed by further customization facilitated by the Huisgen 1,3-dipolar cycloaddition click reaction, culminating in the creation of mGO-TA-Me-BTA. Lastly, CuSO₄ has been anchored to the surface of mGO-TA-Me-BTA through supramolecular coordination with the benzotriazole motif, exploiting its well-established effectiveness as a ligand for a diverse array of transition metals. The intriguing aspect of fixing copper sulfate to the substrate of mGO-TA-Me-BTA magnetic nanoparticles is the transformation the nanoparticles undergoes. Copper sulfate is deposited onto the nanoparticles, losing SO₃ in the process and forming stable copper oxide. This transformation can occur as the nanocatalyst dries.

Fig. 3

step-by-step synthesis process of the supramolecular CuO/mGO-TA-Me-BTA nanocatalyst.

The synthesized CuO/mGO-TA-Me-BTA catalyst underwent comprehensive characterization to clarify its structural, morphological, and size-related attributes. Techniques such as Fourier transform infrared (FT-IR) spectroscopy, X-ray diffraction (XRD), field emission scanning electron microscopy (FESEM), energy-dispersive X-ray (EDX) spectrometry, elemental mapping, thermogravimetric analysis (TGA), atomic absorption spectroscopy (AAS), and vibrating sample magnetometry (VSM) were employed. For this purpose, Fig. 4 highlights the FT-IR analysis of free graphene oxide (Fig. 4a), magnetic graphene oxide (Fig. 4b), and the CuO/mGO-TA-Me-BTA nanocomposite (Fig. 4c). The broad peak observed at 3328 cm^-1 corresponds to the stretching vibrations of hydroxyl groups on the magnetic graphene oxide surface. Additionally, the peak at 570 cm¹ signifies the characteristic Fe-O bond, confirming the presence of Fe₃O₄ magnetic nanoparticles in the CuO/mGO-TA-Me-BTA. Peaks at 1207 and 1022 cm^-1 are attributed to the stretching vibrations of C‒O and C‒OH groups, respectively. Moreover, sharp peaks at 1735 and 1612 cm^-1 are assigned to the C = O and C = C stretching vibrations of graphene oxide nano sheets. In the spectrum of 1-((1H-1,2,3-triazol-5-yl)methyl)-1H-benzo[d][1,2,3]triazole (Fig. 4c), new peaks emerge at 1535 and 1396 cm^-1, indicative of the C = C and C‒N stretching vibrations of the benzotriazole group. Additionally, peaks at 3190 and 2920 cm^-1 relate to the stretching vibrations of aromatic C-H and aliphatic C-H groups. These results confirm the presence of 1-((1H-1,2,3-triazol-5-yl)methyl)-1H-benzo[d][1,2,3]triazoles as linkers on the mGO surface.

Fig. 4

FTIR spectra of a) GO, b) mGO, and c) the CuO/mGO-TA-Me-BTA.

In the next step, X-ray diffraction analysis was utilized subsequently to explore the crystalline structure, phase purity, and particle size of the CuO/mGO-TA-Me-BTA nanocatalyst, as illustrated in Fig. 5. The X-ray diffraction pattern of the copper-supported nanocatalyst was compared with reference cards for graphene oxide, Fe₃O₄, and copper oxide to facilitate comparison. In Fig. 5, the presence of two distinct peaks at 2θ = 8.8° (with a d-spacing of 1.00 nm) and 2θ = 26.7° (with a d-spacing of 0.33 nm) indicates the presence of crystallized graphene oxide. Additionally, peaks at 2θ = 30.8°, 35.7°, 45.3°, 55.4°, 57°, and 61.8° correspond to the (220), (311), (400), (422), (511), and (440) crystalline layers of Fe₃O₄ cubic spinel (as per JCPDS card No. 11–0614).¹²¹ This indicates the presence of highly crystalline magnetic Fe₃O₄ particles within the nanocatalyst structure, with no discernible diffraction peaks indicating the presence of hematite impurities. Additionally, the diffraction peaks observed at 2θ = 17.8°, 19.8°, 25.2°, 31.8°, 35.6°, 40°, and 53° can be attributed to the presence of immobilized CuO on the nano-composite (according to JCPDS card No. 5-0661).¹²¹ The average particle size, as determined by Scherrer’s equation, is approximately 15 nm.

