Four-component Reaction Research Articles

Ultrasonic Mediated Synthesis of Dihydropyrano [2, 3-C] Pyrazole Derivatives Catalyzed By Cyanuric Acid/1-Methyl Imidazole

A Novel approach for the synthesis of dihydropyrano[2,3-c] pyrazoles via four-component reaction of ethyl acetoacetate, hydrazine hydrate, aromatic aldehydes and malononitrile at room temperature under ultrasound irradiation is described. The reaction has been catalyzed by cyanuric acid and 1-methyl inidazole in aqueous medium. This protocol afforded several advantages such as easily available catalyst, simple operational procedure, excellent yield and ultrasound irradiation.

Asymmetric Carbene Insertion into Se-S Bonds by Synergistic Rh(II)/Guanidine Catalysis Involving Chalcogen-Bond Assistance.

The efficient construction of chalcogen-atom-based chiral compounds remains a challenge, despite the importance of organoselenium and organosulfur compounds in life and materials science. Chalcogen atoms can form net attractive interactions called chalcogen bonds, but it is an undeveloped tool to assist asymmetric catalysis. Herein, we report an enantioselective insertion platform to install a stereogenic center bearing selenyl and thiocyano functional groups. Our method operates by synergistic catalysis by a chiral guanidine and an achiral dirhodium complex in a three-component or four-component reaction, through Se-S bond insertion into carbene species, competing successfully with the spontaneous racemic process and showing high regioselectivity. As elucidated by spectroscopic experiments and computational studies, a unique mechanism involving chalcogen as well as hydrogen bonding was established to account for the enantiocontrol. The high stereoselectivity holds for a broad array of selenylthiocyanatopropanoates, which showed excellent anti-inflammatory toward IL-1β and low cytotoxicity.

Precisive Incorporation of Multiple Nitrogen Sources into Benzoxazoles via an Iodine-Mediated Electrochemical Four-Component Reaction.

An iodine-mediated electrochemical four-component reaction was developed to construct aromatic C-N bonds by making use of a simple nitrogen source, such as NH4+ and formamide. By virtue of this reaction, a variety of benzoxazoles bearing different substituents can be selectively modulated by using different bases. This protocol features a broad substrate scope and good scalability, is transition metal-free and chemical oxidant-free, and exhibits controlled product distribution. Additionally, it also enables a versatile platform for various isotope-labeled (15N and CD3) benzoxazoles.

A Reactivity Study of 4-Hydroxy-2H-chromene-2-thione and 4-Hydroxy-2H-thiochromene-2-thione with tert-Butyl Nitrite and Aromatic Amines: An Environmentally Benign Synthesis of New Hydrazone Derivatives

AbstractThe synthesis of biologically active coumarin-based hydrazone derivatives is achieved through a one-pot, three-component reaction of 4-hydroxy-2H-chromene-2-thiones with aniline derivatives and tert-butyl nitrite under solvent- and catalyst-free conditions in yields of 76–86%. Similarly, the reactions of 4-hydroxydithiocoumarins with aniline derivatives and tert-butyl nitrite under identical conditions provided the corresponding hydrazone products in 79–85% yield through a four-component reaction. It is observed in both cases that the C=S group at the C2 position is converted into a C=O moiety. However, the intermediate products derived from 4-hydroxydithiocoumarin react further with another aniline molecule leading to thioesters. 4-Hydroxy-2H-chromene-2-thione and 4-hydroxydithiocoumarin exhibit distinct reactivity pathways, resulting in the formation of two different types of product. In addition, quantum chemical analysis of the mechanistic steps show that this reaction is exergonic. This protocol offers broad substrate scope and tolerates various functional groups, leading to high product yields in short reaction times.

