Biginelli Product Research Articles

O,S,Se-containing Biginelli products based on cyclic β-ketosulfone and their postfunctionalization.

A one-pot three-component Biginelli synthesis of dihydropyrimidinones/thiones/selenones via acetic acid or solvent-free Yb(OTf)3-catalyzed tandem reaction of β-ketosulfone (dihydro-2H-thiopyran-3(4H)-one-1,1-dioxide), an appropriate urea, and arylaldehyde has been developed. The reaction proceeds with high chemo- and regioselectivity to give diverse DHPMs in reasonable yields up to 95%. Moreover, an SO2-containing analogue of anticancer drug-candidate enastron (SO2 vs C=O) was obtained by using the here reported method in gram scale. We also demonstrate the reactivity of the Biginelli product in various directions - synthesis of condensed thiazoles and tetrazoles. In silico assessment of ADMET parameters shows that most compounds meet the lead-likeness requirements. The biological profiles of new compounds demonstrate high probability levels of activity against the following pathogens/diseases: Candida albicans, Alphis gossypii, Tripomastigote Chagas, Tcruzi amastigota, Tcruzi epimastigota, Leishmania amazonensis, and Dengue larvicida.

Synergistic effects of covalently coupled eosin-Y with Ben-graphitic carbon nitride framework for improved photocatalytic activity in solar light-driven Biginelli product generation and NADH regeneration.

Elevated global pollution level is the prime reason that contributes to the onset of various harmful health diseases. The products of Biginelli reaction are enormously used in the pharmaceutical industry as they have antiviral, antibacterial, and calcium channel modulation abilities. This work reports a novel eosin Y sensitized boron graphitic carbon nitride (EY-Ben-g-C3N4) as a photocatalyst that efficiently produced 3,4-dihydropyrimidine-2-(1H)-one by the Biginelli reaction of benzaldehyde, urea, and methyl acetoacetate. The photocatalyst EY-Ben-g-C3N4 showed a successful generation of 3,4-dihydropyrimidine-2-(1H)-one (Biginelli product) in good yield via photocatalysis which is an eco-friendly method and has facile operational process. In addition to the production of Biginelli products, the photocatalyst also showed a remarkable NADH regeneration of 81.18%. The incorporation of g-C3N4 with boron helps increase the surface area and the incorporation of eosin Y which is an inexpensive and non-toxic dye, and in Ben-g-C3N4, enhanced the light-harvesting capacity of the photocatalyst. The production of 3,4-dihydropyrimidine-2-(1H)-one and NADH by the EY-Ben-g-C3N4 photocatalyst is attributed to the requisite band gap, high molar absorbance, low rate of charge recombination, and increased capacity of the photocatalyst to harvest solar light energy.

EXPLORING Mn+/SILICALITE-1 AS A CATALYST FOR BIGINELLI REACTION TO PRODUCE DIHYDROPYRIMIDINONE DERIVATIVES

A series of Mn+/silicalite-1 was prepared to be used as a Lewis acid heterogeneous catalyst for a one-pot multicomponent Biginelli reaction. The catalysts were characterized by FTIR, XRD, NH3-TPD, and BET. The mesoporous catalysts possess a pore diameter of 13.83 nm (138.3 Å), a surface area of 282.43 m2 /g, and a pore volume of 0.98 cm3/g, which can facilitate the transport of reactants and products smoothly during the catalytic process. Besides the acidity of the catalyst, the maximum temperature of NH3-desorption plays an important role in the catalytic activity. Cr3+/silicalite-1 showed the most active catalyst, while Zn2+/silicalite-1 showed the most selective one. Besides DHPM derivatives as a major Biginelli product, C6-styril of DHPM and Knoevenagel products were isolated if the reaction was conducted using Cr3+/- and Fe3+/silicalite-1. Catalyst Cr3+/silicalite-1 can be used to produce DHPM attaching various substituents and showed a green catalyst potential due to its reusability capacity.