Fig. 5

XRD pattern of the CuO/mGO-TA-Me-BTA nanocatalyst.

SEM analysis revealed that the CuO/mGO-TA-Me-BTA composite features nearly spherical nanoparticles evenly distributed across the GO sheets, as depicted in Fig. 6. The average nanoparticle size of 17 nm, determined from FESEM images, concurs well with the findings derived from XRD analysis

Fig. 6

FESEM images of the CuO/mGO-TA-Me-BTA nanocatalyst.

The EDX analysis was employed to ascertain the elemental composition of the CuO/mGO-TA-Me-BTA nanocatalyst, confirming the presence of C (44.36 wt%), N (18.45 wt%), O (20.49 wt%), Fe (10.36 wt%), and Cu (6.34 wt%), as shown in Fig. 7. Furthermore, the mapping pattern of the CuO/mGO-TA-Me-BTA nanocatalyst indicates a uniform distribution of all elements on the surface, as clearly demonstrated in Fig. 8.

Fig. 7

EDX pattern of the CuO/mGO-TA-Me-BTA nanocatalyst.

Fig. 8

Elemental mapping of different elementals in the structure of CuO/mGO-TA-Me-BTA nanocatalyst.

Thermogravimetric/derivative thermal gravimetric analysis (TGA-DTG) was employed to evaluate the thermal stability of the synthesized nanocatalyst. As illustrated in Fig. S6, the TGA-DTG curves reveal four distinct stages of weight loss occurring within different temperature ranges: below 300°C, 340–450°C, 450–740°C, and above 740°C. In the process of thermogravimetric analysis (TGA) for graphene oxide (GO), the initial weight gain is commonly attributed to the oxidation of double bonds situated on the basal plane of GO. This is followed by the absorption or adsorption of moisture through hydrogen bonding occurring at the both the edges and basal plane, or chemisorption via the ring opening-reaction of epoxide groups. It's apparent that the removal of these compounds from the GO surface led to a partial decrease in weight at temperatures blew 300°C. The subsequent phase, occurring between approximately 340°C and 450°C, involves both the decomposition of the triazole motif and the generation of epoxy groups through the condensation of adjacent hydroxyl groups on the surface of the GO layers. Following this, the third phase occurs within the temperature range of 450–740°C, primarily associated with the breakdown of carboxyl or epoxy functional groups. At temperatures attributed 740°C, the ultimate phase of weight reduction occurs, primarily attributed to the thermal degradation of the carbon framework of graphene oxide nanosheets. Additionally, it involves the condensation of hydroxyl groups present on the surface of Fe₃O₄, and potentially, any residual CuO components. Moreover, apart from thermal analysis, DTG analysis also delineates the phases of weight loss. The DTG analysis highlights a significant drop in weight during the last stage, at a temperature of 740°C.

In the next step, the magnetic properties of Fe₃O₄-GO nanosheets and CuO/mGO-TA-Me-BTA nanocatalyst were examined at room temperature using the VSM technique (Fig. S7). The hysteresis curves reveal that the maximum saturation magnetization values are 44.45 emu/g for Fe₃O₄-GO and 34.22 emu/g for CuO/mGO-TA-Me-BTA. The lower saturation magnetization value for CuO/mGO-TA-Me-BTA is attributed to the surface modifications and the inclusion of non-magnetic elements such as BTA and CuO on the catalyst's surface. Additionally, both magnetization curves show a decrease from the plateau state to zero after removal of the magnetic field, indicating typical superparamagnetic behavior.

Ultimately, to determine the amount of Cu(II) loade on the CuO/mGO-TA-Me-BTA nanocomposite, atomic absorption spectroscopy (AAS) elemental analysis was conducted. The analysis indicated that the copper concentration on the magnetic substrate was 0.1 mg/liter. From this concentration, it was calculated that the CuO loading on the magnetic substrate amounts to 0.32 mmol/g.

