Four-component Domino Reaction Research Articles

Pseudo Four-Component Synthesis of 5,6-Dihydroindolo[2,1-a]isoquinolines.

An easy synthesis of novel highly functionalized 5,6-dihydroindolo[2,1-a]isoquinolines was developed via a pseudo four-component domino reaction of 1-aroyl-3,4-dihydroisoquinolines, terminal α,β-ynones, and malononitrile. The selective formation of this biologically relevant heterocyclic core was achieved using a one-pot approach under microwave irradiation. The formation of the same skeleton through the reaction of 5,6-dihydropyrrolo[2,1-a]isoquinolines with malonic acid dinitrile supports the proposed mechanism, involving the intermediate product of the three-component reaction. Furthermore, the disproval of an alternative reaction pathway, which involved the dimerization of malononitrile followed by three-component transformation, was demonstrated. Introducing the malononitrile dimer as a CH acid resulted in the formation of a different pyrido[3',4':4,5]pyrrolo[2,1-a]isoquinoline core. Additionally, the synthesized 5,6-dihydroindolo[2,1-a]isoquinolines were examined for their photophysical properties, revealing their attractive luminescent characteristics.

Electrochemical assembly of isoxazoles via a four-component domino reaction.

Multicomponent domino reactions via electrochemical annulations have emerged as a robust strategy for the rapid assembly of heterocyclics. Herein, an electrochemical annulation via a [1 + 2 + 1 + 1] four-component domino reaction was accomplished in a user-friendly undivided cell setup to assemble valuable five-membered isoxazole motifs. Our approach is characterized by a high level functional group tolerance and operational simplicity, avoiding the tedious and time-consuming preparation of pre-functionalized substrates. Detailed mechanistic studies were conducted including isotopic labeling, kinetic studies, cyclic voltammetry (CV) analysis, and intermediate characterization, providing support for a radical pathway.

A facile access to the synthesis of highly functionalized novel 4H-pyrano[2′,3′:4,5]imidazo[1,2-a]pyridine hybrid via one-pot four-component domino reaction

A facile one-pot four-component domino protocol has been successfully developed for the combinatorial synthesis of novel N-methyl-3-nitro-4-aryl-4H-pyrano[2′,3′:4,5]imidazo[1,2-a]pyridine-2-amine 7 and 2-amino-4-aryl-4H-pyrano[2′,3′:4,5]imidazo[1,2-a]pyridine-3-carbonitrile 8. The protocol employs readily available starting materials, leading to high yields of the products (83–89%). The transformation involves a domino Knoevenagel-intramolecular Michael reaction sequence, enabling the formation of three new bonds (two CC, two CN, and one CO) and two rings in a single step. Notably, this reaction exhibits several remarkable features, including short reaction time, eliminating the need for extensive workup and column chromatographic purification. Additionally, the reaction demonstrates good scalability, producing satisfactory yields even on a gram-scale.

A four-component domino reaction for the synthesis of novel bridgehead nitrogen-containing pyrido[1,2-d][1,4]diazepines

An efficient methodology for the synthesis of a new family of novel bridgehead nitrogen-containing pyrido[1,2-d][1,4]diazepines has been described and its mechanism has been proposed, which follows a ring-closure and ring-cleavage pathway.

Regioselective Synthesis, Spectroscopic Characterization, and Computational Chemical Study of Spiro[Indoline-3,4’-Pyrazolo[3,4-b] Pyridine Derivatives as Agrochemical Agents