Palladium immobilized on functionalized halloysite: A robust catalyst for ligand free Suzuki–Miyaura cross coupling and synthesis of pyrano[2,3-c]pyrazole motifs via four component cascade reaction and their in-silico antitubercular screening

This research introduces a novel organically functionalized halloysite-supported palladium catalyst, HMF-EDA-TMS@HAL-Pd(II) that was synthesized and thoroughly characterized using various analytical techniques like HR-TEM, FEG-SEM, EDX, XPS, FTIR, XRD, TGA, ICP-AES, EXAFS and DFT studies. The catalyst exhibited exceptional performance in Suzuki–Miyaura cross coupling reactions, demonstrating high efficiency and reusability up to seven cycles in aqueous ethanol medium. Motivated by its promising catalytic activity, we extended our investigation to explore its applicability in the synthesis of pyrano[2,3-c]pyrazole motifs via a four-component cascade reaction affording the desired products in good to excellent yields with broad substrate scope under green reaction conditions. In-silico antitubercular screening of pyrano[2,3-c]pyrazole motifs against DprE1 enzyme have shown promising results with inhibition constants ranging between 0.030 and 0.1 μM for compounds 5b, 5k and 5 l. This protocol has the advantages of wide substrate scope, high yield, excellent functional group tolerance, high efficiency and environmental benign procedure. These findings emphasized the catalyst's versatility and potential in diverse organic transformations, highlighting its importance in advancing sustainable synthetic methodologies.

Base-Promoted One-Pot Four-Component Domino Strategy Involving Aldehydes and Ketones to Access Multifunctionalized Dihydropyridinones.

The synthesis of multifunctionalized dihydropyridinones from aldehydes and ketones involves at least a three-step process, making route shortening a challenging task, especially in achieving a one-pot four-component synthesis via aldehydes and ketones precondensation. Herein, we discovered a [1 + 2 + 1 + 2] four-component domino cyclization reaction, a novel concept in 4CRs with commercially available ketones and aldehydes, which by initially combining aldehydes and ketones with Meldrum's acid and ammonium acetate (NH4OAc), respectively, they give dihydropyridones (>110 examples). This transformation features inexpensive additives and readily available starting materials, making it appropriate for rapid access to relevant pharmaceutical molecules containing dihydropyridinone-derived heterocycles. Also these compounds can be conveniently converted into trisubstituted and tetrasubstituted pyridines.

Synthesis and biological activity of substituted 5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxamides

A four-component solvent-free reaction of acetoacetic acid amide with dimedone, aromatic aldehydes and ammonium acetate leads to new substituted 5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxamides. The structures of the products were proved using IR, 1H and 13C NMR spectroscopy, mass spectrometry and X-ray diffraction analysis. The synthesized compounds were tested for antimicrobial and antinociceptive activities.

Multicomponent Construction of Tertiary Alkylamines by Photoredox/Nickel-Catalyzed Aminoalkylation of Organohalides.

Tertiary alkylamines are privileged structural motifs widely present in natural products, pharmaceutical agents, and bioactive molecules, and their efficient synthesis has been a longstanding goal in organic chemistry. The functionalization of α-amino radicals derived from abundant precursors represents an emerging approach to accessing alkylamines, but application of this strategy to obtain tertiary alkylamines remains challenging. Here, we show that dual photoredox/nickel catalysis enables aminoalkylation of organohalides (sp2- and sp3-hybridized) in combination with secondary alkylamines and aldehydes. The multicomponent process proceeds through selective generation of α-amino radicals from the reduction of in situ-generated iminium ions by photoredox catalysis, followed by nickel-catalyzed cross-coupling to build a wide array of functionally diverse tertiary alkylamines. This strategy could also be extended to unprecedented four-component reactions and their asymmetric variants to deliver enantioenriched α-aryl-substituted γ-amino acid derivatives. Taken together, this work offers a streamlined synthetic route to aliphatic tertiary amines.