Synthesis and ct-DNA binding study of a donor-π-acceptor dihydropyrimidinone fluorophore

We have described the synthesis of a Donor-π-Acceptor dihydropyrimidinone (DHP) fluorophore via functional group modification of dihydropyrimidinone, commonly known as Biginelli product, to probe ds-DNA. The intermediates including the target compounds was characterized by NMR, mass, and XRD. The inherent fluorescence of the synthesized DHP is very weak. However, in the presence of ds-DNA, the fluorescence emission intensity enhances up to 5 times. The type of interactions of the DHP with ds-DNA was investigated thoroughly by spectroscopic methods. The combined result of Gaussian calculation and the time-resolved fluorescence spectroscopy suggested the formation of an effective charge transfer of Donor-π-Acceptor system. The results of the iodide quenching effect and displacement assay with Hoechst and Ethidium bromide indicated a minor groove binding mechanism. A theoretical model has been constructed by using the AutoDoc Vina package to visualize different types of non-bonded interaction of the DHP with other heteroatomic units in the narrow and shallow cut of the minor groove of ds-DNA. We observed the incorporation of 3a within the cell and the targeting of the nucleus by using a confocal microscope.

Stepping Further from Coupling Tools: Development of Functional Polymers via the Biginelli Reaction.

Multicomponent reactions (MCRs) have been used to prepare polymers with appealing functions. The Biginelli reaction, one of the oldest and most famous MCRs, has sparked new scientific discoveries in polymer chemistry since 2013. Recent years have seen the Biginelli reaction stepping further from simple coupling tools; for example, the functions of the Biginelli product 3,4-dihydropyrimidin-2(1H)-(thi)ones (DHPM(T)) have been gradually exploited to develop new functional polymers. In this mini-review, we mainly summarize the recent progress of using the Biginelli reaction to identify polymers for biomedical applications. These polymers have been documented as antioxidants, anticancer agents, and bio-imaging probes. Moreover, we also provide a brief introduction to some emerging applications of the Biginelli reaction in materials and polymer science. Finally, we present our perspectives for the further development of the Biginelli reaction in polymer chemistry.

Metal-Free Synthesis of Pyrimidinone Derivatives via Biginelli Reaction Using Aqueous NaICl2

Metal-free synthesis of pyrimidinone (alky/aryl) via Biginelli reaction in the presence of aqueous sodium dichloroiodate (NaICl2) was studied under reflux conditions. Herein, we first time report the synthesis of the aliphatic Biginelli product by using aliphatic aldehyde, cyclopentane, and urea. Several aromatic and heteroaromatic aldehydes were studied for the confirmation of the wide applicability of aq. NaICl2 for the synthesis of corresponding Biginelli products. The obtained desired products provide good to excellent yield.

3,4-Dihydropyrimidin-2(1H)-One Analogues: Microwave irradiated Synthesis with Antimicrobial and Antituberculosis Study

Background:For rapid and sustainable synthesis, microwave irradiation method is serviceable. This present study deals with the preparation of oxadiazole and pyridine bearing 1,2,3,4- tetrahydro pyrimidine derivatives by microwave irradiation.Objective:The present study aims to carry out rapid synthesis of chloro-acetamides of oxadiazoles of Biginelli product and amino cyano derivative of pyridine by microwave-assisted heating. Our efforts are focused on the introduction of chemical diversity in the molecular framework in order to synthesize pharmacologically interesting compounds.Methods::Microwave irradiation was used for the synthesis of 2-((3-cyano-4-(3,4-dichloro phenyl)- 6-(4-hydroxy-3-methoxyphenyl) pyridin-2-yl) amino)-N-(5-(substituted) -(6-methyl-2-oxo -1,2,3,4- tetrahydro pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)acetamide by using Biginelli reaction. New structural analogues were confirmed by spectral studies followed by their screening for in vitro antibacterial activity against Staphylococcus aureus, Staphylococcus Pyogenus, Escherichia coli and Pseudomonas aeruginosa bacterial strains and for antifungal activity against Candida albicans, Aspergillus niger and Aspergillus clavatus by micro-broth dilution method. In vitro antimycobacterial activity determined out against (Mycobacterium tuberculosis) H37Rv strain using Lowenstein-Jensen medium.Results:As compared to the conventional method, microwave irradiation method is advantageous for the synthesis of 1,2,3,4-tetrahydropyrimidin derivatives. Potent antimicrobial activities and antitubercular activity were found for some of the compounds.Conclusion:Microwave irradiation method provided an effective way to discover a novel class of antimicrobial and antituberculosis agents. 1,2,3,4-tetrahydropyrimidin derivatives showed improved antimicrobial and good antituberculosis activity.

Urease immobilization on magnetic micro/nano-cellulose dialdehydes: Urease inhibitory of Biginelli product in Hantzsch reaction by urea.

