Magnetic Nanoparticle-Catalysed One-Pot Multicomponent Reactions (MCRs): A Green Chemistry Approach

Abstract

The synthesis of heterocyclic compounds has gained significant attention in organic chemistry due to their diverse pharmacological properties. However, traditional synthetic approaches often involve hazardous chemicals, high energy consumption, and tedious workup procedures, leading to environmental concerns and low yields. In response, green chemistry strategies have emerged, emphasizing safer and more sustainable alternatives. Among these, magnetic nanoparticle (MNP)-based catalysts have shown remarkable promise in facilitating one-pot multicomponent reactions (MCRs), offering enhanced catalytic efficiency, ease of recovery, and reusability. This article provides a comprehensive overview of multicomponent reactions (MCRs) for the construction of a wide range of heterocyclic scaffolds—including chromenes, pyrazoles, phenazines, triazoles, tetrazoles, xanthenes, furans, indoles, imidazoles, pyridines, pyrimidines, oxazoles, and acridine derivatives—catalyzed by magnetic nanoparticles under sustainable and environmentally benign conditions. This review highlights recent advances (2018–2024) in the development and application of modified magnetic nanoparticles for green multicomponent synthesis. Emphasis is placed on their structural features, catalytic roles, and benefits in eco-friendly organic transformations.

1. Introduction

Nanoparticles (NPs) have attracted considerable interest in organic synthesis owing to their distinct physicochemical characteristics that set them apart from bulk materials. With sizes typically between 1 and 100 nm, NPs possess a high surface-to-volume ratio, which enhances their catalytic efficiency and makes them ideal supports for immobilizing homogeneous catalysts [1,2,3,4,5]. Among these nanomaterials, magnetic nanoparticles (MNPs) are especially appealing for catalytic applications due to their simple recovery using an external magnetic field, cost-effectiveness, high surface reactivity, and ease of use [6,7,8].

Despite their advantages, MNPs face certain limitations. They tend to aggregate due to anisotropic dipolar attractions, which impairs their dispersibility and catalytic efficiency [9]. Additionally, in acidic environments, MNPs are prone to degradation, resulting in the loss of their magnetic properties. These challenges can be overcome by coating MNPs with chemically stable and sustainable layers, creating core–shell nanostructures that enhance both stability and functionality [10,11].

In the context of green chemistry, catalysts play a central role in minimizing environmental impact. Ideal green catalysts must possess properties such as high activity, selectivity, low production cost, operational stability, and excellent recyclability [12]. Conventional catalysts fall into two categories: homogeneous and heterogeneous. Homogeneous catalysts offer high activity and selectivity, and their mechanisms can be studied in detail, allowing for precise optimization. However, their separation from reaction media is challenging, often leading to metal contamination—an issue particularly critical in the pharmaceutical industry [13,14,15].

On the other hand, heterogeneous catalysts are more environmentally benign due to their reusability and ease of separation, although they sometimes exhibit lower catalytic activity due to reduced surface interaction with substrates [16,17,18,19]. To address this trade-off, nano catalysts—especially MNP-based systems—offer a hybrid solution, combining the benefits of both catalyst types. The immobilization of homogeneous metal complexes onto MNPs enhances catalytic efficiency while allowing magnetic separation for reuse [20,21,22,23,24,25,26].

Multicomponent reactions (MCRs), which involve the combination of three or more reactants in a single reaction vessel to yield complex products, have emerged as an essential tool in synthetic chemistry [27]. MCRs offer several advantages: they are atom-economical, time-efficient, energy-saving, and environmentally friendly. These one-pot reactions reduce the need for multiple purification steps and minimize waste generation, aligning perfectly with the principles of green chemistry [28,29,30,31]. MCRs have found widespread applications in fields ranging from pharmaceutical development and drug discovery to materials science and chemical biology [32,33]. An ideal MCR allows all reagents, catalysts, and solvents to interact under unified conditions, streamlining synthesis and increasing overall efficiency [34,35]. The one-pot nature of these transformations enables the construction of complex molecular architectures with high yields, excellent regioselectivity, and product purity, making them especially attractive for the synthesis of bioactive compounds.

The growing field of green chemistry provides a framework for developing sustainable synthetic methodologies. As outlined by Anastas and Warner’s 12 principles of green chemistry, the focus is on reducing hazardous substances, improving energy efficiency, and using renewable feedstocks [36,37,38,39,40]. Several innovative green methods have been developed in recent years, including aqueous-phase organic synthesis [41], nanoparticle-catalyzed protocols [42], microwave-assisted techniques [43], and ultrasound-assisted reactions [44,45].

The integration of magnetic nano catalysts with multicomponent reactions is poised to emerge as a promising strategic research direction, offering an optimal platform for advancing sustainable approaches in green synthetic chemistry [46,47,48,49]. Between 2018 and 2024, a wide range of magnetic nano catalysts has been explored for use in MCRs. This review provides a comprehensive overview of recent advances in this area, emphasizing the design, functionalization, and catalytic applications of MNPs in green, one-pot multicomponent synthesis.

2. Magnetic Nanoparticle-Catalysed One-Pot Multicomponent Reactions

In this review, we present a comprehensive overview of various types of magnetic nano catalysts employed in one-pot multicomponent reactions (MCRs) for the synthesis of biologically active derivatives, highlighting the key advantages and green chemistry benefits of the reported methodologies.

2.1. Preparation of Pyrazole and Pyrano Pyrazole Derivatives

Pyrazoles represent a prominent class of heterocyclic compounds that hold significant potential in the development of novel pharmaceutical agents. Extensive research has revealed the presence of pyrazole moieties in numerous established drugs across diverse pharmacological categories, underscoring their versatility and medicinal relevance [50]. In recent years, pyrazole chemistry has garnered growing attention owing to the extensive array of biological activities revealed by its derivatives. These include antidiabetic [51], antibacterial [52], antioxidant [53], anticancer [54], antiviral [55], and antituberculosis [56] properties.

