Four-component Reaction Research Articles

Eco-friendly design of TiO2 nanoparticles supported on Fe3O4 coated carbon-based biochar substrate for the synthesis of pyrano-[2, 3-c]-pyrazole derivatives

The novel naturally based magnetic biochar/Fe3O4–TiO2 nanocatalyst was developed, characterised, and used to manufacture biologically active dihydropyrano-[2,3-c]-pyrazole [DHPP] derivatives. The one-pot four-component reaction between hydrazine hydrate, malononitrile, ethyl acetoacetate, and various aromatic aldehydes was carried out to synthesize the DHPP. The reaction was carried out in the presence of H2O:EtOH (1:1) as solvent at 60 °C with excellent yield (91–98%). This operationally simple approach has numerous benefits, including a green and clean reaction profile, easy workup and purification methods, a very fast reaction time, high atom efficiency, and low cost as well as magnetically separable nanocatalyst. XRD, FT-IR, TGA, HR-TEM, FE-SEM, EDAX, VSM were used to characterize the nanocatalyst and 13C NMR, 1H NMR, and mass spectrometry were investigate to studies the structure of products. Antimicrobial activity was tested on the resulting products (5a-5l). According to the data, the synthesized compounds were found to have substantial antimicrobial activities against the Gram-positive bacteria S. aureus and S. phyogens, Gram-negative bacteria E. coli and P. aeruginosa, and fungi Candida albicans.

Ionic Liquid [(EMIM)Ac] Catalyzed Green and Efficient Synthesis of Pyrano[2,3-c]Pyrazole Derivatives

A Green, efficient and clean route for synthesis of biologically potent pyrano[2,3-c]pyrazole derivatives has been developed in excellent yield, by using biodegradable ionic liquid 1-ethyl 3-methyl imidazolium acetate [(EMIM)Ac)] as a green catalyst via one-pot four-component condensation reaction of ethyl-acetoacetate, hydrazine-hydrate, malononitrile and carbonyl compounds at reflux condition in ethanol. The striking features of the protocol are a cleaner reaction profile, mild experimental procedure, applicable to extensive range of substrates and short reaction time.

Highly Stereoselective Ugi/Pictet-Spengler Sequence.

Discovering novel synthetic routes for rigid nitrogen-containing polyheterocycles using sustainable, atom-economical, and efficient (= short) synthetic pathways is of high interest in organic chemistry. Here, we describe an operationally simple and short synthesis of the privileged scaffold dihydropyrrolo[1,2-a]pyrazine-dione from readily accessible starting materials. The alkaloid-type polycyclic scaffold with potential bioactivity was achieved by a multicomponent reaction (MCR)-based protocol via a Ugi four-component reaction and Pictet–Spengler sequence under different conditions, yielding a diverse library of products.

A New Pathway for the Preparation of Pyrano[2,3-c]pyrazoles and molecular Docking as Inhibitors of p38 MAP Kinase.

We report a new pathway to synthesize pyrano[2,3-c]pyrazoles and their binding mode to p38 MAP kinase. Pyrano[2,3-c]pyrazole derivatives have been prepared through a four-component reaction of benzyl alcohols, ethyl acetoacetate, phenylhydrazine, and malononitrile in the presence of sulfonated amorphous carbon and eosin Y as catalysts. All products were characterized by melting point, 1H and 13C NMR, and HRMS (ESI). The products were screened in silico for their binding activities to both the ATP-binding pocket and the lipid-binding pocket of p38 MAP kinase, using a structure-based flexible docking provided by the engine ADFR. The results showed that eight synthesized compounds had a higher affinity to the lipid pocket than to the other target site, which implied potential applications as allosteric inhibitors. Finally, the most biologically active compound, 5, had a binding affinity comparable to those of other proven lipid pocket inhibitors, with affinity to the target pocket reaching −10.9932 kcal/mol, and also had the best binding affinity to the ATP-binding pockets in all of our products. Thus, our research provides a novel pathway for synthesizing pyrano[2,3-c]pyrazoles and bioinformatic evidence for their biological capability to block p38 MAP kinase pockets, which could be useful for developing cancer or immune drugs.

