Three-component Coupling Reaction Research Articles

Silver–N‐heterocyclic carbene complexes‐catalyzed multicomponent reactions: Synthesis, spectroscopic characterization, density functional theory calculations, and antibacterial study

Nowadays, silver-N-heterocyclic carbene (silver-NHCs) complexes are widely used in medicinal chemistry due to their low toxic nature toward humans. Due to the success of silver-NHCs in medicinal applications, interest in these compounds is rapidly increasing. Therefore, the interaction of N,N-disubstituted benzimidazolium salts with Ag2 O in dichloromethane to prepare novel Ag(I)-NHCs complexes was carried out at room temperature for 120 h in the absence of light. The obtained complexes were identified and characterized by 1 H and 13 C nuclear magnetic resonance, Fourier-transform infrared, UV-Vis, and elemental analysis techniques. Then, the silver complexes were applied for three-component coupling reactions of aldehydes, amines, and alkynes. The effect of changing the alkyl substituent on the NHCs ligand on the catalytic performance was investigated. In addition, it has been found that the complexes are antimicrobially active and show higher activity than the free ligand. The silver-carbene complexes showed antimicrobial activity against specified microorganisms with MIC values between 0.24 and 62.5 μg/ml. These results showed that the silver-NHC complexes exhibit an effective antimicrobial activity against bacterial and fungal strains. A density functional theory calculation study was performed to identify the stability of the obtained complexes. All geometries were optimized employing an effective core potential basis, such as LANL2DZ for the Ag atom and 6-311+G(d,p) for all the other atoms in the gas phase. Electrostatic potential surfaces and LUMO-HOMO energy were computed. Transition energies and excited-state structures were obtained from the time-dependent density functional theory calculations.

Efficient synthesis of novel indolizine C-nucleoside analogues via coupling of sugar alkynes, pyridines and α-bromo carbonyl compounds in one pot

The synthesis of novel indolizine C-nucleoside analogues has been achieved by the three-component coupling reaction of sugar alkynes, pyridines and α-bromo carbonyl compounds in one pot. The corresponding products are obtained in good to excellent yields. 49 examples have been given. The synthetic method is convenient, practical and efficient. It is suitable for various substrates including structurally diversified sugar alkynes with sensitive groups. The sugar alkynes include pyranosides, furanosides, and acyclic sugars. A plausible mechanism for the formation of indolizine C-nucleoside analogues has been elucidated.

Palladium-Catalyzed Three-Component Coupling Reaction via Benzylpalladium Intermediate.

Transition-metal catalyzed multi-component reactions have captured the attention of researchers in organic synthesis and drug synthesis due to their advantages of simple operation, easy availability of raw materials and without separation of intermediates. Among the multi-component reactions, the three-component processes have been developed into effective organic procedures. This personal account reviews our and other group's studies on the development of three-component coupling reaction for the rapid construction of two new chemical bonds simultaneously via benzylpalladium intermediates. Catalyst-switched three-component reactions of benzyl halides, activated olefins, and allyltributylstannane were successfully conducted to produce the corresponding benzylallylation products. Activation and conversion of carbon monoxide and carbon dioxide via π-benzylpalladium intermediates provide access to a wide range of unsaturated ketones and esters with excellent functional group tolerance. Meanwhile, other methods to produce benzylpalladium intermediates, including Heck insertion of alkenes into arylpalladium complexes, the oxidative addition of benzyl carbonate to palladium complexes and palladium-carbene migratory insertion, were also highlighted.

Solvent-free coupling of aldehyde, alkyne, and amine over a versatile catalyst: Ag-functionalized mesoporous S, P-doped g-C3N4

In the present study, we introduce mesoporous g-C3N4/Ag co-doped with P and S which was designed and acquired by using mesoporous silica (SBA-15) as a hard templating agent and thiourea and chitosan phosphate as the dopants. The prepared catalyst was completely identified by FT-IR (Fourier-transform infrared spectroscopy), XRD (X-ray powder diffraction), FE-SEM (field-emission scanning electron microscopy), EDX (energy-dispersive spectroscopy), TEM (transmission electron microscopy), and Raman spectroscopy. The efficiency of the synthesized catalyst was evaluated toward the three-component coupling reaction, frequently named as A3 coupling. The higher activity of the prepared catalyst is because of the synergistic effects of phosphorus and sulfur co-doped together with Ag deposition. The desired products were achieved by an environmentally safe catalyst under the optimized conditions in high yields and short reaction time ranges.

