One-pot Multicomponent Reaction Research Articles

Revisiting the Synthesis of Betti Bases: Facile, One-pot, and Efficient Synthesis of Betti Bases Promoted by FeCl3•6H2O.

Betti bases are pharmaceutically and synthetically important scaffolds due to their diverse range of biological activities and applications in key synthetic transformations in organic synthesis. This work has been sought to contribute to the development, design, and implementation of an improved green methodology with higher atom economy and lower E-factor values for the synthesis of Betti bases. To realize our objectives, we screened out different catalysts and reaction conditions using one-pot multicomponent modified Mannich reaction/Betti reaction by employing 2-naphthol, benzaldehyde and pyrrolidine as model substrates. The developed methodology afforded functionalized Betti bases in 60-100% yields via FeCl3•6H2O catalyzed one-pot multi-component Betti reaction under neat conditions at 110 °C (5-15 min) using several aromatic aldehydes and secondary amines. A facile synthetic methodology with higher atom economy and lower E-factor values to synthesize Betti bases via FeCl3•6H2O catalyzed one-pot multicomponent Betti reaction of 2-naphthol, aromatic aldehydes, and secondary amines under neat conditions at 110 °C has been reported. The developed methodology offers various advantages, such as excellent yields (60-100%), short reaction time (5-15 min), wide substrate scope (12 examples), green reaction conditions, use of readily available catalyst, and easy purification (without column chromatography).

Concise One-Pot Multicomponent Reaction Approach to Mono­fluo­rinated Spiro-pyrazole-pyridine Derivatives without Additional Catalyst

AbstractMonofluorinated bis-heterocyclic spirocycles: functionalized ethyl 9-fluoro-8-methyl-1,4-dioxo-2,3,6,10-tetraphenyl-2,3,7-triazaspiro[4.5]dec-7-ene-9-carboxylate derivatives were efficiently synthesized from readily available 1,2-diphenylpyrazolidine-3,5-dione, ethyl 2-fluoroacetoacetate, aromatic aldehydes, and ammonium acetate via one-pot four-component reactions in the absence of additional catalyst. In the protocols, ammonium acetate serves not only as the fourth component but also as the catalyst.

A Quick Access to Structurally Diverse Triazoloquinazoline Heterocycles via the MIL-101(Cr)-Catalyzed One-Pot Multi-Component Reaction of a Series of Benzaldehydes, Dimedone, and 1H-1,2,4-Triazol-3-Amine Under Green Conditions.

A one-pot multicomponent reaction of a variety of benzaldehydes, dimedone, and 1H-1,2,4-triazol-3-amine for the efficient synthesis of quinazolinone derivatives under green conditions is reported. It was proved that MIL-101(Cr) could carry out successfully this multicomponent strategy to afford target products in high yields. The scope and limitation of this catalytic system concerning the aldehyde substrates were explored. Different aldehydes could be conveniently delivered to quinazolinones at room temperature with short reaction times in an atom-economy way. Notably, MIL-101(Cr) was also characterized by different analytic methods such as FT-IR, SEM, and EDX. The outstanding benefits of this methodology are the availability of substrates, using green conditions, excellent functional group compatibility, and reusability of catalysts, therefore providing easy access to a range of products of interest in organic and medicinal chemistry.

Green Synthesis and Antioxidant Activity Investigation of New Thiazinotriazines: Reduction of Organic Pollutant Using Fe3O4/TiO2/CuO@MWCNTs MNCs