Expeditious microwavable one-pot synthesis and biological exploration of spiro[indoline-3,4′-pyrazolo[3,4-b] pyridine derivatives

A rapid and efficient microwave-promoted one-pot strategy has been utilized to synthesize differentially functionalized spiro[indoline-3,4′-pyrazolo[3,4-b] pyridine derivatives. Different optimized reaction conditions have been exploited when one-pot four-component (hydrazines, 1,3-dicarbonyl compounds, isatin, and malononitrile) reactions took place to afford satisfying yields of compounds [5–28]. Among different methodologies, the catalyst-free microwave-assisted fusion process has been proved to be the strategy with desirable traits to give good-to-excellent yields of the target compounds. Structural features of the obtained compounds were confirmed by the basis of elemental analyses, mass, 1H-NMR, and 13C-NMR spectrometry.

Four-Component Ugi Reaction for Optical Chirality Sensing and Surface Nanoengineering of Chiral Self-Assemblies.

Using green chemistry to control chirality at hierarchical levels as well as chiroptical activities endows with new opportunities to the development of multiple functions. Here, the four-component Ugi reaction is introduced for the general and precise optical chirality sensing of amines as well as the surface nanoengineering of chiral soft self-assemblies. To overcome the relatively weak Cotton effects, direct synthesis of a folded peptide structure on a rotatable ferrocene core with axial chirality was accomplished from chiral amine, 1,1'-ferrocenyl dicarboxylic acid, formaldehyde and isocyanide. Enhanced Cotton effects benefiting from the folded structure allow for the precise and quantitative sensing of natural and synthetic chiral amines covering alkyl, aromatic amines and amino acid derivatives. In addition, aqueous reaction enables the modification of amine-bearing dye to microfibers self-assembled from π-conjugated amino acids. Surface dye-modification via Ugi reaction barely changes the pristine morphology, showing non-invasive properties in contrast to dye staining, which is applicable in soft nano/microarchitectures from self-assembly. This work which combines the four-component Ugi reaction to enable precise ee% detection and surface nanoengineering of soft chiral assemblies sheds light on the advanced application of green chemistry to chirality science.

Rapid, Greener and One-pot Four Component Synthesis of 1, 4-Dihydropyridine Derivatives

In this current research framework, an efficient greener synthesis has been developed for new pyridine derivatives using one-pot four-component reaction. We have synthesized a new series of 1,4-dihydropyridine derivatives in excellent yield via telescopic multicomponent reaction among the aldehyde, malononitrile, anilines and diethyl acetylenedicarboxylate in the presence of piperidine at mild reaction condition without further purification. All the synthesized compounds were characterized by 1H NMR, 13C NMR, FT-IR and mass spectrometry analysis.

An orally available Mpro inhibitor is effective against wild-type SARS-CoV-2 and variants including Omicron.

Emerging SARS-CoV-2 variants continue to cause waves of new infections globally. Developing effective antivirals against SARS-CoV-2 and its variants is an urgent task. The main protease (Mpro) of SARS-CoV-2 is an attractive drug target because of its central role in viral replication and its conservation among variants. We herein report a series of potent α-ketoamide-containing Mpro inhibitors obtained using the Ugi four-component reaction. The prioritized compound, Y180, showed an IC50 of 8.1 nM against SARS-CoV-2 Mpro and had oral bioavailability of 92.9%, 31.9% and 85.7% in mice, rats and dogs, respectively. Y180 protected against wild-type SARS-CoV-2, B.1.1.7 (Alpha), B.1.617.1 (Kappa) and P.3 (Theta), with EC50 of 11.4, 20.3, 34.4 and 23.7 nM, respectively. Oral treatment with Y180 displayed a remarkable antiviral potency and substantially ameliorated the virus-induced tissue damage in both nasal turbinate and lung of B.1.1.7-infected K18-human ACE2 (K18-hACE2) transgenic mice. Therapeutic treatment with Y180 improved the survival of mice from 0 to 44.4% (P = 0.0086) upon B.1.617.1 infection in the lethal infection model. Importantly, Y180 was also highly effective against the B.1.1.529 (Omicron) variant both in vitro and in vivo. Overall, our study provides a promising lead compound for oral drug development against SARS-CoV-2.