Intramolecular C-N Bond Formation via Thermal Arene C-H Bond Activation Supported by Au(III) Complexes.

One of the main tactics to access C-N bonds from inactivated C-H functionalities is direct transition metal-supported aminations. Due to the often harsh reaction conditions, the current goal in the field is the search for more mild and sustainable transformations. Herein, we present the first solvent-free thermally induced C-N bond formation driven by Au(III) salts. The general structure of the products was confirmed by 1H, 13C, 15N NMR, TGA-DTA and ATR/FT-IR analysis. Additionally, all derivatives were tested as catalysts in a three-component coupling reaction between phenylacetylene, benzaldehyde and piperidine and as anticancer agents on HL-60 and MCF-7 cell lines.

Metric-Based Analysis of Convergence in Complex Molecule Synthesis.

Convergent syntheses are characterized by the coupling of two or more synthetic intermediates of similar complexity, often late in a pathway. At its limit, a fully convergent synthesis is achieved when commercial or otherwise readily available intermediates are coupled to form the final target in a single step. Of course, in all but exceptional circumstances this level of convergence is purely hypothetical; in practice, additional steps are typically required to progress from fragment coupling to the target. Additionally, the length of the sequence required to access each target is a primary consideration in synthetic design.In this Account, we provide an overview of alkaloid, polyketide, and diterpene metabolites synthesized in our laboratory and present parameters that may be used to put the degree of convergence of each synthesis on quantitative footing. We begin with our syntheses of the antiproliferative, antimicrobial bacterial metabolite (-)-kinamycin F (1) and related dimeric structure (-)-lomaiviticin aglycon (2). These synthetic routes featured a three-step sequence to construct a complex diazocyclopentadiene found in both targets and an oxidative dimerization to unite the two halves of (-)-lomaiviticin aglycon (2). We then follow with our synthesis of the antineurodegenerative alkaloid (-)-huperzine A (3). Our route to (-)-huperzine A (3) employed a diastereoselective three-component coupling reaction, followed by the intramolecular α-arylation of a β-ketonitrile intermediate, to form the carbon skeleton of the target. We then present our syntheses of the hasubanan alkaloids (-)-hasubanonine (4), (-)-delavayine (5), (-)-runanine (6), (+)-periglaucine B (7), and (-)-acutumine (8). These alkaloids bear a 7-azatricyclo[4.3.3.01,6]dodecane (propellane) core and a highly oxidized cyclohexenone ring. The propellane structure was assembled by the addition of an aryl acetylide to a complex iminium ion, followed by intramolecular 1,4-addition. We then present our synthesis of the guanidinium alkaloid (+)-batzelladine B (9), which contains two complex polycyclic guanidine residues united by an ester linkage. This target was logically disconnected by an esterification to allow for the independent synthesis of each guanidine residue. A carefully orchestrated cascade reaction provided (+)-batzelladine B (9) in a single step following fragment coupling by esterification. We then discuss our synthesis of the diterpene fungal metabolite (+)-pleuromutilin (10). The synthesis of (+)-pleuromutilin (10) proceeded via a fragment coupling involving two neopentylic reagents and employed a nickel-catalyzed reductive cyclization reaction to close the eight-membered ring, ultimately providing access to (+)-pleuromutilin (10), (+)-12-epi-pleuromutilin (11), and (+)-12-epi-mutilin (12). Finally, we discuss our synthesis of (-)-myrocin G (13), a tricyclic pimarane diterpene that was assembled by a convergent annulation.In the final section of this Account, we present several paramaters to analyze and quantitatively assess the degree of convergence of each synthesis. These parameters include: (1) the number of steps required following the point of convergence, (2) the difference in the number of steps required to prepare each coupling partner, (3) the percentage of carbons (or, more broadly, atoms) present at the point of convergence, and (4) the complexity generated in the fragment coupling step. While not an exhaustive list, these parameters bring the strengths and weaknesses each synthetic strategy to light, emphasizing the key contributors to the degree of convergence of each route while also highlighting the nuances of these analyses.