Herein, new four-component domino reactions are described and utilized to synthesize spiro[indoline-3,4’-pyrazolo[3,4-b]pyridine derivatives via one-pot reaction. Different hydrazine derivatives such as hydrazine hydrate, methyl hydrazine, and phenylhydrazine were allowed to react with active methylene precursors (CH2CN) as malononitrile, ethyl cyanoacetate, isatin, and 1,3-dicarbonyl compounds in the presence of (+)-camphor-10-sulfonic acid (CSA) as the acid catalyst under microwave condition using water as the solvent. Two and three fused heterocyclic rings were obtained in a single synthetic operation with a facile work-up and less waste generation due to the absence of extraction and purification steps. Structural features of the obtained compounds were confirmed by utilizing elemental analyses, mass spectrometry, 1H-NMR, and 13C-NMR microanalyses. Insecticidal assessments for some of the synthesized pyrazole derivatives against the cotton leafworm Spodoptera littoralis were conducted. In addition, fungicidal activities against Rhizoctonia solani and Fusarium solani soil-borne fungi were also performed. The tested compounds showed poor insecticidal activity compared with the standard insecticide chlorpyrifos ethyl. Meanwhile, they showed remarkable fungicidal activity against tested pathogens. Analysis of the fungicidal study indicated that R. solani fungus was found to be more sensitive to the tested compounds than F. solani fungus. Some pyrazole derivatives particularly possessed close or even higher fungicidal activities than the standard fungicide Pencycuron (Monceren 25%WP). The density functional theory was then applied to explore the structural and electronic characteristics of these materials.

A Four-Component Domino Reaction: An Eco-Compatible and Highly Efficient Construction of 1,8-Naphthyridine Derivatives, Their In Silico Molecular Docking, Drug Likeness, ADME, and Toxicity Studies

A multicomponent domino reaction of enaminone, malononitrile, and o-phthalaldehyde has been established, providing direct access to novel highly functionalized pentacyclic cyclopenta [b] indeno [1, 2, 3-de] [1,8] naphthyridine derivatives. The simplicity of execution, readily available substrates, high yields, excellent functional group tolerance, scalability, and good scores of environmental parameters make this synthetic strategy more sustainable and worthy of further attention. This one-pot transformation, which involved multiple steps and did not require the use of a catalyst, constructed four new C-C bonds, two new C-N bonds, and three new rings, with efficient use of all reactants. Furthermore, we performed in silico molecular docking analysis for prediction of anticancer (against human topoisomerase IIβ protein) and antimicrobial (against E.coli. DNA gyrase B protein) activities. Drug likeness and ADMET studies were also predicted. Overall investigation indicates that compound 6i may serve as a candidate that could be developed as potential anticancer and antimicrobial agent among all.

Stable monovalent aluminum(i) in a reduced phosphomolybdate cluster as an active acid catalyst.

Low-valent aluminum Al(i) chemistry has attracted extensive research interest due to its unique chemical and catalytic properties but is limited by its low stability. Herein, a hourglass phosphomolybdate cluster with a metal-center sandwiched by two benzene-like planar subunits and large steric-hindrance is used as a scaffold to stabilize low-valent Al(i) species. Two hybrid structures, (H3O)2(H2bpe)11[AlIII(H2O)2]3{[AlI(P4MoV6O31H6)2]3·7H2O (abbr. Al6{P4Mo6}6) and (H3O)3(H2bpe)3[AlI(P4MoV6O31H7)2]·3.5H2O (abbr. Al{P4Mo6}2) (bpe = trans-1,2-di-(4-pyridyl)-ethylene) were successfully synthesized with Al(i)-sandwiched polyoxoanionic clusters as the first inorganic-ferrocene analogues of a monovalent group 13 element with dual Lewis and Brønsted acid sites. As dual-acid catalysts, these hourglass structures efficiently catalyze a solvent-free four-component domino reaction to synthesize 1,5-benzodiazepines. This work provides a new strategy to stabilize low-valent Al(i) species using a polyoxometalate scaffold.