The Petasites hybridus rhizome water extract was used as a green media for the preparation of the Fe3O4/TiO2/CuO@MWCNTs magnetic nanocomposites (Fe3O4/TiO2/CuO@Multi-Walled Carbon Nanotubes) and its activity was evaluated by using it in the one-pot multicomponent reaction of isatoic anhydrides, electron deficient acetylenic compounds, α-haloketones, ammonium acetate, isothiocyanates and hydrazoyl chloride in aqueous media at room temperature for the production of novel derivatives of thiazinotriazines in excellent yields. Moreover, reduction of organic pollutants such 4-nitrophenol (4-NP) was performed by synthesized Fe3O4/TiO2/CuO@MWCNTs magnetic nanocomposites in water at room temperature. The outcomes showed this catalyst decreased organic pollutants in few seconds. The synthesized thiazinotriazines have OH and NH functional groups that have acidic hydrogen and show high antioxidant activity. The employed process for the production of thiazinotriazines has some benefits such as short time of reactions, excellent efficiency of product, easy separation of catalyst and products. HIGHLIGHTS In medicinal chemistry, the heterocyclic compounds have a well-known subject due to having wide area of biological activities of these compounds. Therefore these compounds are very important and for the synthesis of these compounds existed many procedures. Multicomponent reactions (MCRs) is one of the process for the preparation of biological activities heterocyclic compounds with many benefits such as having atom economic, an useful and excellent efficiency in the generation of heterocyclic compounds relative to many stage reactions for preparation of organic compounds The present procedure avoids the use of toxic solvent. Benzazepines, which have a seven-membered aza-heterocyclic fused aromatic ring, are of interest because of their biological activity and use as building blocks for natural product synthesis and drug discovery.

Novel and sustainable synthesis of tetrahydrobenzo[b]pyrans using magnetic zinc ferrites modified SBA-15 supported ionic liquids as efficient and reusable catalysts

A series of magnetic zinc ferrites modified SBA-15 supported ionic liquids has been synthesized and evaluated as effective catalysts for the one-pot multi-component reaction of equimolar amounts of aldehydes, malononitrile and 1,3-cyclohexanedione in aqueous medium. Most of these magnetic supported ionic liquids showed good results in the reaction, especially the catalysts Zn0.2Fe2.8O4@SBA-150.5@CH3COO(0.2) and Zn0.2Fe2.8O4@SBA-150.5@ILCH3COO(0.3). The most active and suitable catalyst was the catalyst Zn0.2Fe2.8O4@SBA-150.5@CH3COO(0.2), which containing synergestic zinc ferrites and ionic liquid active sites effect and can efficiently and selectively produce the corresponding tetrahydrobenzo[b]pyrans in high to excellent yields at room temperature. Moreover, the catalyst exhibited excellent stability and could be easily recovered and reused for six times without a considerable decrease in catalytic activity. Green reaction conditions, ease work-up, feasibility, cleaner reaction profile, simple purification, sustainable and stable recyclability of catalyst are some advantages of the present protocol.

Lipase Catalyzed One-Pot Synthesis of 3-Methyl-4-(Hetero) Arylmethyleneisoxazole-5(4H)-Ones under Aqueous Conditions

Present work reports an efficient and environmentally benign approach for the synthesis of isoxazole-5(4H)-ones derivatives using lipase as biocatalyst. The one-pot multicomponent reaction of aldehyde, ethyl acetoacetate, and hydroxylamine hydrochloride at room temperature gives a 3-methyl-4-(hetero) arylmethylene isoxazole-5(4H)-ones derivatives using water as a solvent. The present protocol has many advantages such as shorter reaction time, excellent yields of products, easy work-up procedure, wide substrate scope tolerance, economical, etc. Moreover, the catalyst (lipase) was recovered and can be reused (up to four to five cycles) without significant loss of its catalytic activity.

Copper-catalyzed cascade reaction of indole and benzimidazole radicals to synthesize 3-haloindole-benzimidazole compounds

A one-pot multi-component cascade reaction strategy between benzimidazole, indole, and N-halosuccinimides was developed through the combination of the Cu(II) catalyst and (bis(trifluoroacetoxy)iodo)benzene, mediated by initiating the formation of benzimidazole nitrogen-centered radicals. This strategy realizes the formation of nitrogen radicals centered on the aromatic nitrogen atoms in the ring. On this basis, the radical-level combined synthesis of substituted 3-haloindole-benzimidazole compounds was achieved. Furthermore, this study provides a reference direction for subsequent work utilizing nitrogen radicals.