Micro/nano celluloses (MC)/NC) were magnetized by nanoγ-Fe2O3 into the nanoγ-Fe2O3@MC (NMMC) and nanoγ-Fe2O3@NC (NMMC) which oxidized to NMMCD and NMNCD dialdehydes for Schiff-base immobilization of urease as NMMCD/urease and NMMCD/urease. The relative enzyme-activity of the immobilized ureases were comparable with the free-urease, although 75%-80% of the enzyme activity preserved for NMMCD/urease and NMNCD/urease after six cycles. The compared catalytic activities of the NMMCD/urease and NMMCD/urease in Biginelli/Hantzsch reactions in water at 60 °C surprised us by 100% selectivity for the Biginelli product 3,4-dihydropyrimidin-2(1H)-one (DHPM1). With the superiority of NMNCD/urease, this high selectivity using immobilized ureases is owing to the admirable urease inhibitory of the formed Biginelli product DHPM1 by urea condensation instead of urea hydrolysis. The robust enzyme inhibitory of the DHPM1 for free urease was also confirmed by phenol red test to show the deactivation of enzyme for enzymatic hydrolysis of urea and ammonia production in water.

Magnesium modified calcium hydroxyapatite: An efficient and recyclable catalyst for the one-pot Biginelli condensation

Magnesium modified calcium hydroxyapatite Ca(10-x)Mgx(PO4)6(OH)2, 0 ≤ x ≤ 3, have been synthesised using double decomposition method. The resulting materials have been fully characterised by X-ray powder diffraction, chemical analysis and infrared spectroscopy. X-ray diffraction analysis shows that the obtained materials consist of a single phase having an apatitic structure. The catalytic activity of the synthesised compounds was tested on the one pot Biginelli reaction for the synthesis of 3,4-dihydropyrimidin-2-(1H)-one. The substitution of calcium by magnesium ions has a positive effect on the efficiency of the catalyst. Moreover, increasing the magnesium ion concentration in the apatite leads to better yields in Biginelli product and a faster rate of the reaction. The catalyst is easily recyclable can be used at least five times without significant change in activity.

Biginelli Reaction: Polymer Supported Catalytic Approaches.

The Biginelli product, dihydropyrimidinone (DHPM) core, and its derivatives are of immense biological importance. There are several methods reported as modifications to the original Biginelli reaction. Among them, many involve the use of different catalysts. Also, among the advancements that have been made to the Biginelli reaction, improvements in product yields, less hazardous reaction conditions, and simplified isolation of products from the reaction predominate. Recently, solid-phase synthetic protocols have attracted the research community for improved yields, simplified product purification, recyclability of the solid support, which forms a special economic approach for Biginelli reaction. The present Review highlights the role of polymer-supported catalysts in Biginelli reaction, which may involve organic, inorganic, or hybrid polymers as support for catalysts. A few of the schemes involve magnetically recoverable catalysts where work up provides green approach relative to traditional methods. Some research groups used polymer-catalyst nanocomposites and polymer-supported ionic liquids as catalyst. Solvent-free, an ultrasound or microwave-assisted Biginelli reactions with polymer-supported catalysts are also reported.

Iron(III)-catalyzed selective direct olefination of dihydropyrimidinone with aromatic aldehyde

Herein, we describe a practical approach for direct vinylogous aldol condensation of Biginelli product for carbon–carbon double bond formation at methyl group of 6-methyl dihydropirimidinone by using hydrated ferric chloride. With aromatic aldehydes, the method yields stereoselectively trans products. The olefination reaction is applicable with aldehyde without chelating (with Fe III) functional group. DHPMs with carboxylate ester and arylidene at C-6 methyl are not known. The method opens up a new avenue for the synthesis of a wide variety of DHPMs. The olefin products were subjected to dihydroxylation reaction. SYNOPSIS A convenient and facile C6-olefination at methyl centre of dihydropyrimidinones (DHPMs) has been observed in acetonitrile in the presence of hydrated $$\hbox {FeCl}_{3}$$ . The method is simple, inexpensive, and stereoselectively trans.

Urea/thiourea: efficient, inexpensive and reusable catalysts for the synthesis of pyrazole derivatives with 2-iminothiazolidin-4-one and 2,4-thiazolidinediones under solvent-free conditions.