In 2020, Amirnejat co-workers. Ref. [57] developed a superparamagnetic nano catalyst, Fe₃O₄@alginate-supported L-arginine, representing a robust inorganic–organic hybrid system with heterogeneous and recyclable properties. The catalytic performance of this material was assessed in a one-pot cyclocondensation reaction involving malononitrile (1), aromatic aldehydes (2), and phenyl hydrazine (3) to synthesize annulated pyrazole derivatives (4). The reaction proceeded efficiently under mild conditions, delivering excellent yields between 90% and 97%, as illustrated in Scheme 1. The catalyst was recovered after the first run, washed with ethanol and acetone, dried, and reused for up to seven consecutive cycles without significant loss of activity.

In 2020, Nikpassand and co-workers [58] reported the synthesis of silica-coated NiFe₂O₄ nanoparticles functionalized with amino glucose, yielding a magnetically separable and reusable nano catalyst. This catalyst demonstrated excellent efficiency in a multicomponent reaction involving pyrazole carbaldehydes (5), semicarbazide (6), and alcohols (7), leading to the formation of novel 3-pyrazolyl-4H-1,2,4-triazole derivatives (8) with excellent yields ranging from 89% to 95% (Scheme 2). After the reaction, the catalyst was recovered, washed with warm ethanol, dried at 80 °C, and reused under identical conditions. NiFe₂O₄@SiO₂-nPr@aminoglucose demonstrated excellent reusability, retaining its activity over six consecutive cycles without significant loss. The protocol aligns well with green chemistry principles and offers notable advantages such as high yields, magnetic recovery, catalyst recyclability, environmental benignity, and reduced waste generation.

In 2024, Ramezaninejad and co-workers [59] introduced a novel magnetic heterogeneous nano catalyst synthesized by co-precipitating tris (hydroxymethyl)aminomethane with MgFe₂O₄ nanoparticles. The catalytic performance of this nanomaterial was demonstrated in the one-pot multicomponent synthesis of pyrazolo[3,4-d]pyrimidine derivatives (13) via the reaction of barbituric acid (10), aromatic aldehydes (9), hydrazine hydrate (12), and ethyl acetoacetate (11), using water as a green solvent at room temperature (Scheme 3). The protocol afforded excellent yields ranging from 80% to 98%, under mild and environmentally friendly conditions. The reusability was evaluated and the catalyst maintained consistent performance over five cycles with no significant loss in activity. A key advantage of this methodology is the magnetic separability of the catalyst, allowing for easy recovery and reuse.

Ghasemzadeh and co-workers [60] (2019) developed Fe₃O₄@L-arginine nanocomposite as an efficient heterogeneous catalyst for the solvent-free, room-temperature multicomponent synthesis of spirooxindole derivatives (18) (Scheme 4). The reaction involved isatins (14), β-keto esters (15), hydrazine (16), and ethyl cyanoacetate or malononitrile (17) in a one-pot fashion. The catalyst demonstrated excellent reusability, retaining its activity over at least five cycles. This green and operationally simple method offers a sustainable alternative to traditional multi-step syntheses, highlighting the advantages of solid-supported nano catalysis.

In 2020, Hosseini Mohtasham [61] and co-workers synthesized a high surface area nanomesoporous silica using horsetail (Equisetum arvense), a medicinal plant, as a natural silica source. This bio-derived silica served as a platform for the development of a highly efficient magnetically retrievable solid acid catalyst, Fe₃O₄@SiO₂−EP−NH−HPA, by immobilizing H₃PW₁₂O₄₀ (a heteropoly acid) onto aminated epibromohydrin-functionalized Fe₃O₄@SiO₂ nanoparticles. This catalyst exhibited excellent performance in the one-pot synthesis of pyrano−pyrazole derivatives (23) by reacting hydrazine hydrate (19), ethyl acetoacetate (20), various benzaldehyde (21) and malononitrile (22) in aqueous media at room temperature, affording excellent yields ranging from 89% to 99%, as illustrated in Scheme 5.

2.2. Preparation of Pyrano-Phenazine Derivatives

Phenazines constitute a broad class of nitrogen-containing heterocyclic compounds [62] and are recognized as key structural elements in various bacterial species [63,64]. Both naturally occurring and synthetically derived phenazine compounds have been extensively studied for their diverse biological properties. These include antimalarial [62], trypanocidal [65], fungicidal [66], antiplatelet [67], and antiphrastic activities [62]. Moreover, phenazines are known for their strong DNA intercalating capabilities and have demonstrated significant antitumor potential, particularly against leukemia and various solid tumors [68].

In 2020, Taheri and co-workers [69] reported the synthesis of a sulfonic acid-functionalized magnetic nano catalyst, Fe₃O₄@TiO₂-SO₃H, and evaluated its catalytic performance in the one-pot multicomponent synthesis of pyrazolo[4′,3′:5,6]pyrano[2,3−c]phenazin−15−yl)methanone derivatives (28). The reaction involved 5-methyl-2-phenyl-2,4-dihydro-3H-pyrazol-3-one (24), benzene−1,2−diamine (25), 2−hydroxynaphthalene−1,4−dione (26), and aryl glyoxal (27) under microwave irradiation, affording the desired products in high yields ranging from 80% to 91%, as illustrated in Scheme 6. Furthermore, the antibacterial properties of the synthesized compounds were evaluated, with most exhibiting promising activity against Gram-positive Staphylococcus aureus, highlighting their potential as bioactive agents.

In 2018, Esmaeilpour and co-workers [11] developed an efficient, environmentally benign, and cost-effective method for the synthesis of poly-substituted benzo[a]pyrano[2,3-c]phenazine derivatives (33) via a four-component reaction involving aldehydes (29), diamines (30), malononitrile (31), and 2−hydroxynaphthalene−1,4−dione (32), catalysed by a Fe₃O₄-based magnetic nano catalyst under reflux conditions (Scheme 7). The reaction progressed efficiently, reaching completion within 20–60 min and yielding the desired products in excellent yields of 81–95%. The reusability studies demonstrated that the catalyst could be effectively reused for five consecutive cycles without any significant loss in catalytic activity. The use of this recyclable nano catalyst was associated with a short reaction time and high efficiency.