New s-Triazine/Tetrazole conjugates as potent antifungal and antibacterial agents: Design, molecular docking and mechanistic study

A novel hybrid N2-(tetrazol-5-yl)-6-substituted-5,6-dihydro-1,3,5-triazine-2,4-diamines have been synthesized in excellent yields through one-pot multi-component reaction of 5-amino-1,2,3,4-tetrazole, cyanamide and aromatic/heteroaromatic aldehydes in acetic acid promoted by controlled microwave heating. All the obtained heterocycles were screened for their antimicrobial and antifungal activities. New series (4a-j) were developed through binding of s-triazine and tetrazole in one compact structure. The tested compounds showed excellent antibacterial activity against the Gram-negative bacterial strains, P. aeruginosa and E. coli compared to ciprofloxacin. The same derivatives experienced high outstanding activity against C. albicans compared to Fluconazole. Investigation of the mode of action as antibacterial agents revealed that the most active compound 4a has good inhibitory effect for DNA gyrase and topoisomerase IV ATPase and E. coli TOPO IV and DNA gyrase supercoiling. Additionally, 4a and 4g showed good in vitro inhibitory activity to lanosterol 14-α-demethylase (CYP51 protein) and good fitting to the same protein as possible antifungal target. Similarly, the target compounds have acceptable ADME and drug-likeness properties without any violation. Hence, new highly potent antibacterial and antifungal candidates were introduced that require further optimization.

Functionalized Triazines and Tetrazines: Synthesis and Applications.

The molecules possessing triazine and tetrazine moieties belong to a special class of heterocyclic compounds. Both triazines and tetrazines are building blocks and have provided a new dimension to the design of biologically important organic molecules. Several of their derivatives with fine-tuned electronic properties have been identified as multifunctional, adaptable, switchable, remarkably antifungal, anticancer, antiviral, antitumor, cardiotonic, anti-HIV, analgesic, anti-protozoal, etc. The objective of this review is to comprehensively describe the recent developments in synthesis, coordination properties, and various applications of triazine and tetrazine molecules. The rich literature demonstrates various synthetic routes for a variety of triazines and tetrazines through microwave-assisted, solid-phase, metal-based, [4+2] cycloaddition, and multicomponent one-pot reactions. Synthetic approaches contain linear, angular, and fused triazine and tetrazine heterocycles through a combinatorial method. Notably, the triazines and tetrazines undergo a variety of organic transformations, including electrophilic addition, coupling, nucleophilic displacement, and intramolecular cyclization. The mechanistic aspects of these heterocycles are discussed in a detailed way. The bioorthogonal application of these polyazines with various strained alkenes and alkynes provides a new prospect for investigations in chemical biology. This review systematically encapsulates the recent developments and challenges in the synthesis and possible potential applications of various triazine and tetrazine systems.

An Environmentally Benign Multicomponent Cascade Reaction of 3-Formylchromones, 2-Naphthols, and Heterocyclic Ketal Aminals: Site-Selective Synthesis of Functionalized Morphan Derivatives.

A novel protocol has been developed for the preparation of highly functionalized 2-azabicyclo[3.3.1]nonane (morphan) derivatives by the interesting three-component cascade reaction of 3-formylchromones, 2-naphthol, and heterocyclic ketal aminals (HKAs) in the ionic liquid [BMIM]PF6 promoted by the organic base Et3N. A complex cascade reaction is required, which includes a 1,2-addition, two Michael reactions, two tautomerizations, and an N-alkylation accompanied by a ring-opening reaction and involving the cleavage of one C-O bond and the formation of four bonds (one C-N bond, one C-O bond, and two C-C bonds). As a result, functionalized morphans (5 and 6) bearing naphthalene-structured skeletons were prepared by simple heating of a mixture of 3-formylchromones, 2-naphthols, and HKAs in the environmentally friendly ionic liquid [BMIM]PF6. This protocol can be used in the synthesis of various morphans and is suitable for combinatorial and parallel syntheses of natural-like morphan derivatives. This approach has several advantages such as the use of an environmentally friendly solvent, simple and practical operation (multicomponent one-pot reaction), and satisfactory yields (65-88%).

