Search Results (64)

The growing demand for sustainable and efficient synthetic methodologies has brought nanocatalysis to the forefront of modern organic chemistry, particularly in the construction of heterocyclic compounds through multicomponent reactions (MCRs). Among various nanocatalysts, calcium oxide nanoparticles (CaO NPs) have gained significant attention because of their strong basicity, thermal stability, low toxicity, and cost-effectiveness. This review provides a comprehensive account of the recent strategies using CaO NPs as heterogeneous catalysts for the green synthesis of nitrogen- and oxygen-containing heterocycles through MCRs. Key reactions such as Biginelli, Hantzsch, and pyran annulations are discussed in detail, with emphasis on atom economy, reaction conditions, product yields, and catalyst reusability. In many instances, CaO NPs have enabled solvent-free or aqueous protocols with high efficiency and reduced reaction times, often under mild conditions. Mechanistic aspects are analyzed to highlight the catalytic role of surface basic sites in facilitating condensation and cyclization steps. The performance of CaO NPs is also compared with other oxide nanocatalysts, showcasing their benefits from green metrics evaluation like E-factor and turnover frequency. Despite significant progress, challenges remain in areas such as asymmetric catalysis, industrial scalability, and catalytic stability under continuous use. To address these gaps, future directions involving doped CaO nanomaterials, hybrid composites, and mechanochemical approaches are proposed. This review aims to provide a focused and critical perspective on CaO NP-catalyzed MCRs, offering insights that may guide further innovations in sustainable heterocyclic synthesis. Full article

In this work, eco-friendly ceric ammonium nitrate (CAN) and ferric chloride hexahydrate catalysts in ethanol/acetonitrile systems were used to efficiently synthesize novel dihydropyrimidinone (-thione) derivatives via the Biginelli reaction. The obtained compounds with phenolic fragments at the C4 position demonstrated enhanced antioxidant properties. Significant structure–activity relationships were indicated by three complementary assays (PFRAP, ABTS, and AAPH-induced DNA oxidation): oxo-derivatives demonstrated superior ferric ion reduction (PFRAP), while thio-substituted analogs consistently outperformed their carbonyl counterparts in radical scavenging. Remarkably, all compounds surpassed the reference antioxidant BHT, demonstrating the potential of synthesized dihydropyrimidine structures as multifunctional antioxidants for therapeutic applications. The study also shows the relationship between the catalyst–solvent system and its effect on product yields, using ceric ammonium nitrate and ferric chloride hexahydrate. Full article

This study introduces an efficient and sustainable catalytic system utilizing cobalt ferrite nanoparticles (CoFe₂O₄-NPs) for the synthesis of valuable 6-amino-2-oxo-4-phenyl (or 4-chlorophenyl)-1,2,3,4-tetrahydropyrimidine-5-carbonitrile derivatives. Recognizing the limitations of traditional methods for the Biginelli reaction, we thoroughly characterized CoFe₂O₄-NPs, alongside individual iron oxide nanoparticles (Fe₂O₃-NPs) and cobalt oxide nanoparticles (CoO-NPs), using FTIR, XRD, TEM, SEM, XPS, TGA, and BET analysis. These characterizations revealed the unique structural, morphological, and physicochemical properties of CoFe₂O₄-NPs, including an optimized porous structure and significant bimetallic synergy between Fe and Co ions. Catalytic studies demonstrated that CoFe₂O₄-NPs significantly outperformed individual Fe₂O₃-NPs and CoO-NPs under mild conditions. While the latter only catalyzed the Knoevenagel condensation, CoFe₂O₄-NPs uniquely facilitated the complete Biginelli reaction. This superior performance is attributed to the synergistic electronic environment within CoFe₂O₄-NPs, which enhances reactant activation, intermediate stabilization, and proton transfer during the multi-step reaction. This work highlights the potential of CoFe₂O₄-NPs as highly efficient and selective nanocatalysts for synthesizing biologically relevant 1,2,3,4-tetrahydropyrimidines, offering a greener synthetic route in organic chemistry. Full article

Here, we describe some well-known multicomponent reactions and the progress made over the past decade to make these processes even more environmentally friendly. We focus on the Mannich, Hantzsch, Biginelli, Ugi, Passerini, Petasis, and Groebke–Blackburn–Bienaymé reactions. After describing the origin of the reactions and their mechanisms, we summarize some advances in terms of the eco-compatibility of these different MCRs. These are followed by examples of some reactions, considered as variants, which are less well documented but which are promising in terms of structures generated or synthetic routes. Full article