2.3. Preparation of Pyran Derivatives

Pyran-based compounds are pharmacologically active heterocycles known for their diverse therapeutic applications. They have been reported to exhibit antitubercular [64], antifungal [70], antidiabetic [71], antibacterial [72], calcium channel antagonistic [73], anticancer [74], and anti-HIV activities [75]. Notably, a novel pyran-based phosphodiesterase 9A inhibitor has shown promising efficacy in the treatment of neurodegenerative disorders [76], in addition to demonstrating insulin-sensitizing properties [77].

Ahankar and co-workers [78] (2020) reported a green synthesis of Ni_0.5Cu_0.5 Fe₂O₄ MNPS magnetic nanoparticles (MNPs) using Arabic gum as a natural, non-toxic template and stabilizing agent. These MNPs served as efficient nano catalysts for a one-pot, multi-component synthesis of tetrahydropyran derivatives (37) (Scheme 8) via the reaction of dimedone (34), aldehydes (35), and malononitrile (36) under solvent-free, microwave-assisted conditions. The method afforded excellent product yields ranging from 82% to 97%.

In 2018, Maleki and co-workers [79] developed and characterized a magnetic bio-nanocomposite based on chitosan, which was subsequently utilized as an efficient heterogeneous catalyst for the one-pot multicomponent synthesis of various heterocyclic compounds. The nano catalyst facilitated the synthesis of 2-amino-4H-pyrans (46) via the reaction of aryl aldehydes (38), malononitrile (41), and ethyl acetoacetate (43); 2-amino-4H-chromene derivatives (45) through the reaction of dimedone (39), aryl aldehydes (38), and malononitrile (41); and polyhydroquinoline derivatives (42 & 44) using aryl aldehydes (38), malononitrile (41), ammonium acetate (40) and ethyl acetoacetate (43) or dimedone (39), all under mild conditions at room temperature in ethanol as a green solvent (Scheme 9). This methodology offers several advantages, including the use of a non-toxic, biodegradable catalyst, easy magnetic separation, recyclability up to seven runs, and high yields making it a promising green synthetic protocol for heterocyclic scaffolds.

In 2019, Aghajani and co-workers [80] developed Fe₃O₄ nanoparticles functionalized with a molybdenum Schiff base complex, named MoO₂5CML@Fe₃O₄@SiO_2, and utilized them as an efficient nanocatalyst for the solvent-free synthesis of 2-amino-4H-benzo[h]chromene derivatives (50). This one-pot condensation reaction of benzaldehyde (47), 1-naphthol (48), and malononitrile (49) produced the target compounds in excellent yields ranging from 81% to 98%, as depicted in Scheme 10. Furthermore, the catalyst demonstrated good reusability, maintaining significant catalytic activity over at least seven consecutive reaction cycles with minimal loss of performance.

Nikpassand and co-workers [81], in 2020, synthesized silica-coated Fe₃O₄ nanoparticles functionalized with tannic acid (Fe₃O₄@SiO₂@Tannic acid), adhering to green chemistry principles. These magnetically separable nanocatalysts were employed in a solvent-free and environmentally benign synthesis of 1,3-oxazine-2-thione derivatives (54) through a multicomponent reaction involving thiourea (51), aldehydes (52), and β-naphthol (53), carried out by manual grinding using a mortar and pestle. After the reaction, the mixture was dissolved in hot ethanol, and the catalyst was magnetically separated. The method afforded excellent product yields ranging from 87% to 94% (Scheme 11), highlighting its efficiency, eco-friendliness, and potential for sustainable organic synthesis.

2.4. Preparation of Furan Derivatives

Furans are significant structural motifs frequently present in numerous natural products and pharmaceutical agents [82]. A wide array of furan-containing compounds has exhibited diverse biological activities, such as antitumor [83], antioxidant [84], anticancer [85], antifungal [86], antiplasmodial [87], and anti-inflammatory [88] as well as anti-HIV and estrogenic properties [89].

In 2020, Shirzaei and co-workers [90] reported the synthesis of functionalized furan derivatives (58) via a one-pot multicomponent reaction using equimolar amounts of dialkyl acetylene dicarboxylic acid (55), aromatic aldehydes (56), and amines (57), catalysed by a reusable nano catalyst, Fe₃O₄@SiO₂(CH₂)₃-thiocarbohydrazide–SO₃H (Scheme 12). The reaction was performed at room temperature in ethanol, a green solvent, with reaction times ranging from 19 to 51 min. The catalyst’s reusability was evaluated using magnetic separation, it was washed, dried, and reused for seven consecutive runs, showing no significant loss of activity compared to the fresh catalyst. The protocol yielded excellent product yields in the range of 89–97%. Key advantages of this method include mild reaction conditions, the use of non-toxic ethanol as a solvent, and the facile magnetic separation and recyclability.

Ahankar and co-workers [91] reported the use of silica-coated iron oxide magnetic nanoparticles functionalized with tetramethylguanidine (Fe₃O₄-TMG) as a green, efficient, and recyclable catalyst for the three-component, one-pot synthesis of furanone derivatives (62) (Scheme 13). The reaction involved aniline (61), dialkyl acetylenedicarboxylate (59), and aromatic aldehydes (60), carried out in ethanol at 40 °C for 10 to 13 h. Fe₃O₄-TMG was reused for five cycles with consistent yields (91–92%), showing excellent stability and catalytic performance. This method stands out for its high efficiency, excellent product yields ranging from 85% to 92%, environmentally friendly reaction conditions, and easy magnetic separation and reuse of the nano catalyst.

2.5. Preparation of Xanthene Derivatives

Xanthenes are a class of oxygen-containing heterocyclic compounds that are commonly found in natural products, synthetic bioactive molecules, and fluorescent dyes [92]. The xanthene core structure imparts a wide range of physicochemical and pharmacological properties. Compounds bearing this scaffold have demonstrated diverse biological activities, including antiviral [93], analgesic [94], antibacterial [95], anti-inflammatory [96], and anticancer [97].