Passerini-type reaction of boronic acids enables \u03b1-hydroxyketones synthesis

Multicomponent reactions (MCRs) facilitate the rapid and diverse construction of molecular scaffolds with modularity and step economy. In this work, engagement of boronic acids as carbon nucleophiles culminates in a Passerini-type three-component coupling reaction towards the synthesis of an expanded inventory of α-hydroxyketones with skeletal diversity. In addition to the appealing features of MCRs, this protocol portrays good functional group tolerance, broad substrate scope under mild conditions and operational simplicity. The utility of this chemistry is further demonstrated by amenable modifications of bioactive products and pharmaceuticals as well as in the functionalization of products to useful compounds.

Recent advances in the synthesis of 1,1-diarylalkanes by transition-metal catalysis

1,1-Diaryl moieties are core structures in a wide range of bioactive and pharmaceutical compounds. Transition-metal catalysis is a convenient approach to accessing these invaluable compounds affording high yields and enantioselectivities. This review summarizes 1,1-diarylalkanes synthesis through transition metal catalysis. Particular focus is given to recent developments, such as reductive cross-electrophile couplings, benzylic C–H bond arylation, transformations involving metal migration, asymmetric hydrogenation of 1,1-diarylalkenes and three-component coupling reactions.

Nickel-Catalyzed Carboalkenylation of 1,3-Dienes with Aldehydes and Alkenylzirconium Reagents: Access to Skipped Dienes.

A regio- and stereoselective nickel-catalyzed three-component coupling reaction of aldehydes, 1,3-dienes, and alkenylzirconium reagents was realized. The ligand- and additive-free protocol afforded a convenient approach to the synthesis of skipped diene compounds bearing various functionals (e.g., hydroxyl, carbonyl, halide) and heterocyclic groups. The products were readily transformed into structurally diverse polyenes. The utility of this reaction was also demonstrated by the one-pot operation and scale-up preparation.

One-pot, three-component regioselective coupling reaction of triphenylamine/carbazole derivatives with [60]fullerene and indoles via an “umpolung relay” strategy

An “umpolung relay” three-component regioselective coupling reaction of triphenylamine/carbazole derivatives with C60 and indoles was developed, which features high regioselectivity, broad substrate scope, and excellent functional group tolerance.

Correction: One-pot, three-component regioselective coupling reaction of triphenylamine/carbazole derivatives with [60]fullerene and indoles via an “umpolung relay” strategy

Correction for ‘One-pot, three-component regioselective coupling reaction of triphenylamine/carbazole derivatives with [60]fullerene and indoles via an “umpolung relay” strategy’ by Xin-Rui Chen et al., Org. Chem. Front., 2021, DOI: 10.1039/D1QO01058A.

Metal-free multicomponent approach for the synthesis of propargylamine: a review.

Propargylamines are important classes of alkyne coupled amine compounds used in heterocyclic chemistry and pharmaceuticals chemistry and have a large impact as a pharmacophore used in medicinal chemistry. One of the straightforward approaches for the synthesis of this class of compound is A3 coupling, a three-component coupling reaction among aldehyde, alkyne (terminal acetylene) and amine. However, there are many methods other than conventional three component alkyne–aldehyde–amine (A3) coupling which have also been reported for the synthesis of propargylamine. Most of these methods are based on the metal catalyzed activation of terminal alkyne. From the perspective of green and sustainable chemistry, the scientific community should necessarily focus on metal-free techniques which can access a variety of propargylamines. There are only a few reports found in the literature where propargylamines were successfully synthesized under metal-free conditions. This present review article neatly and precisely encompasses the comprehensive study of metal-free protocols in propargylamine synthesis putting forth their mechanisms and other aspects.

Three-component coupling reaction for the synthesis of fully substituted triazoles: reactivity control of Cu-acetylide toward alkyl azides and diazo compounds

Herein, we report a Cu-catalyzed three-component coupling reaction of alkynes, azides, and diazo compounds for the synthesis of fully substituted triazoles.

A three-component iodine-catalyzed oxidative coupling reaction: a heterodifunctionalization of 3-methylindoles.