Green catalyst-free one-pot synthesis of novel tetrahydropyridine-3-carboxamides by microwave-assisted approach

A clean, facile and catalyst-free four-component domino reaction of aromatic aldehyde, ethyl cyanoacetate, acetoacetanilide and ammonium acetate in ethanol under microwave irradiation (MWI) conditions is described. Eleven novel and diverse tetrahydropyridine-3-carboxamide derivatives were synthesized in excellent yields (91–97%) using this green protocol. The significant benefits of this method are simple handling, ethanol as solvent, catalyst-free reaction under mild conditions, short reaction times (<10 min) and excellent product yields. Easy workup procedure and simple purification technique of the target molecules evade column chromatography. Novel tetrahydropyridine-3-carboxamide derivatives were synthesized under the microwave irradiation (MWI) method in short reaction time (<10 min). All the synthesized compounds confirmed by various spectroscopic techniques such as 1H NMR, 13C NMR, 15N NMR and HRMS. Ethanol as a solvent, easy workup procedure and simple handling are the benefit of green protocol.

“On-water” one-pot four-component synthesis of novel 1H-furo[2,3-c]pyrazole-4-amine derivatives

A catalyst-free, simple and green protocol has been accomplished for the synthesis of novel 1H-furo[2,3-c]pyrazole-4-amines in a one-pot four-component domino reaction involving hydrazines, ethyl acetoacetate, aromatic amines and phenylglyoxal monohydrate in water. The protocol presented herein describes in situ generated pyrazolone as intermediate reactants with phenylglyoxal monohydrate in a Knoevenagel condensation followed by a Michael addition of amine, intramolecular cyclization, dehydration and the resulting to the title compound. It was observed that in this protocol bis(pyrazole-5-ols) are formed with amines bearing strong electron withdrawing groups under similar reaction conditions instead of the expected products. The reaction merits the use of water as solvent, no additive catalyst, easy workup, easy purification of products by non-chromatography and provides high yield of products with good purity.

A catalyst-free four-component domino reaction for the synthesis of functionalized 3-acyl-1,5-benzodiazepines.

Various functional 3-acyl-1,5-benzodiazepines containing carboxyl, ester and acyl groups at the 2-position were synthesized via an efficient, sustainable and catalyst-free domino reaction. During the synthesis process, one new cycle and four new bonds (one C-C, two C-N and one C[double bond, length as m-dash]C) were constructed by the nucleophilic substitution, nucleophilic addition, dehydration and cyclization reaction by the H+ shift. Furthermore, a total of 26 examples were examined by reacting inexpensive starting materials of N,N-dimethylformamide dimethyl acetal, aromatic ketones, 1,2-phenylenediamine compounds and aldehyde derivatives. Therefore, it displayed a broad substrate scope, good functional group tolerance, high yields (77-97%) and the ease of obtaining target compounds without the involvement of toxic solvents and column chromatography, which provided a novel method for the synthesis of a wide variety of biologically relevant 1,5-benzodiazepines.

Synthesis of pyridopyrimidine derivatives based on benzenesulfonyl acetonitrile compounds via a one-pot sequential four-component domino reaction and microwave-mediated molecular cyclization

A concise, rapid and highly efficient method for the one-pot synthesis of novel pyridopyrimidine derivatives has been demonstrated by the “four-component” domino reaction of aromatic aldehyde, benzenesulfonyl acetonitrile, 1,1-dimethylthio-2-nitroethylene and 1,3-propanediamine, using piperidine as a catalyst and ethanol as solvent under microwave irradiation. This methodology was established with many advantages, including higher reaction yields, broad substrate scopes, experimental simplicity, short time and utility of easily available starting materials. The synthesized compounds are confirmed by 1H NMR, IR and HR-ESI-MS.

Synthesis of new indolylpyrrole derivatives via a four-component domino reaction between arylglyoxals, acetylacetone, indole and aliphatic amines in aqueous media

A novel synthesis of indolylpyrrole derivatives is described by a four-component domino reaction between arylglyoxals, acetylacetone, indole and aliphatic amines in water as solvent at 60 °C without using any catalyst or promoter. The FT-IR, 1H NMR, 13C NMR spectral and elemental analysis confirm the structures of the products.