In 2018, Arzehgar and co-workers [98] developed silver-functionalized hydroxyapatite-coated magnetic γ-Fe₂O₃ nanoparticles (γ-Fe₂O₃@HAp–Ag) and employed them as a magnetically recoverable, environmentally friendly, and reusable catalyst. Their catalytic efficiency was demonstrated in the solvent-free synthesis of aryl-dibenzo-xanthenes (65) through the condensation of substituted benzaldehydes (64) with β-naphthol (63) at 60 °C (Scheme 14). The reaction without the catalyst yielded no product. Furthermore, the magnetically separable MNP catalyst was reused for seven cycles with no significant loss in its initial catalytic activity.

In 2019, Sonei and co-workers [99] developed a magnetically reusable nano catalyst by immobilizing Cu(II) onto Fe₃O₄@APTMS-DFX nanoparticles. This catalyst was effectively utilized for the solvent-free synthesis of substituted 8,9,10,12-tetrahydrobenzoxanthen-11-one derivatives (69) via a three-component reaction involving 2-naphthol (67), dimedone (68), and aromatic aldehydes (66) at 120 °C, achieving excellent yields ranging from 80% to 97% (Scheme 15). Further, the reaction was carried out under solvent-free conditions at 120 °C without any catalyst, yielding only 14% after 24 h. The catalyst was successfully recycled for six runs without appreciable copper leaching from its surface. The method offers several advantages, including short reaction times, high product yields, straightforward work-up, and simple purification through recrystallization.

2.6. Preparation of Imidazole Derivatives

Nitrogen-containing aromatic heterocyclic compounds, particularly imidazoles, have attracted considerable attention in both academic and industrial research due to their wide spectrum of biological and pharmacological activities [100]. Imidazole scaffolds play a crucial role in the design and synthesis of biologically active molecules [101], contributing to the development of therapeutic agents with anticancer [102], anticoagulant [103], anti-inflammatory [104], antitubercular [105], antimicrobial [106], antimalarial [107], and antioxidant [108] properties.

In 2021, Sakhdari and co-workers [109] reported the synthesis and application of magnetic nanoparticle-supported sulfonic acid (γ-Fe₂O₃–SO₃H) as an efficient and reusable catalyst for the preparation of imidazole derivatives (Scheme 16). The catalyst facilitated the formation of 1,2,4,5-tetrasubstituted imidazoles (75) via a one-pot four-component reaction involving ammonium acetate (72), aldehydes (71), benzil (70), and amine (74) derivatives, as well as 2,4,5-trisubstituted imidazoles (73) through a three-component reaction using benzil (70), aldehydes (71), and ammonium acetate (72). The reactions proceeded rapidly, with tetrasubstituted imidazoles forming in 30–40 min and trisubstituted imidazoles in 40–70 min. The method afforded excellent yields, ranging from 94–98% for tetrasubstituted and 92–98% for trisubstituted imidazole derivatives, highlighting the catalyst’s high efficiency and selectivity.

In 2020, Khalifeh and co-workers [110] developed a novel core–shell structured, green, and recyclable nano catalyst, Fe₃O₄@SiO₂−EPIM, synthesized by modifying Fe₃O₄@SiO₂ with 1-methylimidazole and epichlorohydrin. The catalytic activity of this material was evaluated in the one-pot synthesis of trisubstituted imidazoles (79) using a condensation reaction between aldehydes (76), benzil (78), and ammonium acetate (77) in polyethylene glycol (PEG−200) as a green solvent. The reaction proceeded efficiently, affording the desired imidazole derivatives in moderate to excellent yields ranging from 57% to 98%, as shown in Scheme 17. After each reaction, the catalyst was separated, washed, dried, and reused under identical conditions. It retained high activity over six runs, confirming excellent stability. The catalyst demonstrated environmentally friendly features, including ease of recovery, reusability, and high efficiency under mild reaction conditions.

2.7. Preparation of and Indole Derivatives

The indole core, a well-established pharmacophore in medicinal chemistry, is a versatile heterocyclic scaffold known for its broad range of biological activities [111]. Indole-containing compounds have demonstrated diverse pharmacological properties, including anticancer, antifungal, anti-HIV, anti-inflammatory, antiviral, antitubercular, and antimicrobial activities [112]. Additionally, they exhibit antihypertensive [111], antidiabetic [113], and photochemotherapeutic effects [114], making the indole nucleus a valuable structural motif in the development of new therapeutic agents.

In 2018, Esmaeilpour and co-workers [11] reported a green, single-step multicomponent synthesis of spirooxindole derivatives (83) using ethyl cyanoacetate or malononitrile (82), 5-amino-1,3-dimethyluracil (80), and isatin (81), catalyzed by a Fe₃O₄@SiO₂-TCT-theophylline nanomagnetic catalyst under reflux conditions in water as a green solvent (Scheme 18). The protocol successfully yielded twelve spirooxindole derivatives with excellent yields ranging from 90% to 95%, within a reaction time of 6 to 12 h. After the reaction, the mixture was cooled, and the catalyst was magnetically separated, washed with hot ethanol, dried, and reused. It maintained its activity over five consecutive cycles without significant loss.

Safari and co-workers [115] (2019) reported the synthesis of indeno[1,2-b]indole derivatives (87) using montmorillonite (MMT)-supported Fe₃O₄ magnetic nanoparticles (MMT@Fe₃O₄) as a heterogeneous catalyst (Scheme 19). The reaction involved aromatic amines (84), 1,3-dicarbonyl compounds such as 1,3-cyclohexadione or dimedone (85), and ninhydrin (86), carried out in water at 70 °C with stirring for 20–40 min. After the reaction, the catalyst was magnetically separated, washed, air-dried, and reused with fresh substrates for six runs without significant loss of activity.