As the performed analysis indicates that our objective indesigning magnetic nanocatalysts is consistently achieved, in the following the synthesis of various 3,4-DHPM/3,4-DHPMTs and 1,4-DHPs skeleton derivatives in the presence of CuO/mGO-TA-Me-BTA nanoparticles to demonstrate its more efficacy was investigated. In this context, the three-component condensation involving benzaldehyde 1a (1.0 mmol), ethyl acetoacetate 2a (1.0 mmol), and urea 3a (1.2 mmol) was as a representative reaction. Various parameters, including solvent options, temperature variations, and catalyst quantities were examined. Initially, to determine the best solvent, a systematic investigation of the model reaction was examined in the presence of various solvents, including water, ethanol, water:ethanol (1:3), water:ethanol (3:1), ethylacetoacetate, acetonitrile, and dimethylformamide, as well as under solvent-free conditions, with 5 mg of catalyst, at room temperature (Entries 1–8). As usual, the progress of the model reaction was monitored by TLC using a 3:1 mixture of hexane:ethyl acetate. As summarized in Tables 1, the model reaction under ambient temperature conditions did not yield a high amount of the desired product after 2 hours, and extending the reaction time did not significantly improve the yield. However, the water:ethanol mixture (3:1) (Entry 3) showed better performance compared with the other solvents. One of the important reasons for the better performance of the designed nanocatalyst in aqueous solvent is the high dispersibility of graphene oxide nanoparticles in water. Graphene oxide (GO) exhibits excellent dispersibility due to its hydrophilic nature, with oxygen-containing functional groups such as hydroxyl, epoxy, and carboxyl groups increasing its affinity for water molecules. This enables GO to form stable colloidal suspensions without the need for additional stabilizing agents. The good dispersibility and colloidal stability of GO in water significantly enhance the efficiency and effectiveness of the nanocatalyst in aqueous environments. Moreover, ethanol's capacity to efficiently dissolve organic compounds facilitates the rapid formation of the desired product. In the next steps, to enhance the yield of the desired product, the reaction model in the solvent of water:ethanol under reflux conditions were investigated (Entry 9). Under reflux conditions, as expected, a satisfactory yield (58%) of the product was obtained within a 30-minute timeframe. In the subsequent steps, the model reaction was repeated with different amounts of 7.5, 10, and 12.5 mg of CuO/mGO-TA-Me-BTA under reflux temperature conditions (Entries 10–12). Ultimately, 10 mg was determined as the most effective amount of catalyst (Entry 11). Increasing the catalyst amount from 5 to 10 mg resulted in a significant enhancement of the reaction yield from 58 to 90% and reduced the reaction time from 30 minutes to 15 minutes (Entries 10–11). However, increasing the catalyst amount from 10 mg to 12.5 mg did not show any significant impact on the reaction yield (Entries 11–12). It is noteworthy that altering other conditions did not significantly impact the reaction yield and reaction time. The results indicated that the magnetic support had little influence on the catalytic activity, with the active site of the catalyst for the model reaction being copper oxide (Entries 13–14).

Ultimately, following thorough investigations, 10 mg of the magnetic nanocatalyst CuO/mGO-TA-Me-BTA and a mixture of water:ethanol solvent (3:1, 2 ml) were chosen as environmentally friendly solvent and reflux temperature conditions as the optimal conditions for expanding to other aromatic carbonyl compounds.

Thoroughly examining the optimal conditions in the model reaction effectively showcased the remarkable efficiency of designed CuO/mGO-TA-Me-BTA nanoparticles in organic reactions, particularly highlighting its effectiveness in the Biginelli reaction. Moreover, to conduct a comprehensive assessment of these nanoparticles' efficiency in the synthesis of a wide array of 3,4-DHPM/3,4-DHPMTs derivatives, the optimal conditions were expanded to encompass not only other aromatic aldehyde derivatives with both electron-withdrawing and electron-donating substituents but also heteroaromatic carbonyl compounds. The results of these investigations include reaction yield, reaction time, and analyses for identifying derivatives, all meticulously detailed and presented in Table 2.

