Biginelli Reaction Research Articles

Solvent-free and efficient heterogeneous Biginelli reactions catalyzed by copper (II)-incorporated iminophenol-based porous organic polymer

The copper (II)-incorporated iminophenol containing porous polymer (Cu-TAzo-TAPB), which was reported to be a recyclable catalyst for click reactions, is now exploited as an efficient catalyst in the solvent-free one-pot process to make 3,4-dihydropyrimidinone derivatives (DHPMs) by a three-component condensation reaction of urea/thiourea, aldehydes, and active methylene compounds. Usually, these reactions are complicated to carry out in a neutral medium. We describe here an eco-friendly method to produce Biginelli products with 5 mol% catalyst loading with a simple isolation technique. The high product yields show the effective Biginelli reaction technique. The catalyst is highly stable and easily recoverable for reuse without significant loss of catalytic efficiency.

Recent advances in the synthesis of dihydropyrimidinones via biginelli reaction

Recent advances in the synthesis of dihydropyrimidinones via biginelli reaction

Two Thiophene-Functionalized Co-MOFs as Green Heterogeneous Catalysts for the Biginelli Reaction.

Two Co(II) metal-organic frameworks (Co-MOFs), namely, [Co(DMTDC)(bimb)]n (Co-MOF-1) and {[Co(DPTDC)(bimb)(H2O)]·2DMF}n (Co-MOF-2) (H2DMTDC = 3,4-dimethylthieno[2,3-b]thiophene-2,5-dicarboxylic acid, H2DPTDC = 3,4-diphenylthieno[2,3-b]thiophene-2,5-dicarboxylic acid, bimb = 1,4-bis((1H-imidazol-1-yl)methyl)benzene), were obtained by the reaction of flexible N-containing ligand bimb and two structurally related thiophene-containing ligands H2DMTDC and H2DPTDC, respectively. These Co-MOFs displayed a 3D framework and porous structure, respectively. Co-MOF-1 and the activated sample Co-MOF-2' could act as green heterogeneous catalysts for the one-pot multicomponent Biginelli reaction, specifically the dehydration condensation process involving aldehydes, acetoacetates, and urea to yield dihydropyrimidin-2(1H)-ones. The reaction has advantages such as solvent-free conditions, water as only byproduct, readily accessible starting materials, excellent functional group compatibility, and simple operation. Both catalysts exhibited a wide substrate scope and maintained significant catalytic activity over five cycles. The special catalytic performance may be ascribed to functional groups within the ligand.

Synthesis, characterization, and evaluation of pyrimidinone-linked thiazoles: DFT analysis, molecular docking, corrosion inhibition, and bioactivity studies

The paper describes the construction of a new series of pyrimidinone-linked thiazole derivatives through bromination of the initial Biginelli reaction product followed by the Hantzsch thiazole synthesis route. Various analytical techniques, including FT-IR, 1H NMR, 13C NMR, and LCMS analysis, were employed to confirm the formation of the products. The synthesized compounds were primarily evaluated for their antibacterial activity, with a specific focus on their IC50 values. Compound 4c demonstrated the most potent efficacy, displaying MIC and MBC values that varied from 0.23 to 0.71 mg/mL and 0.46–0.95 mg/mL, respectively. The anti-inflammatory potential was also observed in analogs 4a and 4c with marked activity in the 33.2–82.9 μM concentration range. Moreover, compounds 4a, and 4c demonstrated strong antioxidant effects, as reflected by their excellent IC50 values of 38.6–43.5 μM respectively. DFT investigation showed that B. cereus was more susceptible, and E. coli was more resistant, with chloro-substituted compounds exhibiting potential reactivity. Some molecules with chloro-substituents showed promising results in density functional theory when compared to other substituents. In addition, the molecules underwent a corrosion study and demonstrated a high level of inhibition efficiency (4c) in comparison to other molecules. Further in silico studies of the synthesized thiazoles confirmed the good interactions with the target.