Transition-metal-free synthesis of pyrimidines from lignin β-O-4 segments via a one-pot multi-component reaction

Heteroatom-participated lignin depolymerization for heterocyclic aromatic compounds production is of great importance to expanding the product portfolio and meeting value-added biorefinery demand, but it is also particularly challenging. In this work, the synthesis of pyrimidines from lignin β-O-4 model compounds, the most abundant segment in lignin, mediated by NaOH through a one-pot multi-component cascade reaction is reported. Mechanism study suggests that the transformation starts by NaOH-induced deprotonation of Cα-H bond in β-O-4 model compounds, and involves highly coupled sequential cleavage of C-O bonds, alcohol dehydrogenation, aldol condensation, and dehydrogenative aromatization. This strategy features transition-metal free catalysis, a sustainable universal approach, no need of external oxidant/reductant, and an efficient one-pot process, thus providing an unprecedented opportunity for N-containing aromatic heterocyclic compounds synthesis from biorenewable feedstock. With this protocol, an important marine alkaloid meridianin derivative can be synthesized, emphasizing the application feasibility in pharmaceutical synthesis.

Topologically Driven Pore/Surface Engineering in a Recyclable Microporous Metal-Organic Vessel Decorated with Hydrogen-Bond Acceptors for Solvent-Free Heterogeneous Catalysis.

The use of metal-organic frameworks (MOFs) comprising custom-designed linkers/ligands as efficient and recyclable heterogeneous catalysts is on the rise. However, the topologically driven bifunctional porous MOFs for showcasing a synergistic effect of two distinct activation pathways of substrates (e.g., involving hydrogen bonding and a Lewis acid) in multicomponent organic transformations are very challenging. In particular, the novelty of such studies lies in the proper pore and/or surface engineering in MOFs for bringing the substrates in close proximity to understand the mechanistic aspects at the molecular level. This work represents the topological design, solid-state structural characterization, and catalytic behavior of an oxadiazole tetracarboxylate-based microporous three-dimensional (3D) metal-organic framework (MOF), {[Zn2(oxdia)(4,4'-bpy)2]·8.5H2O}n (1), where the tetrapodal (4-connected) 5,5'-(1,3,4-oxadiazole-2,5-diyl)diisophthalate (oxdia4-), the tetrahedral metal vertex (Zn(II)), and a 2-connected pillar linker 4,4'-bipyridine (4,4'-bpy) are unique in their roles for the formation, stability, and function. As a proof of concept, the efficient utilization of both the oxadiazole moiety with an ability to provide H-bond acceptors and the coordinatively unsaturated Zn(II) centers in 1 is demonstrated for the catalytic process of the one-pot multicomponent Biginelli reaction under mild conditions and without a solvent. The key steps of substrate binding with the oxadiazole moiety are ascertained by a fluorescence experiment, demonstrating a decrease or increase in the emission intensity upon interaction with the substrates. Furthermore, the inherent polarizability of the oxadiazole moiety is exploited for CO2 capture and its size-selective chemical fixation to cyclic carbonates at room temperature and under solvent-free conditions. For both catalytic processes, the chemical stability, structural integrity, heterogeneity, versatility in terms of substrate scope, and mechanistic insights are discussed. Interestingly, the first catalytic process occurs on the surface, while the second reaction occurs inside the pore. This study opens new ways to catalyze different organic transformation reactions by utilizing this docking strategy to bring the multiple components close together by a microporous MOF.

Chemistry of 2-(Piperazin-1-yl) Quinoline-3-Carbaldehydes

Abstract: This review described the preparation of 2- chloroquinoline-3-carbaldehyde derivatives 18 through Vilsmeier-Haack formylation of N-arylacetamides and the use of them as a key intermediate for the preparation of 2-(piperazin-1-yl) quinoline-3-carbaldehydes. The synthesis of the 2- (piperazin-1-yl) quinolines derivatives was explained through the following chemical reactions: acylation, sulfonylation, Claisen-Schmidt condensation, 1, 3-dipolar cycloaddition, one-pot multicomponent reactions (MCRs), reductive amination, Grignard reaction and Kabachnik-Field’s reaction.