Nongthombam and co-workers [116] (2023) developed a novel acidic ionic liquid supported on ferrite nanoparticles, designated as Fe₃O₄@PCmIm-HSO₄, and employed it as an efficient heterogeneous nano catalyst for the synthesis of bis (indolyl) alkane derivatives (90) (Scheme 20). The reaction involved indole or 2-methylindole (88) and aliphatic or aromatic carbonyl compounds (89), carried out in an ethanol–water mixture at room temperature, yielding products in the range of 83% to 93%. Upon completion, the catalyst was magnetically separated, washed with water and diethyl ether, dried at room temperature, and reused. It retained its catalytic activity for at least six cycles without significant loss. This method offers a green and sustainable approach, and easy magnetic recovery.

2.8. Preparation of Pyridine Derivatives

Pyridine derivatives are a particularly interesting type of heterocycles that can be found in both synthetic and natural molecules. The pyridine ring system is frequently used in responsive pharmacophores, sustainable agrochemicals, cosmetics, and biomimetic applications in addition to being present in bioactive compounds [117]. A wide range of biological and pharmacological activities are also displayed by pyridine-containing heterocyclic compounds, such as antimicrobial [118], antiviral [119], antioxidant [120], antidiabetic [121], anticancer [122], antimalarial [123], and anti-inflammatory [124].

Maleki and co-workers [125] (2018) developed a novel nanomagnetic organocatalyst, Fe₃O₄@SiO₂@propyltriethoxysilane@L-proline (LPSF) and evaluated its catalytic efficiency in the solvent-free synthesis of 2,4,6-triarylpyridine derivatives (94). The reaction was carried out via a three-component condensation of acetophenones (91), various benzaldehydes (92), and ammonium acetate (93) under stirring at 60 °C, affording good to excellent yields (75–94%) as illustrated in Scheme 21. To assess the recyclability of the catalyst, it was magnetically separated, washed with ethanol and water, dried, and reused. It maintained high activity over seven cycles without significant loss in product yield.

Thrilokraj and co-workers [126] (2024) reported a green and cost-effective biogenic synthesis of Fe₃O₄ nanoparticles using Bacopa monnieri (Brahmi) extract. The catalytic efficiency of the biosynthesized Fe₃O₄ NPs was evaluated in a solvent-free multicomponent reaction involving benzaldehyde (95), malononitrile (96), acetophenone (97), and ammonium acetate (98) for the synthesis of 2-amino-3-cyanopyridine derivatives (99). The reaction proceeded smoothly under mild conditions, affording the desired products in excellent yields ranging from 79% to 91%, as illustrated in Scheme 22. The reaction without the catalyst resulted in a poor yield. This approach highlights the potential of plant-mediated magnetic nanoparticles as eco-friendly and efficient catalysts for green organic transformations.

Maleki [127] and co-workers (2020) reported a novel and environmentally friendly method for synthesizing polyfunctionalized pyridines (103) using a magnetic Fe₂O₃@Fe₃O₄@Co₃O₄ nanocomposite as a catalyst. The reaction was carried out under solvent-free conditions via a multicomponent coupling of malononitrile (101), various aldehydes (100), and ammonium acetate (102), affording products in excellent yields ranging from 78% to 97%, as shown in Scheme 23. Furthermore, the same reaction using Co₃O₄ yielded the product in low amounts after 2 h, while Fe₂O₃ and Fe₃O₄ gave only trace yields. The catalyst is magnetically separable and reusable for up to four runs without loss of activity. This method offers high yields, operational simplicity, a straightforward workup, broad applicability, and minimal environmental impact owing to its solvent-free conditions.

In 2019, Rakhtshah [128] and co-workers developed a novel manganese Schiff base complex supported on chitosan-coated iron oxide magnetic nanoparticles (Fe₃O₄@CSBMn). This magnetically recoverable nano catalyst was applied in a multicomponent reaction involving trimethylsilyl cyanide (105), aldehydes (106), and 2-aminopyridine (104) for the synthesis of 3-iminoaryl-imidazo-pyridine derivatives (107), as depicted in Scheme 24. Furthermore, using silica-sulfuric acid as the catalyst gave a low yield even after 3 days. The protocol yielded the desired products in high yields (85–97%) within short reaction times (10–35 min). Although the catalyst exhibited good reusability, recycling studies revealed a noticeable decline in catalytic activity after six cycles.

In 2020, Ahadi and co-workers [129] designed and synthesized a heterogeneous magnetic nano catalyst, MNP@BSAT@Cu(OAc)₂, by functionalizing manganese ferrite (MnFe₂O₄) nanoparticles with a Schiff base encapsulated in a silica shell, followed by coordination with copper acetate. The catalytic efficiency of the nanocomposite was evaluated in a one-pot multicomponent reaction involving dimedone (108), benzaldehyde (111), ethyl acetoacetate (110), and ammonium acetate (109) for the synthesis of 1,4-dihydropyridine derivatives (112). The method afforded excellent yields ranging from 80% to 97%, as shown in Scheme 25. The reaction was also performed in the absence of a catalyst and low yield of product was obtained in a prolonged reaction time. Post-reaction, the catalyst was separated using a magnet, washed with ethanol, dried, and reused. It remained effective for five cycles without significant activity loss.

In 2021, Maleki and co-workers [130] developed a convenient and eco-friendly nano catalyst by supporting glutathione on magnetic Fe₃O₄ nanoparticles. This catalyst was successfully applied in the synthesis of a wide range of 1,4-dihydropyridine derivatives (116 & 119) via a multicomponent reaction involving benzaldehyde (113), ammonium acetate (114), ethyl acetoacetate (115), and dimedone (117) under solvent-free conditions at 110 °C (Scheme 26). Furthermore, the nano-FGT catalyst was employed for the solvent-free synthesis of acridines (118) via the reaction of various aldehydes (113), ammonium acetate (114), and dimedone (117), affording yields of 81–92%. Furthermore, control experiments confirmed that nano-FGT outperformed unfunctionalized nanoparticles and glutathione alone, which yielded significantly less product. After the reaction, nano-FGT was magnetically separated, dried at 50 °C, and reused three times in the same reaction, consistently yielding similar results in each cycle.

