Four-component Reaction Research Articles

Sequential Selective C−H and C(sp3)−+P Bond Functionalizations: An Entry to Bioactive Arylated Scaffolds

Organophosphonium salts containing C(sp3 )-+ P bonds are among the most utilized reagents in organic synthesis for constructing C-C double bonds. However, their use as C-selective electrophilic groups is rare. Here, we explore an efficient and general transition-metal-free method for sequential chemo- and regioselective C-H and C(sp3 )-+ P bond functionalizations. In the present study, C-H alkylation resulting in the synthesis of benzhydryl triarylphosphonium salts was achieved by one-pot, four-component cross-coupling reactions of simple and commercially available starting materials. The utility of the resulting phosphonium salt building blocks was demonstrated by the chemoselective post-functionalization of benzylic C(sp3 )-+ PPh3 groups to achieve aminations, thiolations, and arylations. In this way, benzhydrylamines, benzhydrylthioethers, and triarylmethanes, structural motifs that are present in many pharmaceuticals and agrochemicals, are readily accessed. These include the synthesis of two anticancer agents from simple materials in only two to three steps. Additionally, a protocol for late-stage functionalization of bioactive drugs has been developed using benzhydrylphosphonium salts. This new approach should provide novel transformations for application in both academic and pharmaceutical research.

Attaching a Dipeptide to Fullerene as an Antioxidant Hybrid against DNA Oxidation.

Emerging evidence has revealed that oxidative damages of DNA correlate with the pathogenesis of some diseases, and numerous investigations have also suggested that supplementation of antioxidants is beneficial for keeping health by rectifying in vivo redox status. Here, we construct antioxidative dipeptides with the Ugi four-component reaction (comprising p-aminobenzyl alcohol, benzaldehyde, or vanillin, a series of antioxidative carboxylic acids and isocyanides as reagents) and then attempt to attach the dipeptides to [60]fullerene by the Bingel reaction. However, this endeavor does not lead to the amelioration of the radical-scavenging property because abilities of fullerenyl dipeptides to trap 2,2'-diphenyl-1-picrylhydrazyl and galvinoxyl radicals are still dependent upon the phenolic hydroxyl group in the dipeptide scaffold rather than upon the fullerenyl group. Alternatively, when the obtained fullerenyl dipeptides are evaluated in a peroxyl radical-induced oxidation of DNA, it is found that introducing a fullerene moiety into dipeptide enables antioxidative effect to be enhanced 20-30% because the fullerene moiety facilitates the corresponding dipeptide to intercalate with DNA strands, and thus, to increase the antioxidative efficacy. Our results suggest that connecting an antioxidative skeleton with the hydrophobic fullerene moiety might lead to a series of novel antioxidant hybrids applied for the inhibition of DNA oxidation.

Preparation of novel functionalized ionic liquid: Green, stable, and reusable catalyst for the synthesis of new 2-(phenylsulfonyl)-1H-benzo[a]pyrano[2,3-c]phenazin-3-amine derivatives

A new functionalized stable ionic liquid as 3-(triethoxysilyl)propane-1-aminium formate was prepared and characterized. The ionic liquid as a novel catalyst was carried out for the synthesis of new 2-(phenylsulfonyl)-1H-benzo[a]pyrano[2,3-c]phenazin-3-amine derivatives via four-component reaction of 2-hydroxynaphthalene-1,4-dione, o-phenylenediamine, arylaldehydes, and (phenylsulfonyl)acetonitrile. A simple and an efficient procedure for the synthesis of new un-known compounds using a green and novel reusable ionic liquid as catalyst under solvent-free and thermal conditions was reported. The easy preparation of ionic liquids without any toxic solvent, short reaction times, and simple work-up with excellent yields are advantages of the present reaction.

