Three-component Biginelli Reaction Research Articles

Biginelli reaction in the synthesis of ethyl 4-(6-aryl-5-benzoyl-4-hydroxy-2-thioxohexahydropyrimidine-4-carboxamido)benzoates

Three-component Biginelli reaction of ethyl 4-(2,4-dioxo-4-phenylbutanamido)benzoate, aromatic aldehyde and thiourea in acetic acid in the presence of sodium acetate led to the formation of ethyl 4-(6-aryl-5-benzoyl4-hydroxy-2-thioxohexahydropyrimidine-4-carboxamido)benzoates. Structure of the obtained compounds was established by IR, 1H NMR, 13C spectroscopy methods.

Synthesis of novel adamantane-containing dihydropyrimidines utilizing Biginelli condensation reaction

Novel dihydropyrimidines incorporating an adamantane motif have been synthesized using a three-component Biginelli reaction of adamantane-containing β-keto amide N-1-adamantyl acetoacetamide as active methylene compound, thiourea, and aromatic aldehydes in more convenient condition and high yields. The structures of the synthesized compounds were confirmed by spectral data.

SYNTHESIS OF DIHYDROTETRAZOLOPYRIMIDINE DERIVATIVES AS ANTICANCER AGENTS AND INHIBITOR OF α-GLUCOSIDASE

A series of dihydrotetrazolopyrimidine derivatives were prepared to utilize a three-component Biginelli reaction from ethyl 3-oxo butanoate, 5-amino tetrazole, and various aromatic aldehydes as reactants, pTSA as a Brønsted acid catalyst, and ethanol as the solvent. The structure of the prepared compounds was established by spectroscopic evidence, FTIR, HRMS, and NMR (1H- and 13C-) spectra. The electronic properties of the aromatic aldehyde's substituents affected the reaction's time and yield. Substituents possessing electron-donating character accelerated the reaction time but decreased the reaction yield, whereas substituents with electron-withdrawing properties slowed the reaction but increased the yield. The prepared compounds exhibited moderate to strong anti-proliferative activities against 4T1 and HeLa cancer cell lines. Compound Ethyl (E)-5-methyl-7-(1-phenylprop-1-en-2-yl)-4,7- dihydrotetrazolo[1,5-a]pyrimidine-6-carboxylate and compound Ethyl 7-(1H-indol-3-yl)-5-methyl-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carboxylate) showed strong anti-proliferative activities in vitro through induction apoptotic cells death mechanism. In addition, five of the synthesized compounds exhibited better inhibitory activity of α-glucosidase than quercetin, the positive control.

Biginelli Reaction Synthesis of Novel Multitarget-Directed Ligands with Ca2+ Channel Blocking Ability, Cholinesterase Inhibition, Antioxidant Capacity, and Nrf2 Activation.

Novel multitarget-directed ligands BIGI 4a-d and BIGI 5a-d were designed and synthesized with a simple and cost-efficient procedure via a one-pot three-component Biginelli reaction targeting acetyl-/butyrylcholinesterases inhibition, calcium channel antagonism, and antioxidant ability. Among these multitarget-directed ligands, BIGI 4b, BIGI 4d, and BIGI 5b were identified as promising new hit compounds showing in vitro balanced activities toward the recognized AD targets. In addition, these compounds showed suitable physicochemical properties and a good druglikeness score predicted by Data Warrior software.

Ethyl-4-(aryl)-6-methyl-2-(oxo/thio)-3,4-dihydro-1H-pyrimidine-5-carboxylates: Silica supported bismuth(III)triflate catalyzed synthesis and antioxidant activity