Bodaghifard [131] (2020) introduced silica-coated Fe₃O₄ nanoparticles functionalized with bis-sulfamic acid (MNPs-TBSA), forming a unique inorganic-organic core–shell magnetic nanostructure, as an efficient and reusable heterogeneous acidic catalyst. The catalytic potential of this nanomaterial was demonstrated in the green synthesis of pharmaceutically relevant polyhydroquinoline derivatives (124) via a multicomponent condensation of ethyl acetoacetate (120), dimedone (121), various benzaldehydes (122), and ammonium acetate (123) in ethanol at 70 °C (Scheme 27). Furthermore, the same reaction without a catalyst yielded only ~17% after 90 min. This protocol provided high yields (89–95%) and offered several advantages, including mild reaction conditions, simple work-up, exceptional product purity, short reaction times, and catalyst recyclability.

In 2019, Bodaghifard [132] reported the development of a retrievable heterogeneous catalyst based on 4-aminoquinaldine embedded on silica-coated nano-Fe₃O₄ particles (MNPs-AQ). The catalytic performance of MNPs-AQ was evaluated in the eco-friendly, one-pot multicomponent synthesis of substituted 1,4-dihydropyridine derivatives (129) via the reaction of ethyl acetoacetate (127), malononitrile (125), various benzaldehydes (128), and ammonium acetate (126) under reflux in a H₂O/EtOH mixture, as shown in Scheme 28. Further, performing the same reaction without a catalyst in refluxing ethanol gave only 23% yield after 90 min. This method offered several advantages over conventional approaches, including high yields (83–97%), exceptional product purity, shorter reaction times, and environmental compatibility, along with easy magnetic recovery and reusability of the catalyst.

2.9. Preparation of Pyrimidine and Acridine Derivatives

Heterocyclic compounds are of significant biological interest due to their diverse chemical and physical properties [133]. Among them, pyrimidine derivatives have garnered considerable attention for their wide range of pharmacological activities, including antimicrobial [134] analgesic [135], anticancer [136], antioxidant [137], anti-inflammatory [138], and anti-HIV properties [139]. Although several synthetic routes for pyrimidines have been established for decades, the development of more economical, efficient, and environmentally benign methods remains an area of substantial importance [140,141].

In 2021, Rostami [142] co-workers. developed a reusable heterogeneous magnetic nano catalyst, CoFe₂O₄@SiO₂-PA-CC-guanidine-SA, for green organic synthesis. The catalyst was applied in the one-pot synthesis of pyrido[2,3-d:5,6-d’]dipyrimidine derivatives (133) via a multicomponent reaction of benzaldehyde (130), thiobarbituric acid or barbituric acid (132), and ammonium acetate (131) in water at room temperature. The process afforded high product yields ranging from 86% to 95%, as shown in Scheme 29. The use of water as a solvent, ambient conditions, and the magnetic recyclability of the catalyst underscore the method’s environmental and operational advantages.

In 2023, Sayahi and co-workers [143] synthesized a novel and eco-friendly magnetic nano catalyst, SPION@CS-IL, by modifying chitosan-functionalized ionic liquids with iron oxide nanoparticles. This heterogeneous, reusable catalyst was effectively employed for the synthesis of pyrido[2,3-d]pyrimidine derivatives (137) via a three-component, one-pot reaction involving 4-hydroxycoumarin (134), thiobarbituric acid (135), and various aldehydes (136), conducted in ethanol solvent using ultrasonic-assisted method to produce 84–92% yield (Scheme 30). This methodology offers numerous advantages, including short reaction times, low catalyst loading, absence of toxic reagents, and recyclability of the catalyst for up to five cycles without significant loss of activity.

In 2021, Karimi and co-workers [144] reported the use of magnetic nanoparticles functionalized with 3-(propylthio)propane-1-sulfonic acid as an efficient heterogeneous catalyst for the solvent-free synthesis of various tetrazole-fused heterocycles (Scheme 31). The catalyst demonstrated excellent activity in the one-pot synthesis of dihydro-tetrazolo[1,5-a]pyrimidine derivatives (141) via the reaction of aldehydes (138), acetophenone (140), and 5-aminotetrazole (139), carried out under stirring at 70 °C. Additionally, it was applied to the synthesis of tetrahydro-tetrazolo[5,1-b]quinazolinone derivatives (145) from dimedone (144), aryl aldehydes (138), and 5-aminotetrazole (139), and to the formation of dihydro-tetrazolo[1,5-a]pyrimidine-6-carboxylate (143) derivatives using 5-aminotetrazole (139), aryl aldehydes (138), and ethyl acetoacetate (142). All reactions proceeded efficiently within 15–30 min, affording high yields. Further, under identical conditions without a catalyst, only trace yield was obtained after 60 min. Key advantages of this protocol include solvent-free conditions, short reaction times, excellent yields, and magnetic recoverability of the catalyst, making it a standout method in the field of sustainable synthesis.

In 2021, Wenxin and co-workers [145] successfully synthesized SnCl₂-grafted magnetic nanoparticles (SnCl₂@MNPs) via a co-precipitation method, where the core–shell structure was achieved through alkali-catalyzed hydrolysis of tetraethyl orthosilicate. The catalytic efficiency of SnCl₂@MNPs was evaluated through the Biginelli reaction, a one-pot, three-component synthesis of 3,4-dihydropyrimidinones (149) (Scheme 32). This transformation involved the condensation of thiourea or urea (147), aromatic or heterocyclic aldehydes (148), and α,β-dicarbonyl compounds (146), affording the desired products in excellent yields ranging from 82% to 96%.

In 2020, Alishahi and co-workers [146] developed a novel acidic nicotine-based ionic liquid immobilized on magnetic nanoparticles, denoted as [NicTC]HSO₄@MNPs. The catalytic performance of this material was evaluated in a multicomponent reaction involving β-ketoesters (152), 2-aminobenzothiazole (150), and various benzaldehydes (151) for the synthesis of mono- and pyrimido-benzothiazole derivatives (153). The reaction proceeded efficiently, yielding the target compounds in 69–83%, as illustrated in Scheme 33. Further, under identical conditions without a catalyst, no product was obtained even after 7 h. This approach offers several advantages, including short reaction times, high product yields, simple work-up procedures, elimination of hazardous organic solvents, and excellent catalyst recyclability.