Synthesis and in vitro anticancer activity evaluation of spiro[indolo[2,1-b]quinazoline-pyrano[2,3-c]pyrazole] via sequential four-component reaction

Cancer is still incurable and it is considered as a main health problem worldwide. The identification of novel compounds with high toxicity and low side effects is one of the biggest challenges among interested researchers. In this study, a rapid and simple strategy for synthesis of spiro[indolo[2,1-b]quinazoline-pyrano[2,3-c]pyrazole] derivatives via sequential four-component reaction of isatoic anhydride, isatin, malononitrile, and 3-methyl-pyrazolones in CH2Cl2 at room temperature is described. This procedure has short reaction time and mild reaction conditions. Simple purification and no chromatographic process, are the other notable advantages of this protocol which make it attractive. To evaluate the anticancer activity of our synthetic compounds, pancreatic cancer cell (Panc1), cancer cell of breast (MDA-MB-231), colon cancer cell (HT-29), and normal human adult dermal fibroblast (HDF) were firstly cultured and by using MTT assay, the possible toxicity of related compounds was analyzed. Our results suggested that no compounds have 50% growth inhibitory concentration (IC50) values lower than etoposide (as a reference drug) against all cancer cell lines and among nine synthetic compounds, only 4a compound was effective against Panc1 pancreatic cancer cells.

Assembly of polyfunctional arenes with three contiguous and different substituents by Pd-catalyzed four-component reactions

The innovation of versatile multi-component reaction modes for one-pot assembly of polyfunctional arenes is a highly challenging and important goal in organic synthesis. Here, we report that polyfunctional arenes with three contiguous and different substituents can be assembled efficiently under mild conditions in a one-pot, four-component modular way by orchestrating mechanistically sequential and compatible palladium-catalyzed domino carbopalladation of arynes and norbornene (NBE)-mediated Catellani processes. Optimization of the reaction conditions reveals that balancing the reaction parameters in general, and loading amount of NBE especially, is a linchpin for the reaction. Studies of the reaction scope indicate a wide selection of functional groups, including complex natural product-derived substructures, can be tolerated, making it appealing for early- and late-stage assemblies. Post-transformations show that not only the newly installed substituents but also the parent aromatic nucleus can be derived conveniently, enabling polyfunctional arenes with diverse substitutions in a concise manner. General one-pot, four-component modular domino synthesis Three contiguous and different substituents Benzenes with up to six substituents Shen et al. describe a general, palladium-catalyzed, four-component reaction that can incorporate different functional groups onto three successive positions of benzene rings. The reaction tolerates complex natural product structures, and the products can be derived diversely.

Visible-LED-light-driven photocatalytic synthesis of N-heterocycles mediated by a polyoxometalate-containing mesoporous zirconium metal-organic framework

A mesoporous metal-organic framework with photothermal properties, namely PCN-222, was solvothermally synthesized from meso-tetra(4-carboxyphenyl)porphyrin and zirconium chloride employing both benzoic acid (BA) and trifluoroacetic acid (TFA) as modifiers. The MOF material subsequently served as a porous support for a polyoxometalate (POM), H3PW12O40, via a facile impregnation method which rendered a novel porous POM@PCN-222 composite. The solid was characterized by FT-IR, PXRD, SEM/EDX, TGA/DSC, ICP-OES, UV–Vis DRS, cyclic voltammetry (CV), and BET surface area. The one-pot synthesis of N-heterocycles (pyridine derivatives) was investigated utilizing the hybrid material via one-pot pseudo four-component reaction between aromatic aldehydes, methyl acetoacetate and ammonium acetate promoted under visible LED light irradiation in the presence of molecular oxygen as green oxidant. Products were selectively formed in good yields in the presence of the recyclable heterogeneous solid. Remarkably, POM@PCN-222 showed a superior performance for this procedure as compared to both unfunctionalized MOF and POM. The photosensitizer and photothermal properties of the porphyrin linkers combined with Lewis acidic sites derived from PW12 and Zr6-nodes were responsible for the observed excelling performance. To understand the mechanism, control investigations, electron paramagnetic resonance (EPR) analysis and FT-IR reaction monitoring were performed. The work discloses, for the first time, a simple and environmentally friendly approach for the direct production of pyridines via one-pot thermo-photocatalytic approach using a novel POM-modified MOF in the absence of any chemical additive.

On-Resin Ugi Reaction for C-Terminally Modified and Head-to-Tail Cyclized Antibacterial Peptides.