Unprecedented one-pot synthesis of 3,4-dihydropyrimidine-2-(1h)-ones catalyzed by hydrazine sulfate through Biginelli reaction, ADMET property, molecular docking studies and their antibacterial activity on Bacillus brevis and E. coli

The syntheses of 3,4-dihydropyrimidin-2(1H)-ones by one-pot, three-component condensation of aldehydes, β-ketoesters and urea or thiourea have been made more simple and efficient by using 20 mol% hydrazine sulfate as catalyst. Aldehydes, β-ketoesters and urea are cyclocondensed in the presence of hydrazine sulfate to produce dihydropyrimidines in ethanol under reflux conditions. The advantages of using hydrazine sulfate as a catalyst over the traditional Biginelli reaction conditions include outstanding yields (80–91%) and a shorter (10–15 hours) reaction time. In order to evaluate the antibacterial efficiencies of the synthesized compounds, we have studied the inhibitions of microbial proliferation of both Gram-positive (Bacillus brevis) and Gram-negative (E. coli) bacterial strains in comparison to a control group. The microbial inhibitions occur in the range of 40–98% by different derivatives of dihydropyrimidinones. Molecular docking studies of the synthesized compounds have also been done using software tools such as SwissADME.

High-Shear Enhancement of Biginelli Reactions in Macromolecular Viscous Media.

Chemical reactions and transformations in non-traditional vessels have gained significant interest in recent years. Flow chemistry, with its advantages in mixing, mass transfer, scalability, and automation, is a driving force behind this paradigm shift. In particular, the Vortex Fluidic Device (VFD) has emerged as a versatile tool across various applications, from organic synthesis to materials science. In this study, the role of the VFD in performing the Biginelli reaction, a multicomponent reaction widely used in pharmaceutical and polymer science, for a post-polymerization modification is explored. By conducting the Biginelli reaction in the VFD, rapid product formation with low catalyst loading and without the need for high temperatures is achieved. However, the critical need to understand and know solution viscosity, especially within the context of modifying macromolecules is highlighted.

Highlighting multicomponent reactions as an efficient and facile alternative route in the chemical synthesis of organic-based molecules: a tremendous growth in the past 5 years.

Since Strecker's discovery of multicomponent reactions (MCRs) in 1850, the strategy of applying an MCR approach has been in use for over a century. Due to their ability to quickly develop molecular diversity and structural complexity of interest, MCRs are considered an efficient approach in organic synthesis. Although MCRs such as the Ugi, Passerini, Biginelli, and Hantzsch reactions are widely studied, this review emphasizes the significance of selective MCRs to elegantly produce organic compounds of potential use in medicinal chemistry and industrial and material science applications, as well as the use of the MCR approach to sustainable methods. During synthesis, MCRs provide advantages such as atom economy, recyclable catalysts, moderate conditions, preventing waste, and avoiding solvent use. MCRs also reduce the number of sequential multiple reactions to one step.

TiO2 and ZnO Nanoparticles Immobilized on Magnetic Sulfonated Melamine‐Formaldehyde: Structure Identification and Performance as Recyclable Catalysts for the Biginelli Reaction

AbstractSulfonated melamine‐formaldehyde (SMF) containing high dispersed TiO2 and ZnO nanoparticles were fabricated into magnetic nanocomposites by two different method material incorporation protocols, including calcination and wet impregnation. Their catalytic performance was investigated toward Biginelli reaction. For the preparation of the first catalyst series, a two‐step protocol was used. Initially, Fe3O4 nanoparticles were coated with SMF (Fe3O4/SMF). Subsequently, they were decorated consecutively with TiO2 (Fe3O4/SMF/TiO2) and ZnO (Fe3O4/SMF/ZnO). The second set of catalysts was prepared using a two‐step process. Fe3O4 nanoparticles were first used to modify SMF (SMF/Fe3O4). Following the initial step, the surface of SMF/Fe3O4 was decorated with both TiO2 (SMF/Fe3O4/TiO2) and ZnO (SMF/Fe3O4/ZnO). To understand the characteristics of the synthesized nanocomposites, a variety of characterization techniques were employed. New catalysts enabled the rapid synthesis (30–45 min) of a range of biologically active 3,4‐dihydropyrimidinones based on the Biginelli reaction with high yields (70–95 % isolated).

Fused Thiazolo[2,3‐b]Quinazolinone–Chromone Hybrids: Synthesis, Characterization, In Vitro Antibacterial Activity and In Silico Screening