A simple and highly efficient catalyst-free for the synthesis of dihydro pyrido[1, 2-a]quinoxaline derivatives by four component reactions and evaluation of their antibacterial activity

In the current work, a new series of methyl-10-amino-9-cyano-6-oxo-8-aryl-6,8-dihydro-5H-pyrido[1,2-a]quinoxaline-7-carboxylate derivatives were efficiently designed and prepared using a convenient route in excellent yields by four-component reactions among benzene-1,2-diamine, dimethyl acetylenedicarboxylate, various aromatic aldehydes and malononitrile. These reactions were carried out in acetonitrile at ambient temperature under catalyst-free conditions for 7 h. The structures of the new obtained compounds were confirmed by NMR, IR, EI-MS and elemental analysis. The antibacterial activity of the synthesized products was studied using bacterial strains: Staphylococcus aureus, Bacillus subtilis, Escherichia coli, and Pseudomonas aeruginosa. The results showed that all the synthesized compounds are effective against Staphylococcus aureus, Bacillus subtilis and Escherichia coli bacteria.

Chemo- and diastereoselective four-component reactions with Rh carbynoids

Multi-component reactions (MCRs) provide an efficient method for constructing multiple chemical bonds by combining three or more starting materials in a single operational step, enabling rapid and cost-effective synthesis of structurally diverse compounds. Although carbynoids (R-C:+) have shown potential for the development of selective MCRs due to their unique carbene and carbocation characteristics, their application in four-component reactions (4CRs) has been constrained by challenges in chemoselectivity. Herein, we provide a general solution to the challenges of chemoselective 4CR, using halo diazo reagents as carbynoid precursors, followed by reacting with pyrazoles, alcohols and imines sequentially. This approach allows the simultaneous construction of three different C(sp3)-N, C(sp3)-O, and C(sp3)-C(sp3) bonds on the same carbon. The success of this protocol mainly depends on precise control of chemical kinetics. Detailed experimental studies elucidate that the generation rate of aza-Rh(II)-carbene is faster than oxy-Rh(II)-carbene.

Equipping Uridine with Three Dipeptide Motifs for the Inhibition of Radical-Induced DNA Oxidation.

We report the discovery and characterization of antioxidative effects of uridine linked with three dipeptide motifs against DNA oxidation induced by peroxyl radicals. First, the dipeptide motifs are constructed by using the Ugi four-component reaction (Ugi 4CR), in which caffeic, ferulic, sinapic, and syringic acids are used as the carboxylic acid resources, vanillin, benzaldehyde, and p-hydroxybenzaldehyde are used as the aldehyde resources, tyramine- and dopamine-related isocyanides as well as ethyl isocyanoacetate are used as the isocyanide resources, and 2-(p-aminophenyl)ethanol is used as the amine component. We found that the antioxidative effects of the Ugi 4CR products are 1.3-2.8 times higher than those of caffeic, ferulic, sinapic, and syringic acids in the protection of DNA against peroxyl radical-induced oxidation. Moreover, when three Ugi 4CR products are linked with three hydroxyl groups of uridine by using three succinic anhydrides as the linkage, the inhibitory effects of the afforded uridine-dipeptide hybrids against the DNA oxidation increase 4.4-8.9 times (>3 times) compared to that of the Ugi 4CR product. This is due to the hybrid structure consisting of uridine and three motifs of the Ugi 4CR product enabling binding with the DNA strand more efficiently and quenching free radicals more rapidly. Therefore, the hybrid structure constructed by the nucleoside with antioxidative dipeptides offers an additional advantage for protecting DNA against radical-induced oxidation.

Copper-Catalyzed Four-Component Domino Cyclization for the Synthesis of 2-Methylpyridines.

A convenient protocol for synthesis of unsymmetrical 2-methylpyridines from acetyl ketones, ammonium salts and tertiary amines is described. The construction of two C-C bonds and two C-N bonds via [2 + 2 + 1 + 1] four-component domino cyclization reaction is achieved using Cu(OTf) as catalyst in one pot. This cyclization reaction shows good selectivity and produces multisubstituted 2-methylpyridine derivatives in good yields with various functional groups.

Pyridine-Catalyzed Chemoselective Four-Component Cascade Reaction of Aromatic Aldehydes, Malononitrile/Cyanoacetates, MBH Carbonates, and Alcohols.