Novel ethyl-4-(aryl)-6-methyl-2-(oxo/thio)-3,4-dihydro-1H-pyrimidine-5-carboxylates were synthesized from one-pot, three-component Biginelli reaction of aryl aldehydes, ethyl acetoacetate and urea/ thiourea by catalytic action of silica supported Bismuth(III) triflate, a Lewis acid. All the synthesized compounds were structurally characterized by spectral (IR, 1H NMR &13C NMR spectroscopic and Mass spectrometric) and elemental (C, H & N) analyses. The present protocol has deserved novel as, formed the products in high yields with short reaction times, involved eco-friendly methodology and reusable heterogeneous Lewis acid catalyst. The title compounds were screened for in vitro DPPH free radical scavenging antioxidant activity and identified 4i, 4j, 4h & 4f as potential antioxidants. The obtained in vitro results were correlated with molecular docking, ADMET, QSAR, Bioactivity & toxicity risk studies and molecular finger print properties and found that in silico binding affinities were identified in good correlation with in vitro antioxidant activity and studied the structure activity relationship. The molecular docking study has disclosed strong hydrogen bonding interactions of title compounds with aspartic acid (ASP197) aminoacid residue of 2HCK, a complex enzyme of haematopoietic cell kinase and quercetin. Results of toxicology study evaluated for potential risks of compounds have revealed title compounds as safer drugs. In ultimate the study has established ligand’s antioxidant potentiality as they effectively binds with ASP197 amino acid of Chain A hence confirms the inhibition of growth of reactive oxygen species in vivo. In addition, the title compounds have been identified as potential blood–brain barrier penetrable entities and efficient central nervous system (CNS) active neuro-protective antioxidant agents.

Structural and electronic investigation of 3,4-dihydropyrimidin-2(1H)-ones (DHPMs): Correlations between spectroscopic and molecular docking features upon salmon sperm DNA

A set of 3,4-dihydropyrimidin-2(1H)-ones (DHPMs) was prepared via a “one-pot” three-component Biginelli reaction using different aldehydes, ethyl acetoacetate, urea, and catalyzed by iron chloride hexahydrate. Subsequently, these compounds were submitted to chemical oxidation with nitric acid in order to obtain their respective oxidized forms. Density functional theory (DFT) was applied to investigate the structural, electronic, and bonding characteristics of these compounds. This study results show that in the DHPMs (1-3), the six-membered ring adopts a pseudo-boat conformation, and the heights of the C4 and N1 atoms from the boat plane depend on the type of the substituent on the aryl ring. Experimental electronic spectra for all compounds were recorded and compared with simulations obtained by time-dependent-DFT (TD-DFT). The interaction between those DHPMs and salmon sperm DNA was monitored spectrophotometrically in the UV region, binding constants (Kb) were estimated, and docking studies were performed using the PatchDock® server. Considering the differences in overall planarity and spectral signature of the compounds studied, we concluded that the reduced DHPMs are prone to achieve partial intercalation of their structures between the DNA nitrogen base pairs while the oxidized ones prefer to stay deep inside of the minor groove of this biomolecule.

Triazole based oxidovanadium(V) complex supported on chloromethylated polymer and its catalytic activity for the synthesis of dihydropyrimidinones (DHPMs)

Oxidovanadium(V) complex [VVO(OEt)(µ-Hhptb)]2 (1) of 4-[3,5-bis(2-hydroxyphenyl)-1H-1,2,4-triazol-1-yl] benzoic acid (H3hptb) has been prepared by the reaction of VVO(OEt)3 with ligand in EtOH. Complex 1 has been immobilized on chloromethylated polystyrene (PS–Cl) to obtain PS–[VVO(OEt)(hptb)(EtOH)] (2). The homogeneous complex 1 was characterised by elemental analysis, spectroscopic techniques (FT-IR, UV-Vis, 1H and 13C NMR) and thermogravimetric analysis, while the heterogeneous complex was additionally studied by field emission-scanning electron microscopy, energy dispersive spectroscopy and atomic force microscopy. These complexes have been utilized in catalysing one-pot three-component (benzaldehyde or its derivatives, urea and ethyl acetoacetate) Biginelli reaction producing multifunctionalized 3,4-dihydropyrimidin-2-(1H)-ones (DHPMs) under solvent-free conditions. It was observed that H2O2 helps in improving the yield of the products. Various parameters, such as the amount of catalyst and oxidant, time, temperature, and solvent effects, were optimized for the maximum yield of DHPMs. The heterogeneous complex is found to show excellent catalytic activity giving more than 90% conversion of DHPMs under the optimized reaction conditions. A suitable reaction pathway for this reaction has been proposed with the help of DFT computation.