ABSTRACTAntimicrobial resistance is one of the biggest threats to public health across the globe. Bacteria, fungi, viruses, and protozoans have been exhibiting resistance against antimicrobial drugs making them ineffective. Hence, the development of new antibiotics with a different mode of action is highly desirable. In this study, 10 new chromone‐incorporated fused thiazolo[2,3‐b]quinazolinone derivatives, 8a‐j, have been prepared via Biginelli reaction involving aromatic aldehydes, 1‐tetralone, and thiourea followed by a reaction with 2‐chloro‐N‐phenylacetamide, and Knoevenagel condensation with 3‐formylchromone. All the structures of the compounds were characterized by NMR, FTIR, and mass spectrometry. The in vitro antibacterial activities of all the synthesized compounds against the four different microbial strains were evaluated. Among them, few compounds demonstrated prominent activity against Staphylococcus aureus, Streptococcus pyogenes, and Pseudomonas aeruginosa. No appreciable activity of any compound against Klebsiella pneumoniae was observed. Molecular docking studies were employed to reveal the interactions responsible for the potent compounds' activities against S. aureus, S. pyogenes, and P. aeruginosa. Both in vitro and in silico studies have been carried out by using standard agar well diffusion protocol and Auto Dock Vina in PyRx. The results indicated that compound 8c was the potential compound as it showed good affinity toward the receptors of all three organisms. Molecular dynamics simulation of the 8c‐1JIJ complex for 100 ns further confirmed the potentiality of 8c. The pharmacokinetic properties of the compounds indicate that the studied molecules have exhibited a favorable profile.

The role of carboxylic acid contents in calcium-based metal-organic frameworks for the enhancement of Biginelli reaction

Metal-organic frameworks (MOFs) can carry different functional groups such as COOH, NH2, and SO3H. The most commonly used functional group was COOH due to its Brønsted acidity, polarity, and ability to bond with organic compounds and metals through various interactions. Here, calcium-based MOFs (Ca-MOFs) with different carboxylic arms were successfully prepared and used in heterogeneous Biginelli catalytic reactions. The prepared materials (Ca-BDC-H, Ca-BDC-COOH, and Ca-BDC-(COOH)2) were characterized using different spectroscopic techniques and the morphological structures were determined using microscopic analysis. Besides elucidating the fine form of MOFs, the role of the carboxylic content was tested in multicomponent reaction catalysis in different kinetics and thermodynamic studies, the formation of catalytic products was determined using NMR analysis, and the proposed mechanism was investigated. The results obtained showed that as the carboxylic content in the network increases, the catalytic reaction yield increases which can support the possibility of using the COOH group present in the network with acidic properties in heterogeneous catalysts giving high product yield.

Diverse Methods with Stereoselective Induction in the Asymmetric Biginelli Reaction.

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.

Electronegativity Impact on metal (Copper, Iron, Zinc) Lewis acid catalysts in the Biginelli Reaction: A Comparative Study

The Biginelli reaction is a very practical multi-component reaction, and the products 3,4-Dihydropyrimidine-2(1H)-ones (DHPMs) play an important role in the pharmacy scope. Herein, CuCl2, FeCl3, and ZnCl2 were used to investigate the catalytic activity differences among these metal Lewis acid catalysts for the Biginelli reaction under controlled conditions. Based on reaction mechanism, we believe that highly electronegative metals are beneficial for activating imines and enol intermediates, thereby increasing reaction yields.

Synthesis, in vitro anticancer activity, and pharmacokinetic profiling of the new tetrahydropyrimidines:Part I.

Different vanillin-based aldehydes were used to synthesize novel tetrahydropyrimidines (THPMs) via conventional Biginelli reaction. The THPMs were tested against human normal cells (MRC-5) and cancer cell lines (HeLa, K562, and MDA-MB-231). With IC50 values of 10.65, 10.70, and 12.76 µM, compounds 4g, 4h, and 4i exerted the strongest cytotoxic effects against K562 cells. The best activity was achieved for 4g on MDA-MB-231 cells (IC50 = 9.20 ± 0.14 µM). The effects of compounds 4g, 4h, and 4i on the cell-cycle phase distribution of K562 cells were analyzed. Principal component analysis was carried out for the chemometrics analysis to comprehend the relationship between the anticancer activity of the THPMs, pharmacokinetic properties, and partition coefficients, as well as the relationship between the chromatographic behavior and retention parameters. The highest retention rates are found for molecules 4g, 4h, and 4i, which have the longest carbon chains, indicating that the length of the alkyl chain positively affects the molecule's anticancer activity but only if the number of carbon atoms is not higher than seven. Additionally, molecular docking analysis was performed to determine the preferred binding modes of the investigated ligands (4g, 4h, and 4i) with a DNA dodecamer and bovine serum albumin.

Fabrication of magnetic carbohydrate-modified iron oxide nanoparticles (Fe3O4/pectin) decorated with bimetallic Co/Cu-MOF as an effective and recoverable catalyst for the Biginelli reaction.