Microwave Domino Diastereoselective Synthesis of NovelTrans-4,5-Dihydro-1H-Furo[2,3-c]Pyrazoles Using Pyridinium Salts in an Aqueous Medium

Novel fused 4,5-dihydro-1 H-furo[2,3- c]pyrazole derivatives containing both biologically active pyrazole and furan templates are synthesised by a one-pot two-step four-component domino reaction involving hydrazine hydrate, a β-keto ester, an aromatic aldehyde and a pyridinium salt catalysed by DABCO with high diastereoselectivity in H2O under microwave irradiation. To minimise the formation of byproducts, the hydrazine hydrate and ethyl acetoacetate were first irradiated until a pyrazolone was formed. Next, the aryl aldehyde, the pyridinium salt and DABCO were added and the reaction could be completed in good to excellent yields. The salient features of this eco-friendly methodology are highlighted by its short reaction time (10–12 min), high yields, high atom-economy, efficiency of producing five new bonds (2C–C, C=N, C–N and one C–O), two new rings and two stereocentres in a single operation, absence of any tedious work-up or purification and avoidance of separation of intermediates.

A Rapid and Highly Efficient Microwave-Promoted Four-Component Domino Reaction for the Synthesis of Novel Spiro[benzo[a]chromeno[2,3-c]phenazine] Derivatives Under Solvent-Free Conditions

ABSTRACTp-Toluenesulfonic acid was applied as an efficient, non-toxic and solid acid catalyst for the one-pot, four-component condensation between 2-hydroxy-1,4-naphthoquinone, benzene-1,2-diamine, cyclic 1,3-dicarbonyl compounds and isatin or ninhydrin to afford the corresponding novel spiro[benzo[a]chromeno[2,3-c]phenazine] derivatives via a new two-step domino protocol under conventional heating and microwave irradiation. This solvent-free process produces biologically considerable heterocycles with the formation of five new bonds (two C–C, two C˭N, and one C–O) and two new rings in a single operation and this effective green process provides considerable advantages such as: operational simplicity, very short reaction time, high yields, absence of any tedious process or purification, and it avoids hazardous reagents/solvents.

Heteropolyacid supported on amine-functionalized halloysite nano clay as an efficient catalyst for the synthesis of pyrazolopyranopyrimidines via four-component domino reaction

An efficient heterogeneous hybrid catalyst was developed by functionalization of halloysite clay nanotubes by γ-aminopropyltriethoxysilane and then immobilization of a Keggin type heteropolyacid, phosphotungstic acid. This hybrid catalyst was characterized by SEM/EDX, FTIR and XRD and its catalytic activity for the synthesis of pyrazolopyranopyrimidine derivatives via four-component domino reaction of barbituric acid, hydrazine hydrate, ethyl acetoacetate and benzaldehyde was investigated. The results indicated that the hybrid system can promote the reaction to afford the desired products in high yields and short reaction times. The superior catalytic activity of this system was confirmed when compared with those reported, previously. Moreover, this novel heterogeneous catalyst was found to be easily separable and recyclable. It was re-used at least three times with negligible loss of activity. Significantly, this protocol can be extended to nonconventional green heating sources such as microwave and ultrasonic irradiations.

An Efficient Four-Component Approach for the Synthesis of Novel 5-Methyl-4-(2-(3-methyl-4-nitroisoxazol-5-yl)- 1-arylethyl)-1H-pyrazol-3-ol Derivatives and their Antibacterial Study

A One pot four-component domino reactions were developed for the synthesis of 5-methyl-4-(2-(3-methyl-4-nitroisoxazol-5-yl)-1-arylethyl)-1H-pyrazol-3-ols derivatives in excellent yield from hydrazine hydrate (1), ethyl acetoacetate (2), aldehyde (3) and 3,5-dimethyl-4-nitro-isoxazole (4) using 10 mol% of piperidine. This method is simple, efficient and multiple bonds were generated (two C−C, one C−N, one O−H and one C=N) in a single step. These novel 5-methyl-4-(2-(3-methyl-4-nitroisoxazol-5-yl)-1-arylethyl)-1H-pyrazol-3-ol derivatives are evaluated as anti-bacterial agents.