Nanostructured Na2CaP2O7: A New and Efficient Catalyst for One-Pot Synthesis of 2-Amino-3-Cyanopyridine Derivatives and Evaluation of Their Antibacterial Activity

A facile and novel synthesis of thirteen 2-amino-3-cyanopyridine derivatives 5(a–m) by a one-pot multicomponent reactions (MCRs) is described for the first time, starting from aromatic aldehydes, malononitrile, methyl ketones, or cyclohexanone and ammonium acetate in the presence of the nanostructured diphosphate Na2CaP2O7 (DIPH) at 80 °C under solvent-free conditions. These compounds were brought into existence in a short period with good to outstanding yields (84–94%). The diphosphate Na2CaP2O7 was synthesized and characterized by different techniques (FT-IR, XRD, SEM, and TEM) and used as an efficient, environmentally friendly, easy-to-handle, harmless, secure, and reusable catalyst. Our study was strengthened by combining five new pyrido[2,3-d]pyrimidine derivatives 6(b, c, g, h, j) by intermolecular cyclization of 2-amino-3-cyanopyridines 5(b, c, g, h, j) with formamide. The synthesized products were characterized by FT-IR, 1H NMR, and 13C NMR and by comparing measured melting points with known values reported in the literature. Gas chromatography/mass spectrometry was used to characterize the newly synthesized products and evaluate their purity. The operating conditions were optimized using a model reaction in which the catalyst amount, temperature, time, and solvent effect were evaluated. Antibacterial activity was tested against approved Gram-positive and Gram-negative strains for previously mentioned compounds.

Efficient Synthesis of 2-Aminopyridine Derivatives: Antibacterial Activity Assessment and Molecular Docking Studies.

A new and suitable multicomponent one-pot reaction was developed for the synthesis of 2-amino-3-cyanopyridine derivatives. Background: This synthesis was demonstrated by the efficient and easy access to a variety of substituted 2-aminopyridines using enaminones as key precursors under solvent-free conditions. Methods: A range of spectroscopic techniques was used to determine and confirm the chemical structures (FTIR, 1H NMR, 13C NMR). The antimicrobial potency of synthesized compounds (2a–d) was tested using disk diffusion assays, and the Minimum Inhibitory Concentration (MIC) for the active compounds was determined against a panel of microorganisms, including Gram-positive and Gram-negative bacteria and yeasts. Moreover, a docking analysis was conducted by Molecular Operating Environment (MOE) software to provide supplementary information about the potential, as well as an ADME-T prediction to describe the pharmacokinetic properties of the best compound and its toxicity. Results: The results of the antimicrobial activity indicated that compound 2c showed the highest activity against Gram-positive bacteria, particularly S. aureus and B. subtilis whose MIC values were 0.039 ± 0.000 µg·mL−1. The results of the theoretical study of compound 2c were in line with the experimental data and exhibited excellent antibacterial potential. Conclusions: On the basis of the obtained results, compound 2c can be used as an antibacterial agent model with high antibacterial potency.

Green Synthesis and Biological Activity Investigation of New Thiazinotriazines: A Combined Experimental and Theoretical Investigation

The Petasites hybridus rhizome water extract was used as a green media for the preparation of the Fe3O4/TiO2/CuO@MWCNTs magnetic nanocomposites and its activity was evaluated by using it in the one-pot multicomponent reaction of isatoic anhydrides, electron deficient acetylenic compounds, α-haloketones, ammonium acetate, isothiocyanates and hydrazonoyl chloride in aqueous media at room temperature for the production of novel derivatives of thiazinotriazines in excellent yields. The synthesized thiazinotriazines have OH and NH functional groups that have acidic hydrogen and show high antioxidant activity. Moreover, reduction of organic pollutants such 4-nitrophenol (4-NP) was performed by synthesized Fe3O4/TiO2/CuO@MWCNTs in water at room temperature. The outcomes showed this nanocatalyst was decreased organic pollutants in few seconds. Also, to better understanding reaction mechanism density functional theory based quantum chemical methods have been applied. The employed process for production of thiazinotriazines has some benefits such as short time of reactions, excellent efficiency of product, easy separation of catalyst and products.