One-pot multicomponent synthesis of benzophenazine tethered tetrahydropyridopyrimidine derivatives.

A simple, facile, and efficient green methodology has been developed for the synthesis of benzophenazine tethered tetrahydropyridopyrimidine derivatives by the one-pot four-component reaction of cinnamaldehyde/crotonaldehyde, 2-hydroxy-1,4-naphthoquinone, 1,3-dimethyl-6-amino uracil, and o-phenylenediamine in ethanol medium under reflux conditions using p-TSA as a catalyst. In this environmentally benign methodology, three C-N and two C-C bonds are formed in one pot. The hybrid products have three bioactive moieties such as benzophenazine, tetrahydropyridine, and pyrimidine. Operational simplicity, metal-free conditions, wide substrate scope, readily available starting materials, moderate to good yields of the desired products, presence of pharmaceutically active moieties, and easy purification process are the notable features of this methodology.

A methodological approach for the synthesis of 4-aryl-8-arylidene-2-cyanoimino-1,2,3,4,5,6,7,8-octahydroquinazolines

An efficient methodological approach for the synthesis of a novel series of 4-aryl-8-arylidene-2-cyanoimino-1,2,3,4,5,6,7,8-octahydroquinazolines (aryl-CIOHQs) was presented via one-pot four-component reaction of cyclohexanone, two-folds of various aromatic aldehydes and cyanoguanidine in the presence of sodium ethoxide as basic catalyst. The same target products (aryl-CIOHQs) were also reproduced in good yields using an ordinary method via two-component reaction of 2,6-diarylidinecyclohexanone derivatives with cyanoguanidine in the same condition.

Origin of enantioselectivity and product-distribution control in isocyanide-based multicomponent reaction catalysed by chiral N, N'-dioxide-Mg(II) complex

Reaction mechanism and key factors controlling the stereo- and product-selectivity in isocyanide-based multicomponent reactions (MCRs) of alkylidene malonate and HN3 mediated by chiral N, N'-dioxide-Mg(II) catalyst were studied at the B3LYP-D3(BJ)/6-311G(d,p)//B3LYP-D3(BJ)/def2-SVP(SMD, CH2Cl2) theoretical level. Both three- and four-component reactions carried out via the same chiral-controlling step, with the energy barrier of 29.4 kcal mol−1 in the absence of catalyst. Two kinds of tetrazoles were formed via the construction of five-membered rings through two-stage one-step pathway, followed by carbanion protonation via intramolecular H-shift process. The non-catalytic MCRs were difficult to occur because of high energy barriers of 39.9–52.5 kcal mol−1 in the rate-determining step (RDS). A hexacoordinate-Mg(II) species formed by coordinating alkylidene malonate to Mg2+ center in bidentate fashion accelerated the formation of tetrazole ring via stepwise mechanism. The significant steric hindrance of cyclohexyl group in alkylidene malonate as well as the o-iPr group in the catalyst induced isocyanide to attack from the si-face of alkylidene malonate in the chiral-controlling step, affording predominantly S-configuration products in the two kinds of MCRs. The nucleophilicity of reactants (i.e., isocyanide and HN3) (not the electrophilicity of zwitterionic intermediate) as well as weak π-π interaction of the naphthyl rings in the second CC bonding transition state played important roles to control the distribution of the two kinds of tetrazoles. Isocyanide with high nucleophilicity was preferably trapped by the zwitterionic intermediate to proceed the four-component reaction. In contrast, the isocyanide with electron-withdrawing group exhibited better reactivity in three-component reaction.