Efficient One-Pot Synthesis of 3,4-Dihydropyrimidin-2(1H)-ones via a Three-Component Biginelli Reaction.

Multicomponent reactions are considered to be of increasing importance as time progresses due to the economic and environmental advantages such strategies entail. The three-component Biginelli reaction involves the combination of an aldehyde, a β-ketoester and urea to produce 3,4-dihydropyrimidin-2(1H)-ones, also known as DHPMs. The synthesis of these products is highly important due to their myriad of medicinal properties, amongst them acting as calcium channel blockers and antihypertensive and anti-inflammatory agents. In this study, silicotungstic acid supported on Ambelyst-15 was used as a heterogeneous catalyst for the Biginelli reaction under solventless conditions. Electron-poor aromatic aldehydes gave the best results. Sterically hindered β-ketoesters resulted in lower reaction yields. The reaction was carried out under heterogeneous catalysis to allow easy recovery of the product from the reaction mixture and recycling of the catalyst. The heterogeneity of the reaction was confirmed by carrying out a hot filtration test.

Chitosan-silica Sulfate Nano Hybrid: An Efficient Biopolymer Based-heterogeneous Nano Catalyst for Solvent-free Synthesis of 3,4-Dihydropyrimidine-2(1H)-one/thiones

A green and highly efficient approach for the synthesis of 3,4-dihydropyrimidine-2(1H)-one/thione derivatives is described. In this approach, the three-component Biginelli reaction between (thio)urea, methyl acetoacetate and aldehydes under solvent-free condition in the presence of chitosan-silica sulfate nano hybrid (CSSNH) as a green and heterogeneous nano catalyst affords the corresponding products in good to excellent yields and in short reaction times. CSSNH is a cheap, eco-friendly, and non-toxic nano catalyst that could be easily prepared, handled, and reused for many reaction runs without significant loss of its activity.

Synthesis of 3,4-Dihydropyrimidin-2(1H)-one-phosphonates by the Microwave-Assisted Biginelli Reaction

The synthesis of novel 3,4-dihydropyrimidin-2(1H)-one-phosphonates was elaborated by the microwave (MW)-assisted three-component Biginelli reaction of β-ketophosphonates, aromatic or aliphatic aldehydes and urea derivatives. The condensation was optimized on a selected model reaction in respect of the reaction parameters, such as the heating method, the type of the catalyst and solvent, the temperature, the reaction time and the molar ratio of the starting materials. The fast and solvent-free MW-assisted procedure was then extended for the preparation of further new 3,4-dihydropyrimidin-2(1H)-one-phosphonate derivatives starting from different aromatic aldehydes, β-ketophosphonates and urea derivatives to prove the wide scope of the process. As a novel by-product of the Biginelli-type synthesis of 3,4-dihydropyrimidin-2(1H)-one-phosphonates, the 5-diethoxyphosphoryl-4-phenyl-6-styryl-3,4-dihydropyrimidin-2(1H)-one was also isolated and characterized. Our MW-assisted method made also possible the condensation of aliphatic aldehydes, diethyl (2-oxopropyl)phosphonate and urea, which reaction was previously reported to be impossible in the literature.

Biginelli Synthesis of Regioisomeric 5,6-Dihydro-4H-benzo[4,5]imidazo[1,2-a]pyranopyrimidin-4-ones

A modified version of the three-component Biginelli reaction of 4-hydroxy-6-methyl-2H-pyran-2-one with aromatic aldehydes and 1H-benzimidazol-2-amine has been studied under thermal and microwave activation. Depending on the substituent in the initial aldehyde, angularly fused 5,6-dihydro-4H-benzo[4,5]imidazo[1,2-a]pyranopyrimidin-4-ones or 2-amino-1H-benzimidazol-3-ium arylbis(4-hydroxy-6-methyl-2-oxo-2H-pyran-3-yl)methanides have been obtained. A plausible mechanism of their formation has been proposed.