An expedient synthesis strategy to the 1,4-dihydropyridines and pyrido[1,2-a]quinoxalines: iodine catalyzed one-pot four-component domino reactions

Another aspect concerning enaminone chemistry leading to the one-pot synthesis of functionalized novel 1,4-dihydropyridines and pyrido[1,2-a]quinoxalines has been described. By highly efficient, one-pot, iodine-catalyzed four-component reactions, combining one set of enamine intermediates and arylidene pyruvic acid (APA) in two procedures, heterocyclic skeletal diversity can be achieved. The synthesis involves reaction of the intermediates formed by the 1:1 interaction between primary amines (or o-phenylenediamine) and dialkyl acetylenedicarboxylate with pyruvic acid and benzaldehyde through an iodine-catalyzed Knoevenagel/Michael/cyclization sequence. The reaction is particularly attractive due to the following advantages: atom economy, optimum convergence, high bond-forming efficiency, and avoidance of tedious workup and purification of products. Significantly, the presence of an acidic group at the 9-position on the products make these compounds excellent precursors for further synthetic modifications to meet the need for diverse chemical inputs.

One-pot synthesis and antimicrobial evaluation of novel 3-cyanopyridine derivatives of (−)-β-pinene

A series of novel 3-cyanopyridine derivatives of (−)-β-pinene were designed and synthesized by one-pot four-component domino reactions. The targeted compounds were evaluated for their antimicrobial activity against four bacteria (Klebsiella pneumoniae, Enterobacter aerogenes, Staphylococcus aureus, Staphylococcus epidermidis) and a fungus (Candida albicans). The results showed that most of the minimal inhibitory concentrations (MICs) of these 3-cyanopyridine derivatives against the tested strains was in the range of 15.6–125mg/L. Among these 3-cyanopyridine derivatives, the MICs of compound 5h against S. epidermidis and C. albicans were 15.6mg/L, which revealed that compound 5h featured double fluoro substituents at meta- and para-position was the most active compound. In addition, the preliminary structure–activity relationship analysis indicated that the change of substituents on the pyridine ring and benzene ring of 3-cyanopyridine derivatives was an important factor for inducing antimicrobial activity. This research would promote the development of heterocyclic derivatives of β-pinene with antimicrobial activity.

A Versatile One-Pot Strategy for the Synthesis of [1,4]Thiazepino[5,4-a]isoquinolines Containing Intramolecular Hydrogen Bonds

A simple and efficient one-pot method is described for the construction of [1,4]thiazepino[5,4-<i>a</i>]isoquinolines containing intramolecular hydrogen bonds by a sequential four-component domino reaction of isoquinoline, a 2-bromoacetophenone, an aryl isothiocyanate, and dimethyl acetylenedicarboxylate.

Synthesis, antitumor activity, and structure-activity relationship of some benzo[a]pyrano[2,3-c]phenazine derivatives.

A series of benzo[a]pyrano[2,3-c]phenazine derivatives with a wide range of substitutions at ring C of the benzophenazine were designed and synthesized using the one-pot, four-component domino reactions. The targeted compounds were evaluated for their antitumor activities against HCT116, MCF7, HepG2 and A549 cancer cell lines in vitro. The most active compound 6{1,2,1,9} featured the CN and p-dimethylamino phenyl substituents on γ-pyran structure on ring C. Significantly, compound 6{1,2,1,9} was found to have the highest growth inhibitory activity against the HepG2 cell line with IC50 values of 6.71 µM, which was 1.6-fold more potent than positive control anticancer drug Hydroxycamptothecine (HCPT). Furthermore, structure-activity relationship (SAR) studies on the substitutions at ring C were discussed in details.