Visible Light Mediated, Catalyst Free, One-Pot Convenient Synthesis of Dihydropyridines

: A simple, efficient and green protocol has been developed for the synthesis of polysubstituted dihydropyridines via one-pot, four-component reaction of aldehydes, arylamines, dialkyl acetylenedicarboxylate, and malononitrile. The reaction was proceeded at room temperature in the absence of catalyst in aqueous ethyl lactate under visible light irradiation. The main advantages of the present approach are mild reaction condition, high yield, no column chromatography, clean reaction profile, environmentally friendly and sustainable from the economic point of view

Four-component one-pot synthesis of novel dicyanoaniline-anchored triazoles

A four-component reaction was developed by taking advantage of the reactivity of propargyl functional groups residing on primarily formed dicyanoaniline products. Various enolizable cyclic ketones were reacted with malononitrile and 4-(prop-2-yn-1-yloxy)benzaldehyde derivatives in an aqueous t-BuOH/NaOH medium, and the resulting dicyanoanilines were subjected to a subsequent in situ click reaction to obtain the final dicyanoaniline-anchored triazole products. The enhanced photophysical properties of the novel products are currently under study.

Solvent-Free Synthesis of Pyrrolo [2,1-α] Isoquinolines via One-Pot Four- Component Reaction

Abstract: An efficient four-component reaction to synthesize pyrrolo [2,1-a] isoquinolines from malononitrile, aromatic aldehydes, isoquinoline, and cyclohexyl isocyanide under solvent-free conditions is described. In a convenient, simple, and efficient one-pot procedure, the domino Knoevenagel-nucleophilic cycloaddition reaction affords excellent yields of products in less than 1 h.

Dual-recognition membrane Adsorbers combining hydrophobic charge-induction chromatography with surface imprinting via multicomponent reaction

The combination of mixed-mode chromatography (MMC) and molecular imprinting technology (MIT) has been proven to be successful for protein separation, but suffered from cumbersome material preparation and limited performance. In this work, a new modification method marrying atom transfer radical polymerization (ATRP) and multicomponent reaction was proposed to simplify the preparation process. Using regenerated cellulose (RC) membrane as the substrate, immunoglobulin G (IgG) as the template protein and tryptamine as the ligand, a dual-recognition membrane adsorbers (MIM) was prepared by mild Ugi four-component reaction (Ugi-4CR) and surface initiated ATRP. Control the ATRP time is the key for surface imprinting. The static IgG uptake and selectivity of UGI membrane were 45 mg/mL and 1.8, respectively, while those of MIM-0.5 were 42.5 mg/mL and 14, indicating that the introduction of molecular imprinting technology significantly improved the selectivity of the membrane to IgG. The MIM-0.5 membrane retains the pH-dependent and salt-tolerant of HCIC. The dynamic flow-through results showed that the MIM-0.5 membrane could effectively separate IgG from IgG/BSA mixed solution with the purity of 88% and retained its bioactivity. This work demonstrated the feasibility of bonding HCIC and MIT to the membrane surface by Ugi-4CR and ATRP.

Camphorsulfonic Acid-Mediated One-Pot Tandem Consecutive via the Ugi Four-Component Reaction for the Synthesis of Functionalized Indole and 2-Quinolone Derivatives by Switching Solvents.

A camphorsulfonic acid-mediated one-pot tandem consecutive approach was developed to synthesize functionalized indole and 2-quinolone derivatives from the Ugi four-component reaction by switching solvents. A reaction of the Ugi adduct in an aprotic solvent undergoes 5-exo-trig cyclization to form an indole ring. In a protic solvent, however, the Ugi adduct undergoes an alkyne-carbonyl metathesis reaction to form a 2-quinolone ring.