Table 1

Optimization of influencing factors (solvent, temperature, and catalyst loading) in three-component condensation of benzaldehyde (1a), ethyl acetoacetate (2a), and urea (3a) as a model reaction.a

En.	Catalyst (mg)	Solvent (ml)	Temp. (^oC)	Time (min)	Yield^b (%)
1	CuO/mGO-TA-Me-BTA (5.0 mg)	EtOH (2.0 ml)	r.t	120	20
2	CuO/mGO-TA-Me-BTA (5.0 mg)	H₂O (2.0 ml)	r.t	120	25
3	CuO/mGO-TA-Me-BTA (5.0 mg)	H₂O:EtOH (3:1) (2.0 ml)	r.t	120	40
4	CuO/mGO-TA-Me-BTA (5.0 mg)	H₂O:EtOH (1:3) (2.0 ml)	r.t	120	30
5	CuO/mGO-TA-Me-BTA (5.0 mg)	AcOH (2.0 ml)	r.t	120	Trace
6	CuO/mGO-TA-Me-BTA (5.0 mg)	CH₃CN (2.0 ml)	r.t	120	Trace
7	CuO/mGO-TA-Me-BTA (5.0 mg)	DMF (2.0 ml)	r.t	120	25
8	CuO/mGO-TA-Me-BTA (5.0 mg)	S-F (2.0 ml)	r.t	120	Trace
9	CuO/mGO-TA-Me-BTA (5.0 mg)	H₂O:EtOH (3:1) (2.0 ml)	reflux	30	58
10	CuO/mGO-TA-Me-BTA (7.5 mg)	H₂O:EtOH (3:1) (2.0 ml)	reflux	15	64
11	CuO/mGO-TA-Me-BTA (10.0 mg)	H₂O:EtOH (3:1) (2.0 ml)	reflux	15	90
12	CuO/mGO-TA-Me-BTA (12.0 mg)	H₂O:EtOH (3:1) (2.0 ml)	reflux	15	92
13	mGO-TA-Me-BTA (5.0 mg)	H₂O:EtOH (3:1) (2.0 ml)	reflux	120	Trace
14	mGO (5.0 mg)	H₂O:EtOH (3:1) (2.0 ml)	reflux	120	Trace
^aReaction conditions: benzaldehyde 1a (1.0 mmol), ethyl acetoacetate 2a (1.0 mmol), urea 3a (1.2 mmol), CuO/mGO-TA-Me-BTA and 2.0 ml of solvent. ^bThe yield of the reaction is related to the isolated product.

Table 2

Expansion of the optimized method for the synthesis of diverse derivatives of 3,4-dihydropyrimidin-2(1H)-one/thione skeletons in the presence of CuO/mGO-TA-Me-BTA magnetic nanoparticles.a

En.	Aldehyd (1a-r)	Urea/Thiourea (3)	Product (4a-w)	Time (min)	Yeild^b (%)	M.p (^oC)
1	1a	Urea 3a	4a	10.0	96	209–210
2	1b	Urea 3a	4b	15.0	90	226–227
3	1c	Urea 3a	4c	20.0	91	209–211
4	1d	Urea 3a	4d	15.0	89	215
5	1e	Urea 3a	4e	25.0	92	206–207
6	1f	Urea 3a	4f	12.0	86	223–225
7	1g	Urea 3a	4g	15.0	90	208
8	1h	Urea 3a	4h	15.0	82	229–301
9	1i	Urea 3a	4i	20.0	92	203–204
10	1j	Urea 3a	4j	25.0	87	264–265
11	1k	Urea 3a	4k	15.0	89	174–175
12	1l	Urea 3a	4l	20.0	90	229
13	1m	Urea 3a	4m	25.0	89	232–233
14	1n	Urea 3a	4n	25.0	84	238
15	1o	Urea 3a	4o	20.0	90	210
16	1p	Urea 3a	4p	15.0	89	204–205
17	1q	Urea 3a	4q	15.0	93	210
18	1r	Urea 3a	4r	20.0	88	206–207
19	1a	Urea 3a	4s	15.0	93	204
20	1d	Thiourea 3b	4t	15.0	90	188–190
21	1g	Thiourea 3b	4u	20.0	88	207–208
22	1h	Thiourea 3b	4v	30.0	86	203–204
23	1n	Thiourea 3b	4w	20.0	89	202–203
^aReaction conditions: aromatic or heteroaromatic aldehyde 1a-r (1.0 mmol), ethyl acetoacetate 2 (1.0 mmol), urea/thiurea 3a-b (1.1 mmol), CuO/mGO-TA-Me-BTA (10.0 mg) water: ethanol (2.0 ml, 3:1) under reflux conditions. ^bThe yield of products is related to the purified product.