PPh3/I2-catalyzed one-pot synthesis of 4,6-diarylpyrimidin-2(1H)-ones

A method using PPh3/I2-catalyzed three-component Biginelli reaction of aromatic ketone, aromatic aldehyde and urea to synthesize4,6-diarylpyrimidin-2-(1H)-ones is described. Under the experimental conditions, the main reaction products are 4,6-diarylpyrimidin-2-(1H)-ones not 4,6-diaryl-3,4-dihydropyrimidin-2(1H)-ones. The advantage of this method is to achieve improved product yields with an inexpensive and readily available catalyst, and easy experimental set-up, which provides a good method to synthesize 4,6-diarylpyrimidin-2-(1H)-ones.

CoFe2O4@SiO2-NH2-CoII NPs: An effective magnetically recoverable catalyst for Biginelli reaction

Biginelli reaction entails acid-catalyzed one-pot synthesis of 3,4-dihydropyrimidin-2(1H)-ones (DHPMs) with simply-accessible initial substances, specifically, aldehyde, urea, and active methylene compound. DHPMs have stimulated a resurgence of attention in the previous two decades because of their broad-ranging pharmacological actions and the existence of varied all-natural products. Currently, green methods to asymmetric Biginelli reaction have been researched for anti-inflammatory DHPMs. In materials chemistry, DHPMs are increasingly decision applications in the creation of materials like polymers, adhesives, fabric dyes, etc. In light of the simplicity by which the Biginelli reaction is conducted, numerous interesting prospects expect its exploitation in variety fields. CoFe2O4@SiO2-NH2-CoII is herein turned out to be an effective catalyst at a three-component Biginelli reaction. The yield of the corresponding DHPMs was rather large (20 cases; average 92 percent). Finally, we herein suggest a procedure that shows lots of advantages and benefits such as the whole lack of solvents, mild reaction conditions, comparatively short reaction times. Also, CoFe2O4@SiO2-NH2-CoII NPs catalyst has been readily recovered from the reaction combination and reused, without the decrease of catalytic action.

In silico Design and Synthesis of Tetrahydropyrimidinones and Tetrahydropyrimidinethiones as Potential Thymidylate Kinase Inhibitors Exerting Anti-TB Activity Against Mycobacterium tuberculosis.

Background and PurposeTuberculosis has been reported to be the worldwide leading cause of death resulting from a sole infectious agent. The emergence of multidrug-resistant tuberculosis and extensively drug-resistant tuberculosis has made the battle against the infection more difficult since most currently available therapeutic options are ineffective against these resistant strains. Therefore, novel molecules need to be developed to effectively treat tuberculosis disease. Preliminary docking studies revealed that tetrahydropyrimidinone derivatives have favorable interactions with the thymidylate kinase receptor. In the present investigation, we report the synthesis and the mycobacterial activity of several pyrimidinones and pyrimidinethiones as potential thymidylate kinase inhibitors.MethodsThe title compounds (1a–d) and (2a–b) were synthesized by a one-pot three-component Biginelli reaction. They were subsequently characterized and used for whole-cell anti-TB screening against H37Rv and multidrug-resistant (MDR) strains of Mycobacterium tuberculosis (MTB) by the resazurin microplate assay (REMA) plate method. Molecular modeling was conducted using the Accelry’s Discovery Studio 4.0 client program to explain the observed bioactivity of the compounds. The pharmacokinetic properties of the synthesized compounds were predicted and analyzed.ResultsOf the compounds tested for anti-TB activity, pyrimidinone 1a and pyrimidinethione 2a displayed moderate activity against susceptible MTB H37Rv strains at 16 and 32 µg/mL, respectively. Only compound 2a was observed to exert modest activity at 128 µg/mL against MTB strains with cross-resistance to rifampicin and isoniazid. The presence of the trifluoromethyl group was essential to retain the inhibitory activity of compounds 1a and 2a. Molecular modeling studies of these compounds against thymidylate kinase targets demonstrated a positive correlation between the bioactivity and structure of the compounds. The in-silico ADME (absorption, distribution, metabolism, and excretion) prediction indicated favorable pharmacokinetic and drug-like properties for most compounds.ConclusionPyrimidinone 1a and pyrimidinethione 2a were identified as the leading compounds and can serve as a starting point to develop novel anti-TB therapeutic agents.