Here we report a method to synthesize C-terminally modified peptides on resin. A four-component Ugi reaction of isocyanide resin, an Fmoc-protected amino acid, an amine, and a 6-nitroveratrylaldehyde gives C-terminal photocaged peptide amides, which can be photolyzed to generate C-terminal peptide amides. Changing the amine component in the Ugi reaction gives peptides with different C-terminal modifications including substituted anilides, alkyne, and azide. By installing an N-terminal azide and C-terminal alkyne, we synthesized a head-to-tail cyclized antibacterial peptide through copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC). The cyclized peptide exhibited higher proteolytic stability and antibacterial activity than the linear peptide.

Fe3O4@chitosan-tannic acid bionanocomposite as a novel nanocatalyst for the synthesis of pyranopyrazoles

Recently magnetic nanocatalyst has attracted considerable attention because of its unique properties, including high performance, easy separation from the reaction mixture, and recyclability. In this study, a novel magnetic bionanocomposite was synthesized with chitosan and tannic acid as a natural material. The synthesized bionanocatalyst was characterized by essential analysis. Fe3O4@chitosan-tannic acid as a heterogeneous nanocatalyst was successfully applied to synthesize pyranopyrazole and its derivatives by a one-pot four-component reaction of malononitrile, ethyl acetoacetate, hydrazine hydrate, and various aromatic aldehyde. At the end of the reaction, the nanocatalyst was separated from the reaction mixture and was reused several times with no significant decrease in its catalytic performance. Simple purification of products, the ability for recovering and reusing the nanocatalyst, eco-friendliness, high yields of pure products, mild reaction conditions, short reaction time, non-toxicity, economically affordable are some of the advantages of using the fabricated nanocatalyst in the synthesis of pyranopyrazole.

O2‐Assisted Four‐Component Reaction of Vinyl Magnesium Bromide with Chiral N‐tert‐Butanesulfinyl Imines To Form syn‐1,3‐Amino Alcohols

An O2 -assisted, four-component reaction has been developed to synthesize a wide range of syn-1,3-amino alcohols in one step. The reaction proceeds by oxygenation of vinyl magnesium bromide (component-I) with O2 (component-II) to give a magnesium enolate of acetaldehyde, which undergoes addition to a chiral N-tert-butanesulfinyl imine (component-III) followed by a sequential addition with excess vinyl magnesium bromide (component-IV). The approach allows diastereoselective synthesis of anti/syn- and syn/syn-3-amino-1,5-diols in good yields with high diastereoselectivity. The method was illustrated in an efficient, four-step synthesis of piperidine alkaloid (-)-2'-epi-ethylnorlobelol.

Facile Synthesis of Diversely Functionalized Peptoids, Spectroscopic Characterization, and DFT-Based Nonlinear Optical Exploration.

Compounds having nonlinear optical (NLO) characteristics have been proved to have a significant role in many academic and industrial areas; particularly, their leading role in surface interfaces, solid physics, materials, medicine, chemical dynamics, nuclear science, and biophysics is worth mentioning. In the present study, novel peptoids (1–4) were prepared in good yields via Ugi four-component reaction (Ugi-4CR). In addition to synthetic studies, computational calculations were executed to estimate the molecular electrostatic potential, natural bond orbital (NBO), frontier molecular orbital analysis, and NLO properties. The NBO analysis confirmed the stability of studied systems owing to containing intramolecular hydrogen bonding and hyperconjugative interactions. NLO analysis showed that investigated molecules hold noteworthy NLO response as compared to standard compounds that show potential for technology-related applications.

Antioxidant Activity of Bioactive Peptide Fractions from Germinated Soybeans Conjugated to Fe3O4 Nanoparticles by the Ugi Multicomponent Reaction.

The conjugation of biomolecules to magnetic nanoparticles has emerged as promising approach in biomedicine as the treatment of several diseases, such as cancer. In this study, conjugation of bioactive peptide fractions from germinated soybeans to magnetite nanoparticles was achieved. Different fractions of germinated soybean peptides (>10 kDa and 5–10 kDa) were for the first time conjugated to previously coated magnetite nanoparticles (with 3-aminopropyltriethoxysilane (APTES) and sodium citrate) by the Ugi four-component reaction. The crystallinity of the nanoparticles was corroborated by X-ray diffraction, while the particle size was determined by scanning transmission electron microscopy. The analyses were carried out using infrared and ultraviolet–visible spectroscopy, dynamic light scattering, and thermogravimetry, which confirmed the coating and functionalization of the magnetite nanoparticles and conjugation of different peptide fractions on their surfaces. The antioxidant activity of the conjugates was determined by the reducing power and hydroxyl radical scavenging activity. The nanoparticles synthesized represent promising materials, as they have found applications in bionanotechnology for enhanced treatment of diseases, such as cancer, due to a higher antioxidant capacity than that of fractions without conjugation. The highest antioxidant capacity was observed for a >10 kDa peptide fraction conjugated to the magnetite nanoparticles coated with APTES.