Anefficientandgreensynthesisofpyrazolyl-2,4-thiazolidinediones/pyrazolyl-2-iminothiazolidine-4-ones 7(a-j) has been developed using urea/thiourea as catalyst. Two methods (A and B) have been introduced for the synthesis of these compounds. Method A performed well for the condensation of pyrazole-4-carboxaldehydes 4(a-e) with 2-iminothiazolidin-4-one 5a and with 2,4-thiazolidinedione 5b at 110 [Formula: see text] for 16-20minto furnish (Z)-5-((1,3-diphenyl-1H-pyrazol-4-yl)methylene)thiazolidine-2,4-diones 7(a-j) in excellent yields. In method B, the pyrazole-4-carboxaldehydes 4(a-e) were condensed with urea/thiourea at 110 [Formula: see text] for 10minto give key intermediates 6(a-j) which were later condensed with 5a and 5b to afford 7(a-j) via the elimination of urea/thiourea rather than the formation of a Biginelli product. These two protocols are inexpensive, eco-friendly and high yielding to provide the final products. The synthesis of compound 7f.

A counterion displacement assay with a Biginelli product: a ratiometric sensor for Hg2+ and the resultant complex as a sensor for Cl−

Chemosensors are prepared through a one pot, multicomponent organic synthesis and their activities are evaluated in a DMF : H2O (1 : 9, v/v) solvent system. One chemosensor has demonstrated selectivity for Hg2+ by quenching the fluorescence intensity at 394 nm with enhancement at 460 nm. Thus, the sensor offers an interesting opportunity for the ratiometric determination of Hg2+ in a semi aqueous solvent system with a detection limit of 0.2 μM. The resultant mercury complex of the same sensor is evaluated for anion recognition properties. The metal complex is highly selective for the determination of chloride in a semi aqueous medium through a counterion displacement assay.

A mechanistic investigation of Biginelli reaction under base catalysis

The mechanism of the three component base mediated Biginelli dihydropyrimidines synthesis was investigated using Accurate Mass TOF LC–MS-ESI and Tandem TOF LC–MS-ESI. We suggest hemiaminal as a possible intermediate leading to the formation of Biginelli product. Under our current experimental conditions we did not observe any bis-ureide as reported by ji et al.

Biginelli and Hantzsch-Type Reactions Leading to Highly Functionalized Dihydropyrimidinone, Thiocoumarin, and Pyridopyrimidinone Frameworks via Ring Annulation with β-Oxodithioesters

An efficient and highly convergent route to dihydropyrimidinones (DHPMs) and hitherto unreported dihydropyridopyrimidinones has been developed by one-pot, three-component cyclocondensation of aromatic aldehydes, β-oxodithioesters, and urea/6-amino-1,3-dimethyluracil in the presence of recyclable SiO2-H2SO4. On the other hand, salicylaldehyde, β-oxodithioester, and urea reacted under similar conditions to afford the 3-aroyl/heteroaroyl-2H-chromen-2-thiones in high yields instead of Biginelli product. The attractive feature of this approach is the synthesis of three important bioactive heterocyclic frameworks from the same β-oxodithioester under the similar reaction conditions, making this new strategy highly useful in diversity-oriented synthesis (DOS).

Molecular Models from a Greener, Solvent-Free Synthesis. Biginelli Product, Ethyl Acetoacetate, Monastrol, and Nifedipine

ADVERTISEMENT RETURN TO ISSUEPREVTech ReportMolecular Models from a Greener, Solvent-Free Synthesis. Biginelli Product, Ethyl Acetoacetate, Monastrol, and NifedipineWilliam F. Coleman View Author Information Department of Chemistry, Wellesley College, Wellesley, MA 02481Cite this: J. Chem. Educ. 2009, 86, 6, 768Publication Date (Web):June 1, 2009Publication History Received3 August 2009Published online1 June 2009Published inissue 1 June 2009https://doi.org/10.1021/ed086p768RIGHTS & PERMISSIONSArticle Views1613Altmetric-Citations1LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (123 KB) Get e-AlertsSupporting Info (14)»Supporting Information Supporting Information SUBJECTS:Ethyl groups,Molecular modeling,Molecules Get e-Alerts

Oxidation of Biginelli Reaction Products: Synthesis of 2-Unsubstituted 1,4-Dihydropyrimidines, Pyrimidines, and 2-Hydroxypyrimidines

We have devised a new route toward 2-unsubstituted pyrimidine derivatives from the Biginelli product, dihydropyrimidin-2(1H)-thiones in two steps: Oxidation of dihydropyrimidin-2(1H)-thiones using oxone on wet alumina or hydrogen peroxide in the presence of catalytic amount of vanadyl sulfate provided 1,4-di­hydropyrimidine, which was further oxidized to 2-unsubstituted ­pyrimidines by the treatment of KMnO4. Oxidation of dihydropyrimidin-2(1H)-ones by KMnO4 formed 2-hydroxypyrimidine in excellent yield, whereas attempted direct desulfurative aromatization of dihydropyrimidin-2(1H)-thiones by KMnO4 resulted in the formation of 2-hydroxypyrimidines, the same products obtained in the oxidation of dihydropyrimidin-2(1H)-one.