Verma and co-workers [147], in 2020, developed a green biocatalyst based on starch-functionalized magnetite nanoparticles (s-Fe₃O₄) for use under ultrasonic irradiation conditions. This eco-friendly catalyst was employed in a multicomponent reaction involving benzaldehyde (154), malononitrile (155), and 2-aminobenzimidazole (156) in water as a green solvent to synthesize imidazole-pyrimidine derivatives (157). The method yielded excellent results, with product yields ranging from 91% to 98% (Scheme 34). Under the same reaction conditions, ultrasound irradiation of the reaction mixture without a catalyst resulted in no product formation. The use of ultrasonic irradiation significantly enhanced the reaction rate and efficiency, making this protocol both environmentally sustainable and operationally simple.

Saberikhah [148] and co-workers synthesized a series of pyrido[2,3-d] pyrimidine derivatives (161 & 163) using an organic-inorganic hybrid magnetic nano catalyst, Fe₃O₄@TiO₂@NH₂@PMo₁₂O₄₀. The catalyst was employed in a three-component reaction involving malononitrile (160), 6-amino-2-(thio or alkylthio) pyrimidinone (158 & 162), and various aryl aldehydes (159) in water at 80 °C, affording excellent yields (92–98%) within short reaction times (5–15 min), as illustrated in Scheme 35. Further, under the same reaction conditions without a catalyst, no product was obtained even after 30 h. Notably, the catalyst could be efficiently separated using an external magnet and reused for up to eight consecutive cycles without significant loss of activity.

In 2022, Taheri Hatkehlouei [149] and co-workers developed sulfonated magnetic nanoparticles (Fe₃O₄@C@OSO₃H) and employed them as efficient catalysts for solvent-free Biginelli reactions involving β-dicarbonyl compounds (164 & 166), aromatic aldehydes (162), and urea or thiourea (163). This protocol led to the synthesis of biologically active 3,4,5,6-tetrahydropyrimidinone/thione and 3,4-dihydropyrimidinone/thione derivatives (165 & 167) with excellent yields ranging from 80% to 97%, as illustrated in Scheme 36. Furthermore, under identical conditions without the catalyst, only trace amounts of the product were observed, with most of the starting materials remaining unreacted even after prolonged reaction time. Additionally, the nanoparticles were easily separated magnetically and Fe₃O₄@C@OSO₃H was efficiently recycled for seven runs with minimal loss of catalytic activity. The method features several advantages, including a simple and eco-friendly work-up, high product yields, short reaction times, and easy magnetic recovery of the catalyst for potential reuse.

Ghafuri and co-workers [150] (2021) reported the use of Fe₃O₄@Polyaniline-SO₃H as a reusable, heterogeneous nano catalyst for the rapid and efficient green synthesis of acridine dione derivatives (171) (Scheme 37). The reaction was performed under reflux conditions in ethanol using ammonium acetate (170), dimedone (169), and aromatic aldehydes (168), with a remarkably short reaction time of 10–15 min and excellent product yields ranging from 90% to 98%. The nano catalyst can be easily retrieved from the reaction mixture using a magnet and reused for six cycles without any noticeable decline in its catalytic performance. Key advantages of this methodology include excellent yields, ease of product isolation, and a short reaction time.

In 2021, Mousavi and co-workers [151] developed magnetically recoverable graphene-based nanoparticles (MSrGO NCs) as an efficient catalyst for the synthesis of acridine derivatives (175 & 177). The reaction was carried out under solvent-free conditions using aromatic amines (174) or ammonium acetate (176), dimedone (172), and aromatic aldehydes (173), yielding the desired products with high efficiency (Scheme 38). The reaction carried out without any catalyst at room temperature showed no progress even after 48 h. Furthermore, the MSrGO NCs demonstrated excellent reusability, maintaining their catalytic efficiency over seven consecutive cycles without significant loss of activity. These protocols offer notable advantages such as operational simplicity, low catalyst loading, better control over reaction conditions, shorter reaction times, and high product yields.

2.10. Preparation of Azole and Propargylamine Derivatives

“Azole” is a general term referring to five-membered heterocyclic rings—such as triazole, tetrazole, pentazole, oxazole, thiazole, and isoxazole-that contain at least one nitrogen atom and other heteroatoms [152,153,154]. Numerous azole-based sulfonamide inhibitors have been developed, particularly triazole-based antifungal agents like fluconazole, voriconazole, posaconazole, itraconazole, and isavuconazole, as well as imidazole-based drugs including ketoconazole, miconazole, and clotrimazole [153,154]. These triazole antifungal agents are employed for the treatment and prevention of both superficial and systemic fungal infections [155].

In 2021, Mirshafiee [156] and co-workers reported the synthesis and characterization of magnetic nanoparticles modified with copper iodide supported on 3-thionicotinyl-urea (MNPs@ThNU-CuI). The structure and composition of the catalyst were confirmed using various analytical techniques. Its catalytic performance was evaluated through a one-pot multicomponent reaction involving sodium azide (180), aryl halides (178), and terminal alkynes (179) to synthesize 1,2,3-triazole derivatives (181). The reaction was conducted in a deep eutectic solvent (DES) composed of PEG and choline chloride, which served as an environmentally friendly and recyclable medium. After each cycle, the catalyst was magnetically separated, washed, vacuum-dried at 70 °C, and reused. MNPs@ThNU-CuI maintained its activity over five cycles with no significant loss. This method afforded triazoles in good to excellent yields (69–94%), as shown in Scheme 39.