Long-chain Brønsted acidic ionic liquids catalyzed one-pot three-component Biginelli reaction

Purpose From the atom economy and environmentally friendly point of views, the development of clean and green approaches using ionic liquids (ILs) as recyclable catalysts has attracted increasing attention. The purpose of this study is to investigate the effect of task-specific ILs content on the one-pot three-component Biginelli reaction. Design/methodology/approach A series of halogen-free quaternary ammonium ILs functionalized with –SO3H group were prepared and characterized by 1H nuclear magnetic resonance (NMR), 13C NMR and electrospray ionization mass spectrometry. The ILs were used as catalysts for Biginelli reaction among aromatic aldehydes, urea or thiourea and β-dicarbonyl compounds. Anions and cations of ILs were varied to observe their effects on and contributions to the catalysts. The influencing factors, such as the amount of catalyst, solvent, reaction time and reaction temperature, were investigated. Findings The effect and contribution of cations of ILs were observed. Results showed that 3-(N, N-dimethylhexadecylammonium) propanesulfonic acid toluene sulfate ([DHPA][Tos]) showed comparable catalytic activity. Good adaptability to the reaction substrate and maximum product yield was observed when [DHPA][Tos] was used as catalyst. It was found that Biginelli reaction catalyzed by 10 mol% [DHPA][Tos] for 3 h under solvent-free conditions at 80 °C gave the best yield of 94%. Post-processing steps were simple, and the catalyst could be reused easily. Originality/value This paper demonstrates that ILs containing a long carbon chain and a bulky Tos anion efficiently promoted the reaction, in which the long carbon chains facilitate mass transfer in the reaction system.

Study of polycarbosilane-supported copper(II) as a heterogeneous catalyst

Polycarbosilane containing Cu(II) (Cu-PCS) was prepared. The performance of Cu-PCS as a catalyst was verified using the three-component Biginelli reaction. It was found to be a good catalyst. The product, dihydropyrimidinone, could be easily isolated from the reaction medium. The heterogeneous nature of the catalyst helped in separating the product. The reaction conditions were optimized, and the catalyst was found to be reusable. The catalytic activity of Cu-PCS was compared with that of Cu ion supported on SBA-15 and amorphous silica. Cu-PCS exhibited better catalytic activity, recyclability and was devoid of metal leaching.

Long-chain Brønsted Acidic Ionic Liquids Catalyzed one-pot three-component Biginelli Reaction under Solvent-Free Conditions

A series of halogen-free quaternary ammonium Brønsted acidic ionic liquids (ILs) were prepared and used for Biginelli reaction among aromatic aldehydes, urea or thiourea and β-dicarbonyl compounds. The influencing factors, such as the type and amount of catalyst, solvent, reaction time and reaction temperature, were investigated. The results demonstrated that the 3-(N,N-dimethylhexadecylammonium) propanesulfonic acid toluene sulfate ([DHPA][Tos]) provide the best catalytic activity, with good catalytic performance and reusability under solvent-free conditions. A possible mechanism that accounted for the [DHPA][Tos]-catalyzed reaction was proposed.

The Effects of Different Catalysts, Substituted Aromatic Aldehydes on One-Pot Three-Component Biginelli Reaction.