In the following, to illustrate the greater efficiency of the decorated CuO/mGO-TA-Me-BTA nanocatalyst, its application was investigated in the synthesis of 1,4-dihydropyridine derivatives via the Hantzsch reaction. This involved a three-component condensation of aromatic aldehydes, ethyl acetoacetate, and ammonium acetate as the nitrogen source. The reaction was conducted under previously optimized conditions, employing CuO/mGO-TA-Me-BTA nanoparticles as the catalyst.

This pathway underscores the efficacy of the CuO/mGO-TA-Me-BTA nanocatalyst in facilitating the synthesis through a series of well-coordinated steps, highlighting its potential in promoting multi-component reactions for complex organic syntheses. The overall effectiveness and results of this procedure are summarized in Table 3, including reaction conditions, time, and yields of the products.

Table 3

Expansion of the optimized method for the synthesis of diverse derivatives of 1,4-dihydropyridine skeletons (6a-m) in the presence of CuO/mGO-TA-Me-BTA magnetic nanoparticles.a

En.	Aldehyd (1a-r)	N-Source (5)	Product (6a-m)	Time (min)	Yeild^b (%)	M.p (^oC)
1	1a	NH₄OAc 5	6a	15.0	96	130–132
2	1b	NH₄OAc 5	6b	20.0	90	160–162
3	1d	NH₄OAc 5	6c	15.0	95	142
4	1e	NH₄OAc 5	6d	20.0	88	130–132
5	1g	NH₄OAc 5	6e	20.0	90	156–158
6	1i	NH₄OAc 5	6f	25.0	90	160–162
7	1j	NH₄OAc 5	6g	30.0	92	158–160
8	1k	NH₄OAc 5	6h	20.0	88	147–148
9	1l	NH₄OAc 5	6i	25.0	90	163–164
10	1m	NH₄OAc 5	6j	20.0	88	223
11	1o	NH₄OAc 5	6k	20.0	90	134–136
12	1q	NH₄OAc 5	6l	15.0	89	171–172
13	1r	NH₄OAc 5	6m	20.0	90	164–166
^aReaction conditions: aromatic or heteroaromatic aldehyde 1a-r (1.0 mmol), ethyl acetoacetate 2 (1.0 mmol), NH₄OAc 5 (1.5 mmol), CuO/mGO-TA-Me-BTA (10.0 mg) as a magnetically nanocatalyst, water: ethanol (2.0 ml, 3:1) as a green solvent and reflux conditions. ^bThe yield of products is related to the purified product.

As seen in Tables 2 and 3, the influence of substituents on the phenyl ring is crucial for determining the reaction rate. The nature of these substituents plays a significant role; aromatic aldehydes with electron-withdrawing groups like nitro and halogens facilitate a faster reaction compared to those with electron-donating groups such as methyl, hydroxy and methoxy. In the case of substituents at the ortho position on the phenyl ring, steric hindrance has a significant impactful on the reaction time and yield than the electronic nature of the substituent.

In addition to aromatic aldehydes, the reaction also demonstrates good product yields with heteroaryl aldehydes such as thiophene-2-carbaldehyde and furfural. To further illustrate the efficacy of the proposed method, thiourea was used as a substitute for urea, which also resulted in obtaining the desired products with satisfactory yields. This demonstrates the versatility and efficiency of the method across various chemical environments.