Biginelli-like reaction with dialkyl acetone-1,3-dicarboxylates: a remarkable case of steric control

A Biginelli-type condensation is described using dialkyl acetone-1,3-dicarboxylates as active methylene compounds for the preparation of monastrol analogues. Unexpectedly, the reaction with salicylaldehyde formed two different products depending on the ester alkyl group. This product dichotomy was found to be caused by the steric effects exerted by the alcohol terminus of the ester group in the active methylene component. Previous controversial results as to the structure of the Biginelli product 3 are also discussed.

A microwave-assisted synthesis of 3,4-dihydro-pyrimidin-2-(1 H)-ones catalyzed by FeCl 3-supported Nanopore Silica under solvent-free conditions

Lewis acid supported Nanopore Silica catalysts for microwave-assisted Biginelli reaction under solvent-free conditions were prepared by impregnating FeCl 3 dissolved in ethanol to Nanopore Silica at 40 °C. Biginelli reaction under solvent-free conditions, one-pot three-component condensation of urea, benzaldehyde, and ethyl acetoacetate, catalyzed with porous material or Lewis acid supported porous material, such as MCM-41, SBA-15, VSB-5, Nanopore Silica, FeCl 3/MCM-41, FeCl 3/Nanopore Silica, CeCl 3/Nanopore Silica and InCl 3/Nanopore Silica, was investigated. Our recent results of the microwave-assisted Biginell reaction of some benzaldehyde derivatives starting materials using MCM-41, Nanopore Silica, FeCl 3/Nanopore Silica, under solvent-free conditions are also reported. Aromatic aldehydes carrying either electron releasing or electron withdrawing substituents in the ortho, meta, and para positions afforded good yields of the products using MCM-41 as a catalyst. When Nanopore Silica was used as a catalyst, the yield of the Biginelli product was in the range of 27–56%. However FeCl 3/Nanopore Silica has been employed as a catalyst, the yield of the Biginelli product was increased dramatically. Thus it has been found that the use of FeCl 3/Nanopore Silica as heterogeneous catalyst has made this method very cost effective.

One-pot synthesis of Biginelli and Hantzsch products catalyzed by non-toxic ionic liquid (BMImSac) and structural determination of two products

In this paper, both 1,4-dihydropyridinones (Hantzsch products) and 3,4-dihydropyrimidinones (Biginelli products) are synthesized in one-pot of aldehydes, β-dicarbonyl compounds and urea, catalyzing by non-toxic room temperature ionic liquid 1- n-butyl-3-methylimidazolium saccharinate (BMImSac). The ionic liquid (BMImSac) is environmentally benign associated with ionic liquid with F −. In order to improve the yield and selectivity, the effects of the mole proportion of reactants and solvents are investigated. Interestingly, by increasing the amount of ethyl acetoacetate or utilizing water as solvent, an unexpected by-product, Hantzsch product which is distinct from Biginelli product, is generated. All Biginelli and Hantzsch products are simultaneously purified and characterized by IR, 1H NMR and 13C NMR, of which one Biginelli product ( 4h) and one Hantzsch product (5b) are structurally determinated by X-ray single crystal diffraction. The crystal data for 4h: triclinic system, P-1 space group, a = 7.515(3) Å, b = 9.011(4) Å, c = 11.218(5) Å, α = 106.288(6)°, β = 104.644(6)°, γ = 100.234(6)°, Z = 2, V = 679.7(5) Å 3, D c = 1.36 g/cm 3, R 1 = 0.0603. The crystal data for 5b: monoclinic system, P2(1)/ c space group, a = 9.765(3) Å, b = 7.391(2) Å, c = 24.795(7) Å, β = 93.669(5)°, Z = 4, V = 1785.7(9) Å 3, D c = 1.292 g/cm 3, R 1 = 0.0440.