The Biginelli reaction, first reported in 1893, is one great example of the important multicomponent reactions reported from 1893. Under the same conditions, the influence of the common catalysts on the yield of the Biginelli reaction was investigated. To a round-bottom flask equipped with a spherical condenser were added 1,3- dicarbonyl compound (1.0 eq), urea (1.45 eq), aromatic aldehyde (1.0 eq), catalyst and methanol. The mixture was heated at reflux for 16 h. After cooling off, the mixture was filtered and washed with cold methanol to give DHPMs. Reaction solution was further purified by recrystallization with petroleum ether and ethyl acetate. Six catalytic systems, different 1,3-dicarbonyl compounds and different substituted aromatic aldehydes with varied substitutions are described for the Biginelli reaction. An analysis was also performed to study the factors that affect the yield of the reaction. When 1,3-dicarbonyl compound was ethyl acetoacetate, the CuCl/ conc.H2SO4 system gave the highest yield (90.5%). While when acetoacetamide was used, the yields of DHPMs in presence of PTSA/conc. HCl, conc. HCl or FeCl3•6H2O were all over 90%. Nine DHPMs with different substituents were obtained. The Lewis acid or mixed catalyst had no significant advantage over a single protonic acid as catalyst. Conc. HCl as the catalyst was found to be the most effective condition for the preparation of DHPMs. The aromatic aldehyde with weak electron-withdrawing substituent such as Br resulted in the best yield.

Antioxidant properties of derivatives of 3,4-dihydropyrimidin-2-one with sterically hindered phenolic substituent in heterocycle

In the processes of free-radical oxidation of organic compounds, the inhibitory action of the inhibitor is mainly due to either the breakdown of the reaction chains on its molecules, or the slowdown of the decomposition of intermediate hydroperoxides, or both at the same time. We analysed the inhibitory properties of 4-[3,5-di(tert-butyl)-4-hydroxyphenyl]-5-ethoxycarbonyl-6-methyl-3,4-dihydropyrimidin-2-one (I) and 4-[4-methoxyphenyl]-5-ethoxycarbonyl-6-methyl-3,4-dihydropyrimidin-2-one (II) gasometry and hydroperoxide decomposition methods. These compounds were obtained by the three-component Biginelli reaction. The decomposition of cumene hydroperoxide in dimethylformamide under these conditions is described by a first-order kinetics equation. The first compound significantly inhibits the decomposition of hydroperoxide. The dependence of the effective rate constant of the decomposition of cumene hydroperoxide on the first concentration is described by the equation: . The second compound also slows the decomposition of hydroperoxide, but much less than the first compound. Therefore, both the phenolic moiety and the urea moiety of the dihydropyrimidinone cycle take part in slowing the cumene hydroperoxide decomposition. Initiated oxidation of cumene happened at 343 K with the presence of the initiator azodiisobutyronitrile. The concentration of the first compound varied from 1,5·10-4 to 2,5·10-3 mol/l. With a concentration of the first compound 1,25·10-3 and 2,5·10-3 mol/l, the duration of the induction period exceeds 80 min. In the concentration range (1,5÷6,3)·10-4 mol/l the linear change in the duration of the induction period is observed. 4-[3,5-Di(tert-butyl)-4-hydroxyphenyl]-5-aminocarbonyl-6-methyl-3,4-dihydropyrimidin-2-one is a more effective inhibitor than the ionol due to the urea moiety of the dihydropyrimidinone cycle. Confirmation is the notable antioxidant activity of the second compound. In conclusion, 4- [3,5-di (tert-butyl)-4-hydroxyphenyl]-5-ethoxycarbonyl-6-methyl-3,4-dihydropyrimidin-2-one is a bifunctional inhibitor.

CeCl3-Catalyzed a Highly Efficient and Eco-friendly Synthesis of New and Densely Functionalized Thiazolo[3,2-a]Pyrimidins via Biginelli-type Reaction

5-Carboxanilide-dihydropyrimidinone derivatives were prepared by three-component Biginelli reaction of acetoacetanilide, aromatic aldehydes and thiourea in the presence of CeCl3 as an expedient catalyst and used as key intermediates for the highly efficient and eco-friendly synthesis of new and densely functionalized thiazolo[3,2-a]pyrimidin derivatives with use of dimethyl and diethyl acetylenedicarboxylate in ethanol at ambient temperature (conventional magnetic stirring).