Reaction mechanisms illustrate the catalysts' roles in providing alternative pathways with lower activation energies, enhancing efficiency, selectivity, and reducing by-products. Understanding these mechanisms is essential for designing optimized and sustainable catalytic systems. Therefore, the following section will examine the mechanism of the 3,4-dihydropyrimidin-2(1H)-one/thione derivative synthesis in the presence of CuO/mGO-TA-Me-BTA nanoparticles. As shown in Fig. 9, the synthesis of 3,4-dihydropyrimidin-2(1H)-one/thione begins with the activation of aldehyde carbonyl groups (1) by the Lewis acidic copper (II) sites on the CuO/mGO-TA-Me-BTA catalyst. This activation, facilitated by CuO, creates an electrophilic center, which is subsequently attacked by the nitrogen atoms in urea or thiourea (3a-b). The nucleophilic attack, utilizing the lone electron pairs of nitrogen, followed by dehydration, forms an imine intermediate (9). In the next step, CuO plays a critical role in transforming the keto form of ethyl acetoacetate into its active enol form (2'). The nucleophilic enol then adds to the imine intermediate (9), resulting in the formation of intermediate 10. The final step involves an intramolecular nucleophilic attack by the amide nitrogens of urea or thiourea on the activated carbonyl group of ethyl acetoacetate, a process facilitated by CuO. This reaction, followed by dehydration, leads to the formation of the target 3,4-dihydropyrimidin-2(1H)-one/thione derivatives (4a-w)¹²⁵.

In the proposed mechanism, the roles of electron-donating and electron-withdrawing groups in accelerating the reaction are evident. Aromatic aldehydes with electron-withdrawing groups at the ortho or para positions show high reactivity in forming intermediates 8 and 9. These groups reduce the electron density on the carbonyl carbon, facilitating and speeding up the nucleophilic attack by urea or thiourea. Electron-withdrawing groups stabilize the partial positive charge on the carbonyl carbon, making it more electrophilic and prone to nucleophilic addition. This stabilization lowers the energy barrier for forming the tetrahedral intermediate, a key step in the mechanism, thus enhancing the reaction rate. In the next step, electron-withdrawing groups further reduce the electron density on the imine carbon, enabling a faster enol 2´ attack by increasing its electrophilicity.

Conversely, electron-donating groups increase the electron density on the carbonyl carbon, reducing its electrophilicity and slowing down nucleophilic attack. This decrease in reactivity highlights the contrasting effects of electron-donating and electron-withdrawing groups on reaction kinetics.

Fig. 9

Proposed mechanism for the synthesis of 3,4-dihydropyrimidin-2(1H)-one/thione derivatives in the presence of CuO/mGO-TA-Me-BTA nanoparticles.

As seen in the Fig. 10, the synthesis mechanism of 1,4-dihydropyridine derivatives (6a-m) is similar to that of the 3,4-dihydropyrimidin-2(1H)-one/thione, typically beginning with the activation of aromatic carbonyl aldehydes in the presence of copper oxide (CuO). In the first step, the activated carbonyl aldehyde, in the presence of an enolate system created from ethyl acetoacetate using copper oxide, forms the benzylidene intermediate 11 via a Knoevenagel condensation, making it a Michael acceptor. Here, CuO acts as a Lewis acid, activating the carbonyl group of the aldehyde and facilitating the condensation reaction. Meanwhile, the second mole of ethyl acetoacetate, once activated by copper oxide, undergoes a nucleophilic attack by ammonia, leading to the formation of the enaminone intermediate, referred to as intermediate 12. CuO plays a key role in stabilizing the enolate form of ethyl acetoacetate, enabling the nucleophilic attack by ammonia. Intermediate 13 is formed when enaminone 12 nucleophilically attacks the Michael acceptor, intermediate 11. The coordination of copper oxide as a Lewis acid with the carbonyl group of intermediate 11 is crucial in accelerating this reaction step. CuO enhances the electrophilicity of the carbonyl group, making it more susceptible to nucleophilic attack. Tautomerization of the imine-enamine and keto-enol forms takes place, converting the chemical structure of intermediate 13 into form 14. CuO facilitates this tautomerization by stabilizing the transition states involved in the process. Ultimately, the final product, 1,4-dihydropyridine skeletons (6a-m), are formed through intramolecular attack of the amine on the carbonyl group, cyclization, and elimination of one molecule of water. Similar to previous steps, copper oxide activates the carbonyl group, thereby accelerating the intramolecular attack of the amine and promoting cyclization¹²⁵.