Eisavi and co-workers [35] (2021) introduced a MgFe₂O₄/Cu nanocomposite as a simple and efficient nano catalyst for the regioselective synthesis of β-thiol-1,4-disubstituted-1,2,3-triazole derivatives (185) (Scheme 40). The reaction was carried out via a three-component protocol involving thiirane (182), alkynes (183), and sodium azide (184) in water under magnetic stirring at 60 °C for 2–4 h to produce triazole derivatives from 80 to 95% yield. Both the nano catalyst and the synthesized triazole derivatives were reported as novel, representing a completely new synthetic approach. The nanoparticles were easily recovered using a magnet, washed with ethyl acetate and water, dried, and reused for six cycles without significant loss of activity. This methodology offers several notable advantages, short reaction times, high yields, use of a green solvent (water), and recyclability of the catalyst.

In 2019, Soleimani-Amiri [157] and co-workers reported a green synthesis of magnetic iron oxide nanoparticles (Fe₃O₄-MNPs) using orange peel water extract as a natural reducing agent for ferric chloride. These eco-friendly nanoparticles were employed as catalysts in the room-temperature synthesis of dihydro-2H-cyclopenta[d][1,3] oxazole derivatives (189) via a multicomponent reaction involving dialkyl acetylene dicarboxylates (187), α-haloketones (188), and 1,3-oxazole-2(3H)-thione derivatives (186). The protocol provided excellent yields ranging from 83% to 97%, as illustrated in Scheme 41. Further, these reactions gave low yields and produced a mixture of products in the absence of a catalyst. For catalyst reusability, it was magnetically separated from the reaction mixture, washed with ethyl acetate, air-dried, and reused under identical conditions without further purification. The catalyst maintained its activity over five cycles with no significant reduction in product yield. Furthermore, the antioxidant activity of the synthesized compounds was evaluated using the DPPH assay, revealing that several of them exhibited significant radical scavenging properties.

In 2020, Ahmadi and co-workers [158] developed a copper-supported magnetic nano catalyst, Fe₃O₄@MCM-41-SB-Cu, and explored its catalytic effectiveness in the synthesis of 5-substituted-1H-tetrazole derivatives (193) via a [3+2] cycloaddition reaction. The protocol involved the reaction of hydroxylamine hydrochloride (191), sodium azide (192), and aldehydes (190) at 120 °C, yielding the desired products in 72–91% as illustrated in Scheme 42. Catalyst reusability was studied under optimized conditions, and the catalyst was magnetically separated, washed with ethanol and water, dried at 60 °C, and reused. The immobilized catalyst retained its efficiency and selectivity over five cycles without significant loss of activity.

2.11. Preparation of Propargylamine Derivatives

Propargylamines are highly valuable and versatile intermediates extensively employed in the synthesis of nitrogen-containing bioactive molecules, including agrochemicals, β-lactams, peptides, and isosteres [159]. Several traditional approaches have been developed for their synthesis, which generally involve the direct reaction of amines with propargyl halides, phosphates, or triflates, as well as the nucleophilic addition of metal acetylides to imines. These reactions often require strong bases such as hydroxides, alkoxides, organometallic reagents like butyllithium, or lithium diisopropylamide (LDA) [160,161].

In 2021, Ghasemi [162] and co-workers developed a novel magnetic nanocomposite catalyst, AgNPs/Fe₃O₄@chitosan/PVA, by functionalizing chitosan polymer chains with polyvinyl alcohol (PVA) and incorporating silver nanoparticles (AgNPs) along with magnetic Fe₃O₄. The catalytic performance of this nanocomposite was evaluated in multicomponent A³-coupling and click reactions involving piperidine (194), benzaldehyde (195), and phenylacetylene (196). The reactions efficiently yielded propargylamine derivatives (197) in excellent yields ranging from 80% to 98%, as illustrated in Scheme 43. The nano catalyst was magnetically separated, washed with ethanol (5 mL), vacuum-dried overnight, and reused for six consecutive cycles without significant loss of activity.

In 2023, Hasan and co-workers [163] developed an efficient and magnetically recoverable catalyst based on Fe₃O₄-chitosan functionalized with a Cu(II) Schiff base complex. The catalyst exhibited excellent activity under microwave irradiation for the A³-coupling reaction of amines (199), alkynes (200), and aldehydes (198), affording propargylamine derivatives (201) in good to excellent yields ranging from 65% to 97%, as shown in Scheme 44. The catalyst exhibited excellent recyclability, retaining 95% efficiency after six cycles.

In 2024, Nasrin Moeini-Eghbali and co-workers [164] developed a novel and highly efficient magnetic nanocatalyst by immobilizing nickel (Ni) nanoparticles on the surface of magnetic titanium dioxide (Fe₃O₄/TiO₂), which had been surface-modified using epibromohydrin and N-(2-aminoethyl) piperazine as linkers. The catalytic activity of this material was evaluated in a solvent-free A³ coupling reaction involving various aldehydes (202), terminal alkynes (203), and amines (204), leading to the formation of propargylamine derivatives (205) in good yields (Scheme 45). Notably, the catalyst demonstrated excellent recyclability and could be reused effectively for at least six consecutive cycles without significant loss in activity.

3. Conclusions

This review highlights recent advancements in the green synthesis of heterocyclic compounds through one-pot multicomponent reactions (MCRs) catalysed by magnetic nanoparticles (MNPs). MNPs have emerged as highly versatile and efficient catalysts, finding applications across diverse fields such as biomedicine, agriculture, environmental remediation, catalysis, and biosensing. In this review, we have comprehensively summarized the recent advancements in the functionalization of magnetic nanoparticles (MNPs), with a particular focus on their catalytic applications in the synthesis of heterocyclic compounds.

The studies reviewed, spanning from 2018 to 2024, demonstrate the growing importance of MNPs in facilitating efficient, sustainable, and high-yielding one-pot transformations. Compared to traditional homogeneous catalysis, MNP-based systems offer notable advantages, including ease of catalyst recovery, reusability, operational simplicity, and compatibility with green solvents or solvent-free conditions. Overall, the integration of magnetic nano catalysts into one-pot MCRs offers a powerful and eco-friendly strategy for the construction of structurally diverse heterocycles, especially fused and polyfunctional derivatives, underscoring the potential of MNPs in the advancement of green and sustainable synthetic methodologies.