Due to their biocompatibility, facile recoverability, mechanical and thermal stability, high surface area, and active catalytic sites, magnetic nanocomposites, containing natural polymers and magnetic nanoparticles, have been used to produce supports for catalysts or biocatalysts. Pectin, an important polycarbohydrate, has abundant functional groups with excellent ability to coat the surface of the nanoparticles to fabricate composite and hybrid materials. A novel bimetallic cobalt(ii) and copper(ii)-based metal-organic framework (Co/Cu-MOF) immobilized pectin-modified Fe3O4 magnetic nanocomposite was designed and fabricated. Fe3O4 nanoparticles were modified in situ by pectin and, subsequently, used as a support for growing Co/Cu-MOF [Fe3O4/pectin/(Co/Cu)MOF]. The properties of the nanocomposite were investigated by FT-IR, XRD, SEM, EDS, VSM, STA, and BET. The nanocomposite exhibited both magnetic characteristics and a high surface area, making it a suitable candidate for catalytic applications. Then, the Fe3O4/pectin/(Co/Cu)MOF nanocomposite was utilized in the Biginelli reaction for the production of biologically active dihydropyrimidinones. Due to paramagnetism, Fe3O4/pectin/(Co/Cu)MOF was easily recovered and reused in six cycles without significant loss in reactivity. This green method comprises several benefits, such as mild reaction conditions, free-solvent media, high yields, easy workup, short reaction times and reusability of the prepared catalyst.

Design, synthesis and biological Evaluation of novel chromones having 3,4-dihydropyrimidin-2(1H)-one core at C-8 in combination with triazoles: New α-glucosidase inhibitors and anti-bacterial agents

The Biginelli reaction synthesizes dihydropyrimidones through a multi-component reaction. A β-ketoester, aldehyde, and urea or thiourea react in the presence of an acid catalyst to form these dihydropyrimidones. 3,4-Dihydropyrimidin-2(1H)-One/Chromone/Triazole hybrids (9a-9l) were synthesized by multiple steps including one pot Biginelli multicomponent reaction depicted in the scheme. An efficient method for the Biginelli reaction of Chromone aldehyde, acetoacetate esters, and urea employed in the presence of ferric chloride is described. In the end, we have successfully synthesized twelve derivatives of 3,4-Dihydropyrimidin-2(1H)-One/Chromone/Triazole hybrids and subjected them to testing for Antibacterial activity and α-glucosidase inhibition activity. Among these derivatives, compound 9g (IC50 = 142.92 nmol) and 9e (144.49 nmol) exhibited significant inhibitory activity in comparison to the positive control acarbose (IC50 = 350.91 nmol). Compound 9g demonstrated the most significant suppression against Escherichia coli and Bacillus cereus, with zone diameters of 8.8 ± 1.35 mm and 9.1 ± 0.23 mm, respectively. Compound 9b displayed a clear area where bacterial growth was inhibited, measuring 7.5 ± 1.25 mm against Klebsiella pneumonia. Compound 9k exhibited a zone of inhibition measuring 8 ± 1.2 mm in radius against Staphylococcus epidermidis. The docking results for the synthesized compounds indicate that compound 9b exhibited the most favorable docking score of −10 kcal/mol, whereas compound 9a had the second-best docking score of −8.7 kcal/mol. Molecular docking was utilized to examine the interactions between the title compounds and α-glucosidase, in order to provide valuable insights. The data obtained revealed significant interactions that contribute to the inhibitory effects of the drugs against α-glucosidase. These compounds exhibit significant potential as attractive initial candidates for the development of new α-glucosidase inhibitors.

Design and development of a novel Co‐MOF catalyst for sustainable pyrimidine synthesis via the Biginelli reaction

In this study, we introduce a novel porous metal–organic framework named Co2(bbda)2(DMF)2·5H2O, or MOF‐UoR‐1, synthesized via hydrothermal techniques employing a unique Schiff base ligand. The framework underwent comprehensive characterization, confirming its microporous nature through gas‐sorption measurements. MOF‐UoR‐1 demonstrated remarkable efficacy as a catalyst for the one‐step synthesis of pyrimidine analogs. Structural validation of the synthesized pyrimidines was accomplished via 1H‐nuclear magnetic resonance (NMR) and Fourier transform infrared (FTIR) analyses. Through systematic experimentation, the optimal catalyst dosage (40 mg) was determined, showcasing its effectiveness across various aldehydes, 1,3‐carbonyl compounds, and urea substrates. Noteworthy is the broad applicability of this environmentally friendly protocol, which offers advantages such as high yields (96%), rapid reaction times (90 min), straightforward product isolation, and product purity without necessitating column chromatography. Furthermore, the catalytic integrity of the framework remained intact, enabling its reuse without compromising performance. This research presents a promising approach for the synthesis of pyrimidine derivatives, with significant implications for sustainable and efficient chemical synthesis methodologies.