Graphene quantum dots-crosslinked gelatin via the efficient Ugi four-component reaction: Safe photoluminescent implantable carriers for the pH-responsive delivery of doxorubicin

In this work, citric acid-based graphene quantum dots (GQDs) were used for crosslinking gelatin (G) via the Ugi four-component reaction (Ugi-4CR) with different ratios of Ugi-4CR reactants ratios as an innovative facile, green, and straightforward method. The synthesized GQDs-crosslinked gelatin (GQD-G) hydrogels were analyzed by XRD, FT-IR, NMR, PL, SEM, and Zeta potential techniques. To explain the productivity of synthesized hydrogels as a pH-responsive drug delivery system, doxorubicin (DOX) as a model anticancer drug was loaded into them through the soaking in drug solution. The results of in-vitro swelling and drug release studies revealed dependency on the time, pH, and degree of Ugi-4CR crosslinking. GQD-G hydrogel with 0.25 mmol Ugi-4CR reactant exhibited a higher pH responsivity. It was showed a low release rate at simulated physiological environmental (pH 7.4, 37°C), but it is raised at tumor tissue conditions (pH 4.5, 41°C), extending and sustaining the delivery of DOX. Importantly, by raising the Ugi-4CR-crosslinked contents, the MTT assay exhibits a good cytocompatibility and significant cytotoxicity against breast cancer cell line (MCF-7) for the blank and DOX-loaded GQD-G, respectively. From the obtained results, the synthesized cytocompatible photoluminescent GQD-G hydrogels with suitable pH responsivity have the potential to be utilized as an implantable anticancer and bio-detection agent.

Copper-Catalyzed Regioselective 1,4-Selenosulfonylation of 1,3-Enynes to Access Cyanoalkylsulfonylated Allenes.

By employing CuOAc as the catalyst, we realize a four-component reaction of 1,3-enynes, diselenides, DABCO·(SO2)2, and cycloketone oxime esters, providing facile access to diverse cyanoalkylsulfonylated allenyl selenides in moderate to good yields. This reaction features high functional group tolerance and a broad substrate scope, enabling the regioselective, sequential formation of C-SO2 and C-Se bonds under mild reaction conditions. Moreover, the utility of this methodology is further illustrated through the late-stage functionalization of drug-based molecules.

Copper(II) Anchored on Amine-Functionalized MMT: A Highly Efficient Catalytic System for the One-Pot Synthesis of Bispyrano[2,3-c]pyrazole Derivatives

In this study, preparation of pyridine-2-carboimine copper complex immobilized on amine-functionalized nanoclay montmorillonite K10 was reported. The products were characterized by Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), scanning electron microscopy (SEM), energy-dispersive X-ray spectroscopy (EDX), and thermogravimetric analysis (TGA). The catalytic activity of this new nanocatalyst, as a natural, renewable, inexpensive, and heterogeneous catalyst, was very effective for the four-component condensation reaction of hydrazine hydrate (or phenyl hydrazine), malononitrile, β-ketoester, and terephthalaldehyde (or isophthalaldehyde) toward the synthesis of multisubstituted bispyrano[2,3-c]pyrazole derivatives. From the viewpoint of green chemistry, the advantages of this approach are accessibility, simplicity, and high yields synthesis. The catalyst was recycled and reused four times without significant loss of activity.

Gallium Oxide (Ga2O3): An Efficient Heterogeneous Nanocatalyst for One Pot, Multi-Component Synthesis of Polyhydroquinolines

A novel, facial, highly effective gallium oxide (Ga2O3) nanocatalyst was synthesized and characterized by FT-IR, X-ray diffraction pattern (XRD), Scanning electron microscope (SEM), and Energy-dispersive X-ray spectroscopy (EDAX) analysis. The resulting gallium oxide (Ga2O3) nanomaterial has been successfully used as a catalyst for condensation of various aldehydes, dimedone, ammonium acetate, and ethyl acetoacetate under ethanol condition to yield polyhydroquinoline derivatives via a one-pot four-component Hantzsch condensation reaction. The products were investigated by IR, NMR, and mass spectral techniques. The desired catalyst was recycled and reused without any considerable changes in the yield.