An efficient pyridine-catalyzed chemoselective four-component cascade reaction of aromatic aldehydes, malononitrile/cyanoacetates, Morita-Baylis-Hillman (MBH) carbonates, and alcohols has been established. This one-pot reaction progressed in an unusual reaction with solvent participation via a Knoevenagel condensation/oxa-Michael addition/SN2' substitution sequence. This method allowed for facile access to an array of functionalized chain alkylbenzenes and dihydroquinolinones bearing one all-carbon quaternary center in moderate to excellent yields. It is worth noting that the configuration of the all-carbon quaternary center could be modulated by changing only the electron-withdrawing groups via a tandem reduction/cyclization reaction.

Segregation Pattern in a Four-Component Reaction–Diffusion System with Mass Conservation

Segregation Pattern in a Four-Component Reaction–Diffusion System with Mass Conservation

Development of peptoid-based heteroaryl-decorated histone deacetylase (HDAC) inhibitors with dual-stage antiplasmodial activity

Dynamics of epigenetic modifications such as acetylation and deacetylation of histone proteins have been shown to be crucial for the life cycle development and survival of Plasmodium falciparum, the deadliest malaria parasite. In this study, we present a novel series of peptoid-based histone deacetylase (HDAC) inhibitors incorporating nitrogen-containing bicyclic heteroaryl residues as a new generation of antiplasmodial peptoid-based HDAC inhibitors. We synthesized the HDAC inhibitors by an efficient multicomponent protocol based on the Ugi four-component reaction. The subsequent screening of 16 compounds from our mini-library identified 6i as the most promising candidate, demonstrating potent activity against asexual blood-stage parasites (IC50Pf3D7 = 30 nM; IC50PfDd2 = 98 nM), low submicromolar activity against liver-stage parasites (IC50PbEEF = 0.25 μM), excellent microsomal stability (t1/2 > 60 min), and low cytotoxicity to HEK293 cells (IC50 = 136 μM).

A new route for the synthesis of multi-substituted pyrrole derivatives containing a sulfonyl scaffold via the chemistry of N-sulfonylketenimine

A rapid practical new synthesis of multi-substituted pyrrole derivatives with high yields through a novel four-component reaction of sulfonyl azides, terminal alkynes, nitro compounds, and trichloroacetonitril is a remarkable achievement in organic chemistry. This strategy offers a direct and efficient route to access complex molecular structures from readily available starting materials. To expand the work, the reaction of the final product with sulfinate salt under simple conditions and room temperature, poly-substituted pyrroles with sulfone functional group are formed. The combination of available starting materials, catalytic systems, mild reaction conditions, and ease of purification procedures contributes to the attractiveness of this method for the synthesis of diverse multi-substituted pyrrole derivatives.

A versatile gemini amphiphile-based platform with STING-activating properties for efficient gene delivery into dendritic cells

Encouraging results from clinical trials have underscored the potential of gene-pulsed dendritic cell (DC) vaccines as a viable approach for immunotherapy. However, insufficient gene delivery and functional deficiencies in antigen presentation, migratory capacity and cytokine release of DC vaccines limited its broader clinical application. Here, a combinatorial design of cationic gemini amphiphile (GA) molecular library based on the four-component Ugi reaction (Ugi-4CR) has been developed to identify versatile non-viral vectors for gene-engineered DC vaccines. We demonstrated that the leading GA enabled robust transfection of plasmid DNA or mRNA into the DCs through the formation of minimalist binary complexes, which exhibited great advantages of low carrier/gene ratios, high gene loading efficiency and well biocompatibility. The identified GA stimulated strong type I interferon (IFN) expression via the intracellular stimulator of interferon genes (STING) pathway and enhanced DC maturation and activation, which could potentially facilitate strong immunogenicity of DC vaccines. Importantly, DC maturation and activation could be further strengthened by co-delivering maturation stimuli with mRNA/GA complexes, and adoptive transfer of gene-engineered DC vaccines elicited strong T cell responses and thus inhibited tumor growth in vivo. The further studies indicated GAs can be formulated into lipid nanoparticle (LNP)-like quinary complexes that presented 6.9-fold higher mRNA delivery efficiency on the DCs than the commercial Lipofectamine 2000. These results suggest that GA-based molecular library is a powerful platform to develop versatile gene delivery vectors for immune cell engineering.