The relevance of the asymmetric Biginelli reaction (ABR) has been increased in this century, due to the pharmacological application of its products. This review focuses predominantly on articles published in the period from 2015 to 2024 on asymmetric synthetic advances in the formation of dihydropyrimidinones (DHPMs), dihydropyrimidinethiones (DHPMTs), and related compounds. The relevant bibliography on general processes in the Biginelli reaction and some methods of separation of isomers have also been referenced. Full article

Ursodeoxycholic acid (UDCA) and acetoacetate are natural compounds present in the human intestine and blood, respectively. A number of studies highlighted that besides their well-known primary biological roles, both compounds possess the ability to influence a variety of cellular processes involved in the etiology of various diseases. These reasons suggested the potential of acetoacetate–UDCA hybrids as possible therapeutic agents and prompted us to develop a synthetic strategy to selectively derivatize the hydroxyl groups of the bile acid with acetoacetyl moieties. 3α-acetoacetoxy UDCA was obtained (60% isolated yield) via the regioselective transesterification of methyl acetoacetate with UDCA promoted by the Candida antarctica lipase B (CAL-B). 3α,7β-bis-acetoacetoxy UDCA was obtained instead by thermal condensation of methyl acetoacetate and UDCA (80% isolated yield). This bis-adduct was finally converted to the 7β-acetoacetoxy UDCA (82% isolated yield) via CAL-B catalyzed regioselective alcoholysis of the ester group on the 3α position. In order to demonstrate the value of the above new hybrids as UDCA-based scaffolds, 3α-acetoacetoxy UDCA was subjected to multicomponent Biginelli reaction with benzaldehyde and urea to obtain the corresponding 4-phenyl-3,4-dihydropyrimidin-2-(1H)-one derivative in 65% isolated yield. Full article

In this investigation, 4-antipyrinecarboxaldhyde was reacted with methyl hydrazinecarbodithioate to afford the carbodithioate derivative 3. The as-prepared carbodithioate derivative 3 is considered to be a key molecule for the preparation of new antipyrine-1,3,4-thiadiazole-based molecules (4–9) through its reaction with the appropriate hydrazonoyl halides. Furthermore, a typical Biginelli three-component cyclocondensation reaction involving ethyl acetoacetate, 4-antipyrinecarboxaldhyde, and thiourea under the standard conditions is carried out in the presence of sulfuric acid to afford the corresponding antipyrine–pyrimidine hybrid molecule (10). The latter was submitted to react with hydrazine monohydrate to provide the corresponding hydrazide derivative (11) which, under reaction with ethyl acetoacetate in refluxing ethanol containing catalytic amount of acetic acid, afforded the corresponding derivative (12). The structure of the newly synthesized compounds was affirmed by their spectral and microanalytical data. We also screened for their antimicrobial potential (ZOI and MIC) and conducted a kinetic study. Additionally, the mechanism of biological action was assessed by a membrane leakage assay and SEM imaging technique. Moreover, the biological activities and the binding modes of these compounds were further supplemented by an in silico docking study against E. coli β-carbonic anhydrase. The amount of cellular protein released by E. coli is directly correlated to the concentration of compound 9, which was found to be 177.99 µg/mL following treatment with 1.0 mg/mL of compound 9. This finding supports compound 9’s antibacterial properties and explains how the formation of holes in the E. coli cell membrane results in the release of proteins from the cytoplasm. The newly synthesized compounds represent acceptable antimicrobial activities with potential action against E. coli β-carbonic anhydrase. The docking studies and antimicrobial activity test proved that compound (9) declared a greater activity than the other synthesized compounds. Full article

Phytoremediation has been considered a sustainable environmental technology for heavy metals decontamination. In this work, we evaluated the metal contents by inductively coupled plasma optical emission spectrometry (ICP-OES) of three plant species collected in a mine in the Brazilian Amazonia area. Based on this analysis, Pluchea sagitallis leaves were selected to prepare metallic ecocatalysts. The leaf ashes and the obtained ecocatalysts were characterized by ICP-OES, X-ray diffraction (XRD), scanning electron microscopy (SEM) and N₂-physisorption measurements. Moreover, they were evaluated in the Biginelli and Hantzsch multicomponent reactions, furnishing the corresponding 3,4-dihydropyrimidin-2-(1H)-ones and 1,4-dihydropyridines with good to excellent yields. The best ecocatalyst was easily recovered and recycled in up to six reactions without a significant decrease in its performance. Full article