Four-Component Synthesis of Polysubstituted Pyrazin-2(1H)-ones through a Ugi/Staudinger/Aza-Wittig/Isomerization Sequence.

A new efficient synthesis of polysubstituted pyrazin-2(1H)-ones via the sequential Ugi/Staudinger/aza-Wittig/isomerization reaction has been developed. The four-component Ugi reactions of arylglyoxals 1, primary amines 2, α-azidovinyl acids 3, and isocyanides 4 produced the azides 5, which were treated with triphenylphosphine to give pyrazin-2(1H)-ones 6 in good yields through domino Staudinger/aza-Wittig/isomerization reactions.

Highly efficient azido-Ugi multicomponent reactions for the synthesis of bioactive tetrazoles bearing sulfonamide scaffolds

Recent studies revealed that the contribution of the different bioactive scaffolds in one structure creates modern drugs/compounds with unique synergistic biological properties. In this regard, thanks to the interesting biological and medicinal properties of sulfonamide and tetrazole skeletons, this study describes the engagement of sulfonamides in the Ugi tetrazole reaction to access a library of tetrazole bearing sulfonamide. This four-component reaction was performed in a one-pot among available starting material, i.e., an isocyanide, a sulfonamide, an aldehyde and sodium azide in MeOH at 45 °C using ZnCl 2 as a catalyst, for the synthesis of very versatile products with high atom economy and yields. The key point in this strategy is the formation of an intermediate Schiff base and its activation in the azido-Ugi reaction by a Lewis acid catalyst. Importantly, all products are purified through the group-assisted purification (GAP) chemistry, which can avoid traditional purification such as recrystallization and chromatography methods. Also, the docking study between the synthesized compounds and human serum albumin (HSA) was stimulated to theoretically rationalize their biological activity and potential binding interactions.

Enhancing soil aggregation and acetamiprid adsorption by ecofriendly polysaccharides hydrogel based on Ca2+- amphiphilic sodium alginate

Soil aggregation plays an important role in agricultural production activities. However, the structure of soil aggregation is destroyed by the natural environment and unreasonable farming management, resulting in the loss of water, fertilizers and pesticides in soil. At present, hydrogels have been widely reported to promote the formation of soil aggregation. In this paper, amphiphilic calcium alginate (ASA/Ca2+) was applied to promote the formation of soil aggregation and enhance pesticide retention. Initially, an ASA was obtained through the one-pot Ugi condensation (a four-component green chemical reaction). Then, ASA/Ca2+ hydrogel is prepared by Ca2+ cross-linking. The formation of soil aggregation was determined through the Turbiscan Lab Expert stability analyzer, Confocal Laser Scanning Microscope (CLSM), and Transmission Electron Microscope (TEM). And the effect of soil aggregation on acetamiprid environmental behavior was investigated by adsorption kinetics, adsorption isotherms, and leaching. The results shown that the three-dimensional network structure of ASA/Ca2+ hydrogel can promote the formation of soil aggregation. Aggregate durability index (ADI) was 0.55 in the presence of ASA/Ca2+ hydrogel, indicating that amphiphilic hydrogel can enhance the stability of soil aggregation. The adsorbing capacity of acetamiprid was 1.58 times higher than pure soil, and the release of acetamiprid only about 20% in the presence of ASA/Ca2+ hydrogel. These results would be helpful for the formation of soil aggregation and pesticides adsorption on soil aggregation. Thus, ASA/Ca2+ hydrogel is likely to improve soil quality, simultaneously it can minimize the mobility of pesticides in the agricultural system.

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.

Synthetic Route to Enaminones via Metal-Free Four-Component Sequential Reactions of Aryl Olefins with CHCl3, Et3N, and TBHP.

An efficient and modular strategy was used to obtain enaminones with a wide range of functional groups via a four-component sequential reaction. This reaction proceeded under mild conditions without a catalyst in one pot. Furthermore, the products could be transformed into thiadiazoles.