A similar justification to the previous mechanism (Fig. 9) can be provided regarding the influence of electron-withdrawing and electron-donating groups on product (6a-m) formation in this mechanism.

Fig. 10

Proposed mechanism for the synthesis of 1,4-dihydropyridine derivatives in the presence of CuO/mGO-TA-Me-BTA nanoparticles.

Heterogeneous catalysts are renowned for their recyclability, a property that significantly enhances their practical and economic value. The recyclability of heterogeneous catalysts reduces waste generation, minimizes the need for frequent replacements, and lowers overall production costs. Additionally, their ability to maintain performance over extended use aligns with sustainable practices, making them essential in modern, eco-efficient industrial processes. To demonstrate the recyclability and reusability of the magnetic CuO/mGO-TA-Me-BTA catalyst, a model reaction for the preparation of derivatives 4a and 5a was repeated under optimal conditions for 6 runs. After each cycle, the magnetic catalyst was separated using an external magnetic field and washed several times with distilled water (2 × 5 ml) and ethanol (2 × 5 ml). After drying in an oven, the catalyst was used again in the next cycle. As shown in Table 4, after 6 cycles, a slight decrease in the yield of both reactions is observed, indicating the catalyst's robust stability and reusability. To ensure the purity and stability of the catalyst, a hot filtration test was performed during the reaction. The catalyst was removed from the reaction mixture at elevated temperature, and the filtrate was allowed to react further. The absence of significant reaction progress after catalyst removal confirmed that the catalysis was truly heterogeneous and not due to leached active species.

Table 4

Demonstrate the recyclability and reusability of the magnetic CuO/mGO-TA-Me-BTA catalyst.
Runs	1	2	3	4	5	6
Yield of 4a	96	94	94	93	90	88
Yield of 5a	96	96	93	91	88	87

Finally, to demonstrate the efficacy of synthesizing derivatives of the 4,3-dihydropyrimidinone and 4,1-dihydropyridine using the CuO/mGO-TA-Me-BTA nanocomposite, a comprehensive comparative study carried out. The catalytic performance of this nanocomposite was systematically compared with various catalytic systems introduced over the past few years. The results of this comparative analysis are summarized in Table 5, highlighting key performance metrics. The findings from this comparison reveal that the catalytic activity of CuO/mGO-TA-Me-BTA surpasses to most reported protocols. Specifically, it excels the amount of catalyst required, the yield of the products, the temperature and time needed for the reactions, and the simplicity of catalyst preparation. These advantages underscore the potential of CuO/mGO-TA-Me-BTA to enhance efficiency and cost-effectiveness in the synthesis of these important chemical derivatives.

Table 5

Comparative study of the efficiency of CuO/mGO-TA-Me-BTA nanoparticles with recent reports.
En.	Product	Reaction Conditions	Time (min)	Yield (%)	Ref.
1	4d	Fe₃O₄/pectin/(Co/Cu)MOF, 25 mg, Solvent-Free, 85 ^oC.	30	94	¹²⁷
		Fe₃O₄@SiO₂@GP/Picolylamine-Cu(II), 10 mg, Ethylen Glycol, 80 ^oC.	30	90	⁷³
		Nano-cellulose/BF₃/Fe₃O₄, 50 mg, EtOH, r.t. (3.5 equivalents of ethyl acetoacetate and urea)	6	87	⁷⁵
		Fe₃O₄@SiO₂@Trz–Cu, 5 mg, Solvent-Free, 100 ^oC.	60	75	¹²⁸
		Ni-phen MCM-41, 30 mg, EtOH, Reflux	120	72	¹²⁹
		Cu(II)montmorillonite clays, Ethanol, Reflux	12h	61	¹³⁰
		CuO/mGO-TA-Me-BTA, 10 mg, H₂O:EtOH (3:1), Reflux	15	90	This Work
2	6c	Cell-BCD hydrogel/GO/Cu₂O/Fe₃O₄, 2 mg, EtOH, 70 ^oC.	15	92	¹³¹
		CMC-g-poly(AA-co-AMPS)/Fe₃O₄ hydrogel nanocomposite, 10 wt%, Ultra Sonic, 40 ^oC.	10	98	¹⁰¹
		Cu/Cu₂O@g-C₃N₄, 5 mg, r.t, 5-watt white LED lamp.	40	96	¹³²
		HgFe₂O₄, 10 mol%, EtOH, Reflux	10h	85	⁹⁴
		Ch-RhomboclaseNCs, (1.8 mol%), Solvent free, 80 ^oC	40	92	¹³³
		Graphen oxide, 1.2 g, Water, Reflux	90	84	¹³⁴
		CuO/mGO-TA-Me-BTA, 10 mg, H₂O:EtOH (3:1), Reflux	15	95	This Work