(EtO)3Si(CH2)3NH3+][CH3COO−] as a novel basic ionic liquid catalyzed green synthesis of new 2-(phenylsulfonyl)-1H-benzo[a]pyrano[2,3-c]phenazin-3-amine derivatives

An efficient, one-pot procedure for the preparation new 2-(phenylsulfonyl)-1H-benzo[a]pyrano[2,3-c]phenazin-3-amine derivatives from four-component condensation reaction of 2-hydroxynaphthalene-1,4‑dione, o-phenylenediamine, aromatic aldehydes, and (phenylsulfonyl)acetonitrile in the presence of [(EtO)3Si(CH2)3NH3+][CH3COO−] as a novel basic ionic liquid as catalyst under solvent-free conditions is described. Simple procedure, high yields, short reaction times and an environmentally benign method are advantages of this protocol. The [(EtO)3Si(CH2)3NH3+][CH3COO−] can be recovered and reused several times without loss of its activity.

Ionic liquid mediated four-component synthesis of novel phthalazinone based indole-pyran hybrids as cytotoxic agents

A robust design and synthesis of novel phthalazinone based indole-pyran hybrids as cytotoxic agents is described. A relatively safer ionic liquid medium ([BMIM]BF 4) was utilized to mediate a one-pot, four-component reaction to access the novel hybrids in short reaction time and good yields. The cytotoxic potential of the hybrids was investigated against selected cancer cell lines. The hybrids 5h and 5b displayed potent activity with IC 50 values in the range of 5.8–9.6 μM. The insilico docking demonstrated a pronounced affinity of hybrids 5h and 5b towards the human tankyrase-1 enzyme exhibiting binding energies values of −11.2 and −10.2 kcal/mole, respectively. Additional ADME and drug likeliness analyses revealed the potential of the active hybrids to be taken forward for advanced studies.

An ecofriendly and reusable catalyst RuO2/MWCNT in the green synthesis of sulfonyl-quinolines

A simple and efficient RuO2/MWCNT nanocatalyst has been synthesized and thoroughly characterized by powdered XRD, SEM, SEM-EDX, TEM, and N2 adsorption analysis. The catalytic activity of RuO2/MWCNT nanomaterial was investigated in the effective green synthesis of sulfonyl-quinoline derivatives (5a–j) in higher yields applying a one-pot four-component reactions of substituted aldehydes, dimedone, phenylsulfonyl acetonitrile and NH4OAc in ethanol. The conversion was high under optimal conditions. The catalyst material could be separated easily from the reaction mixture and recyclable eight times via simple filtration without considerable reduction of its catalytic efficiency. Simple handling, eco-friendly, inexpensive, excellent yields (91–98%), minimum reaction time (≤15 min), use of green solvent and easy work-up are the features of this methodology.

Influence of biomass on multi-component reaction model and combustion products of coal gangue

The effects of biomass on coal gangue combustion characteristics, combustion products and combustion reaction model are studied in this paper. Based on the thermogravimetric experimental data, a multi-component combustion reaction model for coal gangue and biomass was established. The CG combustion reaction mechanism can be well explained by the two-component combustion reaction model. The participation degree of organic matter and inorganic matter is 90% and 10%, respectively. C3P1, C1P1 and C1P3 can be better explained by the five-component combustion reaction model. The reaction model corresponding to PS is a four-component combustion reaction model. Moreover, it is found that the addition of biomass can promote the combustion reaction of coal gangue and the production of gas products using Fourier transform infrared spectroscopy technology. Through combustion, the proportion of F4 mode of Cr, Cd, Pb, Cu, and Ni for CG sample increased from 92%, 60%, 52%, 28% and 60% to 95%, 90%, 82%, 91% and 94%, respectively. The toxicity reduction effect for Cd, Pb, Cu, and Ni is obvious, and the proportion of F4 mode is increased by more than 30%. Compared with other mixed samples, the ash formed by C1P1 is less harmful.