Production of Pyrimidobenzazepine Derivatives and Reduction of Organic Pollutant Using Ag/Fe3O4/TiO2/CuO@MWCNTs MNCs

The Petasites hybridus rhizome water extract as green media was used for the preparation of the Ag/Fe3O4/TiO2/CuO@MWCNTs magnetic nanocomposites and its activity was evaluated by using in the one-pot multicomponent reaction of isoquinoline, α-haloketones, 2-amino benzoic acids, diethyl carbonate, electron deficient acetylenic compounds, ammonium acetate, and tert-butyl isocyanide in water at room temperature for the production of novel derivatives of pyrimidobenzazepines in excellent yields. Moreover, reduction of organic pollutants such 4-nitrophenol was performed by synthesized Ag/Fe3O4/TiO2/CuO@MWCNTs in water at room temperature. The outcomes showed this catalyst was decreased organic pollutants in few seconds. Because of having azepine moiety, the synthesized compounds show good antioxidant activity. These synthesized compounds also displayed antimicrobial activity by using the disk diffusion procedure and two Gram-positive and Gram-negative bacteria. The employed process for production of benzazepines has some benefits such as short time of reactions, excellent efficiency of product, easy separation of catalyst and products.

Recent advances in the green synthesis of Betti bases and their applications: a review.

Well-known Betti bases are the products obtained by the one-pot multicomponent reaction of 1-naphthol/2-naphthol, aliphatic/aromatic aldehydes, and secondary amines, and this reaction is known as the Betti reaction. During recent years, due to the unveiling of the pharmacological and synthetic potential of Betti bases, a tremendous increase in the studies reporting novel synthetic methods for the efficient synthesis of Betti bases was observed. This review presents the recent key developments in the green synthesis of the Betti bases and accounts for the significant number of the literature reported during 2019-2022. Both catalyst free as well as the catalyst promoted synthesis (nanocatalyst, biocatalyst, transition metal catalyst, etc.) along with the synthetic applications (catalyst, ligands/chiral auxiliaries, and valuable synthons), optoelectronic applications (fluorescence sensors for phosgene gas, Hg2+, and Cr3+ detection, quasi-reversible redox potential) and biological properties (anticancer agents, antioxidant, anti-inflammatory agents, antitubercular agents, pesticidal agents, anti-Alzheimer agents, Topoisomerase I inhibitors, YAP-TEAD interaction inhibitors, and DNA binding and cleavage activity) are discussed. There is a surge of interest for the development of the green and efficient Betti reaction for the construction of C-C and C-N bond in a single-step reaction accessing Betti bases as products. Along with key methodological developments for the green synthesis of Betti bases, their applications in synthetic organic chemistry, optoelectronic sensors, advanced materials synthesis, agrochemicals and pharmaceutically active scaffolds, during the period of 2019-2022, have been considered.

Bronsted Acid Mediated Facile Greener Multicomponent Synthesis of 2,4-Diaryl-quinoline Derivatives in Water

Quinolines are an important class of natural and synthetic products, with several biological activity and applications in medicine and electronics. In this work we present a greener method of synthesis of 2,4-diaryl-quinoline derivatives by an easy one-pot multicomponent reaction between aniline derivatives, aldehyde derivatives and phenylacetylene in water, with hydrochloric acid as promoter. With this method we could synthesize several compounds with good yield and reaction time, including new alkylamino-containing 2,4-diaryl-quinoline derivatives that could not be synthesized with niobium pentachloride catalyst in similar conditions. DOI: http://dx.doi.org/10.17807/orbital.v14i1.1689

A Facile Synthesis of Bioactive Five- and Six-membered N-heterocyclic Aromatic Compounds Using AlCoFe2O4 as a Green Catalyst.

Nitrogen-containing heterocycles have been extensively studied due to their broad biological and pharmaceutical applications. In this study, we synthesized five- and six-membered nitrogen-containing rings through one-pot multicomponent reaction using an aluminium-doped cobalt ferrite nano-catalyst. The nano-catalyst was prepared by the co-precipitation method from the corresponding metal salts. The obtained results show that the proposed catalyst has a high efficiency and has enabled the formation of the desired products with high efficiency and purity. In addition, simplicity of operation, facile purification of products, shorter reaction times, mild reaction conditions, easy separation and recyclability of the catalyst, are the main advantages of this catalyst.