4. Conclusion

In conclusion, the method for synthesizing diverse derivatives of 3,4-dihydropyrimidin and 1,4-dihydropyridine skeletons using CuO/mGO-TA-Me-BTA magnetic nanoparticles as a catalyst presents a significant leap forward in the field of organic synthesis. The innovative use of CuO/mGO-TA-Me-BTA nanoparticles as a catalytic system not only enhances reaction efficiency and selectivity but also aligns with the principles of green chemistry by offering an environmentally friendly alternative to traditional methods. These nanoparticles operate effectively under mild reaction conditions, that is crucial for preserving the integrity of sensitive functional groups in the substrates. Additionally, the magnetic nature of the catalyst allows for easy separation from the reaction mixture, making the process more economical by enabling catalyst recovery and reuse in multiple cycles without substantial activity loss. The ability of this method to produce a wide range of the 3,4-dihydropyrimidin and 1,4-dihydropyridine derivatives with high yields under these conditions underscores its potential for synthesis compounds with diverse biological activities, making it highly valuable in medicinal chemistry. Moreover, the structural diversity achieved through this method could facilitate the discovery of new pharmacophores and the development of novel therapeutic agents. In the broader context of material science, these synthesized compounds could serve as key building blocks for the creation of advanced materials with specific properties. Overall, using CuO/mGO-TA-Me-BTA magnetic nanoparticles in this synthetic approach not only contributes to the advancement of green and sustainable chemistry but also opens up new avenues for research and application in various scientific fields. This method, with its combination of efficiency, environmental consciousness, and broad applicability, is poised to have a lasting impact on the development of new synthetic strategies and the production of biologically significant molecules.

Data Availability

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

Supporting Information

The electronic supplementary information file, containing images and data from the NMR and FTIR analyses, has been prepared and submitted as a separate file.

Contributions

Dr. Mohammad Eslami

contributed to the conceptualization, formal analysis, investigation, and the writing of the original draft. Prof. Mohammad G. Dekamin was involved in writing, review, and editing, as well as visualization, validation, supervision, software, resources, project administration, methodology, investigation, funding acquisition, formal analysis, data curation, and conceptualization. Elham Mahdavi participated in writing the original draft, methodology, investigation, formal analysis, and data curation.

Conflict of interest

The authors declare that there are no conflicts of interest regarding the publication of this manuscript.

Acknowledgements

We are grateful for the financial support from The Research Council of Iran University of Science and Technology (IUST), Tehran, Iran (Grant No 160/24293) as well as the support of the Iran Nanotechnology Initiative Council (INIC), Iran. The partial financial support from The Research Council of Babol Noshirvani University of Technology, Babol, Iran is highly appreciated.

Electronic Supplementary Material

Below is the link to the electronic supplementary material

Supplementary Material 1

Author Contribution

Dr. Mohammad Eslami contributed to the conceptualization, formal analysis, investigation, and the writing of the original draft. Prof. Mohammad G. Dekamin was involved in writing, review, and editing, as well as visualization, validation, supervision, software, resources, project administration, methodology, investigation, funding acquisition, formal analysis, data curation, and conceptualization. Elham Mahdavi participated in writing the original draft, methodology, investigation, formal analysis, and data curation.

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Yes