Synthesis of 3,4-dihydropyrimidines and octahydroquinazolinones by SBA-15 supported schiff-base iron (III) complex as durable and reusable catalyst under ultrasound irradiation

Biginelli-type heterocyclic compounds are particularly important due to their several chemical reactivities and various range of pharmacological activity. Therefore Biginelli reaction has witnessed several modification and numerous investigations are continuing in this field to develop more effective and efficient methodologies. In this research, Iron (III) schiff base immobilized SBA-15 has been prepared as a valuable, efficient, and recoverable catalyst for the Biginelli reaction. The morphology of the prepared catalyst was identified by spectroscopic characterization techniques and structural microscopic analysis including Fourier transform infrared (FT-IR) patterns, X-ray diffraction (XRD) by powder crystal method, Energy-dispersive X-ray spectroscopy (EDS) study, Thermogravimetric-Differential thermal analysis (TGA-DTA), Transmission electron microscopy (TEM) and Field emission scanning electron microscopy (FE-SEM) images. Biginelli compounds containing 3,4-dihydropyrimidines and octahydroquinazolinones were conveniently synthesized by this catalyzed protocol from the cycloaddition of aromatic aldehydes with the 1,3-dicarbonyl substrates and urea via ultrasonic waves. The several advantages of the presented approach are high yields and easy isolation of products, shorter reaction times, and milder conditions, structural stability and reusable catalyst. The combination of heterogeneous catalyst and ultrasonic radiation can make catalytic reactions more efficient than traditional ways attractive for academic researchers and application scholars in the industry.

Medicinal perspective of a promising scaffold – dihydropyrimidinones: A review

AbstractDihydropyrimidinones (DHMPs) are the most important pharmacophore in Medicinal Chemistry. The synthetic approach for deriving DHMPs involves the Biginelli reaction or a combination of it with other multi‐component reactions (MCRs). The scaffold has received considerable attention due to its diverse therapeutic activity. This review delves into the exploration of the biological characteristics of DHMPs, which play a pivotal role in various therapeutic areas including “anti‐inflammatory, anti‐HIV, anticancer, antitubercular, antifungal, antibacterial, antihyperglycemic, antihypertensive, anticonvulsant, antimalarial, antioxidant,” reverse transcriptase (RT) inhibitor, antispasmodic, calcium channel blockers, antiproliferative, urease inhibitor, cyclooxygenase (COX‐2), and β‐glucuronidase inhibitor activities. The insights provided in this review have the potential to aid researchers in the formulation of novel drugs, facilitating creation of more resilient, efficient, and safer therapeutic agents with reduced toxicity and minimized adverse effects.

Insights into the promising heterogeneous catalysis of eco-friendly synthesized spinel CuFe2O4 nanoparticles for Biginelli reaction

Insights into the promising heterogeneous catalysis of eco-friendly synthesized spinel CuFe2O4 nanoparticles for Biginelli reaction

In silico investigation and biological evaluation viz antimicrobial, genotoxic, and anticancer potentials of new dihydropyrimidinones (DHPMs) synthesized by Biginelli reaction

Dihydropyrimidin-2(1H)-ones (DHPMs) are attracting growing interest in synthetic and medical organic chemistry due to their biological and therapeutic potential. In this study, we synthesized DHPM derivatives via the Biginelli reaction from bisdialdehyde to identify lead compounds. Using SWISSADME analysis, we assessed druglikeness features of the DHPM derivatives. Antimicrobial properties, including antibacterial and antifungal activities, were evaluated, and promising compounds were tested for their ability to inhibit A549 lung cancer cell growth. Thin-layer chromatography confirmed product formation, while spectroscopic methods characterized the structures. Lipophilicity values indicated strong oral absorption potential. In vitro drug release and cell viability studies were conducted. DHPMs 7, 8, and B1 exhibited broad-spectrum antimicrobial activity. Molecular docking revealed DHPM 2′s potential in cancer treatment via effective binding with VEGFR-2 kinase. Genotoxic and anticancer activities were assessed, with DHPM 8 showing promising action against dangerous bacteria and fungi. Further research is warranted to explore therapeutic applications of these compounds.