In this study, we present the highly efficient and rapid synthesis of substituted dihydropyrimidinone derivatives through an ultrasound-accelerated approach. We utilize copper ferrite (CuFe₂O₄) magnetic nanoparticles as heterogeneous catalysts, employing the well-known Biginelli reaction, under solvent-free conditions. The impact of the solvent, catalyst amount, and catalyst type on the reaction performance is thoroughly investigated. Our method offers several notable advantages, including facile catalyst separation, catalyst reusability for up to three cycles with the minimal loss of activity, a straightforward procedure, mild reaction conditions, and impressive yields, ranging from 79% to 95%, within short reaction times of 20 to 40 min. Furthermore, in the context of fighting COVID-19, we explore the potential of substituted dihydropyrimidinone derivatives as inhibitors of three crucial SARS-CoV-2 proteins. These proteins, glycoproteins, and proteases play pivotal roles in the entry, replication, and spread of the virus. Peptides and antiviral drugs targeting these proteins hold great promise in the development of effective treatments. Through theoretical molecular docking studies, we compare the binding properties of the synthesized dihydropyrimidinone derivatives with the widely used hydroxychloroquine molecule as a reference. Our findings reveal that some of the tested molecules exhibit superior binding characteristics compared to hydroxychloroquine, while others demonstrate comparable results. These results highlight the potential of our synthesized derivatives as effective inhibitors in the fight against SARS-CoV-2. Full article

Pyrimidines play an important role in modern medical fields. They have a wide spectrum of biological activities such as antimicrobial, anticancer, anti-allergic, anti-leishmanial, antioxidant agents and others. Moreover, in recent years, 3,4-dihydropyrimidin-2(1H)ones have attracted researchers to synthesize them via Biginelli reaction and evaluate their antihypertensive activities as bioisosters of Nifedipine, which is a famous calcium channel blocker. Our new target compounds were prepared through one-pot reaction of thiourea 1, ethyl acetoacetate 2 and/or 1H-indole-2-carbaldehyde, 2-chloroquinoline-3-carbaldehyde, 1,3-diphenyl-1H-pyrazole-4-carbaldehyde, 3a–c in acid medium (HCl) yielding pyrimidines 4a–c, which in turn were hydrolyzed to carboxylic acid derivatives 5a–c which were chlorinated by SOCl₂ to give acyl chlorides 6a–c. Finally, the latter were reacted with some selected aromatic amines, namely, aniline, p-toluidine and p-nitroaniline, producing amides 7a–c, 8a–c, and 9a–c. The purity of the prepared compounds was examined via TLC monitoring, and structures were confirmed by different spectroscopic techniques such as IR, ¹HNMR, ¹³CNMR, and mass spectroscopy. The in vivo evaluation of the antihypertensive activity revealed that compounds 4c, 7a, 7c, 8c, 9b and 9c had comparable antihypertensive properties with Nifedipine. On the other hand, the in vitro calcium channel blocking activity was evaluated by IC₅₀ measurement and results revealed that compounds 4c, 7a, 7b, 7c, 8c, 9a, 9b, and 9c had comparable calcium channel blocking activity with the reference Nifedipine. Based on the aforementioned biological results, we selected compounds 8c and 9c to be docked onto Ryanodine and dihydropyridine receptors. Furthermore, we developed a structure–activity relationship. The designed compounds in this study show promising activity profiles in reducing blood pressure and as calcium channel blockers, and could be considered as new potential antihypertensive and/or antianginal agents. Full article