Visible-Light Photoredox-Catalyzed Difunctionalization of Alkynes with Quinoxalin-2(1H)-Ones, P4S10, and Alcohols.

Visible-light photoredox-catalyzed method has been developed for the synthesis of quinoxalin-2(1H)-one-containing vinyl phosphorodithioates via direct difunctionalization of alkynes with quinoxalin-2(1H)-ones, P4S10 and alcohols. This four-component reaction could be carried out under metal-free and mild conditions, affording a number of quinoxalin-2(1H)-one-containing vinyl phosphorodithioates in moderate to good yields with Z-isomers as the major products. Photocatalytic radical mechanism is proposed based on the results of radical trapping and fluorescence quenching experiments.

Nano silicated-FeAl2O4 functionalized by DL-alaninium nitrate ionic liquid (FeAl2O4-SiO2@[DL-Ala][NO3]) as versatile promotor for aqua-mediated synthesis of spiro[chromenopyrazole-indene-triones and spiro[chromenopyrazole-indoline-diones

In this work, the spinel FeAl2O4 was prepared and functionalized step-by-step with silica and alaninium nitrate ionic liquid ([DL-Ala][NO3]) to produce a bio-based multi-layered nanostructure (nano FeAl2O4-SiO2@[DL-Ala][NO3]). The obtained magnetized inorganic-bioorganic nanohybrid characterized by Fourier transform infrared spectroscopy (FT-IR), vibrating-sample magnetometry (VSM), field emission scanning electron microscopy (FESEM), energy-dispersive X-ray spectroscopy (EDAX), transmission electron microscopy (TEM), thermogravimetric analysis/differential scanning calorimetry (TGA/DSC), X-ray fluorescence (XRF), and X-Ray diffraction (XRD) analysis. A facile synthesis of some tricyclic dihydro-spiro[chromeno[2,3-c]pyrazole-4,2′-indene]triones and dihydro-spiro[chromeno[2,3-c]pyrazole-4,3′-indoline]diones via domino four-component one-pot reaction of various hydrazine derivatives, ethyl acetoacetate, heterocyclic 1,2-ketones (ninhydrin, isatin, 5-bromoisatin) and cyclic 1,3-diketones (dimedone and 1,3-cyclohexanedine), examined in the presence of nano FeAl2O4-SiO2@[DL-Ala][NO3] nanohybrid in refluxing aqueous media, successfully. The multi-aspect characteristics of the nanohybrid which consist of magnetized inorganic and bioorganic parts, could be the reason of its special catalytic efficacy. The recovery and reusability of the FeAl2O4-SiO2@[DL-Ala][NO3] magnetized nanoparticles (MNPs) were performed in two runs without significant activity loss.

Chemo-, regio- and stereoselective access to polysubstituted 1,3-dienes via Nickel-catalyzed four-component reactions

1,2-Difunctionalization of alkynes offers a straightforward approach to access polysubstituted alkenes. However, simultaneous multi-component cascade transformations including difunctionalization of two alkynes with both syn- and anti-selectivity in one catalyst system is undeveloped and proves to be a significant challenge. Herein, we report a Nickel-catalyzed four-component reaction to access polysubstituted 1,3-dienes using two terminal alkynes, aryl boroxines, and perfluoroalkyl iodides, wherein the reaction forms three new C-C bonds in a single vessel and serve as a modular strategy to access polysubstituted 1,3-dienes with excellent chemoselectivity, good regioselectivity and exclusive stereoselectivity. Control experiments reveal the plausible reaction mechanism and DFT calculations explain the cause for the formation of this unusual four-component reaction. Furthermore, we successfully incorporate two biologically active units into 1,2,3,4-tetrasubstituted 1,3-dienes, which greatly increases the diversity of molecular scaffolds and brings more potential values to medicinal chemistry, the synthetic utility of our protocol is further demonstrated by the late-stage transformations.