Dioxidovanadium(V) complex [V^VO₂(sal-aebmz)] (1) (where Hsal-aebmz = Schiff base derived from the condensation of salicylaldehyde and 2-aminoethylbenzimidazole) has been immobilized on chloromethylated polystyrene (PS-Cl) cross-linked with divinylbenzene to obtain [V^VO₂(sal-aebmz)]@PS (2), a heterogeneous complex. Both complexes, after characterization, have been used as catalysts to explore a single pot multicomponent (benzaldehyde or its derivatives, urea and ethyl acetoacetate) Biginelli reaction producing biologically active 3,4-dihydropyrimidin-2-(1H)-one (DHPM)-based biomolecules under solvent-free conditions in the presence of H₂O₂ as a green oxidant. Various reaction conditions such as amounts of catalyst and oxidant, temperature, time, and solvent have been optimized to obtain the maximum yield of DHPMs. The polymer-immobilized complex has been found to show excellent catalytic activity, giving ca. 95% yield of DHPMs under the optimized reaction conditions selectively. Oxidant plays an important role in enhancing the yield of DHPMs. Full article

Halloysite nanotubes can be used for the preparation of solid catalysts. Owing to their natural availability at low-cost as well as to their large and easy-to-functionalize surface, they can be conveniently activated with mineral acids or derivatized with acidic groups. Nevertheless, the use of HNTs as catalysts in complex transformations is still limited. Herein, we report two strategies to utilize HNT-based materials as solid acidic catalysts for the Biginelli reaction. To this aim, two methods for increasing the number of acidic sites on the HNTs were explored: (i) the treatment with piranha solution (Pir-HNTs) and (ii) the functionalization with phenylboronic acid (in particular with benzene-1,4-diboronic acid: the sample is denoted as HNT-BOA). Interestingly, both strategies enhance the performance of the multicomponent reaction. Pir-HNTs and HNT-BOA show an increased reactivity (72% and 89% yield, respectively) in comparison with pristine HNTs (52%). Additionally, Pir-HNTs can be reused up to five times without significant performance loss. Moreover, the method also displays good reaction scope, as demonstrated by the preparation of 12 different 3,4-dihydropyrimidinones in up to 71% yield. Therefore, the described strategies are promising for enhancing the acidity of the HNTs as catalysts for the organic reaction. Full article

Bioactive dihydropyrimidinones (DHPs) were designed and synthesized by a multicomponent Biginelli reaction. The reaction was catalyzed by the polarized surface of nano-zirconium dioxide with partial positive charge of 0.52e at the Zr center and a negative charge of −0.23e at the oxygen center. There was good corroboration between the computed and experimental ZrO₂ cell parameters and bond distances as determined by in silico and in vitro experimental methods. Since DHPs were found to target the peroxisome proliferator-activated receptor (PPAR)-γ, we tested these ligands toward MCF-7 cell toxicity, which revealed that the compounds 4d [ethyl-4-(4′-fluoro-[1,1′-biphenyl]-4-yl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate] and 4e [ethyl-4-(3′-methoxy-[1,1′-biphenyl]-4-yl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate] inhibited proliferation with IC₅₀ values of 11.8 and 15.8 μM, respectively. Further, our bioinformatic analysis found that the active molecule 4d, fit into the enzyme’s catalytic site, almost in the same position as rosiglitazone, which was buried deep inside the cavity. In conclusion, we herein report novel DHPs which could be better structures to help explore a new class of synthetic PPAR-γ ligands. Full article

Hypertension and cardiovascular diseases related to it remain the leading medical challenges globally. Several drugs have been synthesized and commercialized to manage hypertension. Some of these drugs have a dihydropyrimidine skeleton structure, act as efficient calcium channel blockers, and affect the calcium ions’ intake in vascular smooth muscle, hence managing hypertension. The synthesis of such moieties is crucial, and documenting their structure–activity relationship, their evolved and advanced synthetic procedures, and future opportunities in this area is currently a priority. Tremendous efforts have been made after the discovery of the Biginelli condensation reaction in the synthesis of dihydropyrimidines. From the specific selection of Biginelli adducts to the variation in the formed intermediates to achieve target compounds containing heterocylic rings, aldehydes, a variety of ketones, halogens, and many other desired functionalities, extensive studies have been carried out. Several substitutions at the C3, C4, and C5 positions of dihydropyrimidines have been explored, aiming to produce feasible derivatives with acceptable yields as well as antihypertensive activity. The current review aims to cover this requirement in detail. Full article

This review covers articles published in the period from 2010 to mid-2022 on synthetic advances in the formation of pyrimidine and related heterocyclic compounds. Special emphasis has been given to the different types of cycloadditions, taking into account the number of their components and leading to the formation of the pyrimidine ring. Due to the large number of publications on the Biginelli reaction and related reactions, this will be dealt with in a separate review in the near future. Full article