A metal-free method for the synthesis of heterodifunctional indole derivatives is developed through TBHP/KI-mediated oxidative coupling. The reaction constructs C-O and C-C bonds in succession with the help of tert-butyl peroxy radicals generated by the TBHP/KI catalytic system, enabling the direct realization of the heterodifunctionalization of indole in one pot. The product of this reaction is a novel heterodifunctional compound. This work might provide a new effective method for the synthesis of polycyclic indole compounds.

N-Alkylation/aldol reaction of α-aldimino thioesters: a facile three-component coupling reaction.

Theoretical calculation of the reactivity of α-imino thioesters indicates that they are very reactive substrates for Umpolung N-alkylation. In fact, treatment of α-aldimino thioesters with dialkylzinc reagents in the presence of aldehydes or imines gives three-component coupling products in good yields.

Metal-Free Three-Component Coupling Reaction of Ketones with Electron-rich Arenes and Selenium Dioxide for the Synthesis of α-Arylselanyl Ketones.

A metal-free three-component coupling reaction of aryl alkyl/alkyl ketones, SeO2, and phenols/anisoles is described. This multicomponent reaction provides a straightforward and facile pathway for the synthesis of α-((4-hydroxy/methoxyphenyl)selanyl)-aryl alkyl/alkyl ketones in the presence of p-toluenesulfonic acid for the C-Se bond formation process. The method offers an attractive and simple procedure using commonly available shelf reagents to deliver organoselenides that, to our knowledge, are being reported here for the first time.

Gold nanoparticle stabilized dithiocarbamate functionalized magnetite carbon as promise clean nanocatalyst for A3-coupling organic transformation

A novel, efficient, and core/shell nanosphere catalyst (Fe3O4@C-NHCS-Au0) was successfully synthesized with a movable magnetite core encapsulated in a carbon shell. It was modified using APTES (3-aminopropyltriethoxysilane) to convert dithiocarbamate (DTC) functional group in the carbon surface though post-modification with CS2 (carbon disulfide). Au0-nanoparticles were decorated via DTC binder to improve the catalytic activity. It was applied as a high-efficiency nanocatalyst in promoting three-component A3 coupling reaction of alkynes, aldehydes, and amines for the synthesis of propargyl amines under the optimized condition.

Synthesis of Benzylureas and Related Amine Derivatives via Copper-Catalyzed Three-Component Carboamination of Styrenes.

A direct assembly of secondary benzylureas and related amine derivatives via copper-catalyzed carboamination of styrenes with potassium alkyltrifluoroborates and ureas, anilines, or an amide is reported. Terminal and 1,2-disubstituted alkenes, as well as dienes, participate in this three-component coupling reaction. The reaction mechanism likely involves the addition of an alkyl radical to the styrene, followed by metal-mediated oxidative coupling of the resulting benzylic radical with the amine derivative. Factors that impact substrate reactivity and regioselectivity are discussed.

A Widely Applicable Dual Catalytic System for Cross-Electrophile Coupling Enabled by Mechanistic Studies.

A dual catalytic system for cross-electrophile coupling reactions between aryl halides and alkyl halides that features a Ni catalyst, a Co cocatalyst, and a mild homogeneous reductant is described. Mechanistic studies indicate that the Ni catalyst activates the aryl halide, while the Co cocatalyst activates the alkyl halide. This allows the system to be rationally optimized for a variety of substrate classes by simply modifying the loadings of the Ni and Co catalysts based on the reaction product profile. For example, the coupling of aryl bromides and aryl iodides with alkyl bromides, alkyl iodides, and benzyl chlorides is demonstrated using the same Ni and Co catalysts under similar reaction conditions but with different optimal catalyst loadings in each case. Our system is tolerant of numerous functional groups and is capable of coupling heteroaryl halides, di-ortho-substituted aryl halides, pharmaceutically relevant druglike aryl halides, and a diverse range of alkyl halides. Additionally, the dual catalytic platform facilitates a series of selective one-pot three-component cross-electrophile coupling reactions of bromo(iodo)arenes with two distinct alkyl halides. This demonstrates the unique level of control that the platform provides and enables the rapid generation of molecular complexity. The system can be readily utilized for a wide range of applications as all reaction components are commercially available, the reaction is scalable, and toxic amide-based solvents are not required. It is anticipated that this strategy, as well as the underlying mechanistic framework, will be generalizable to other cross-electrophile coupling reactions.

Porous organic polymer bearing triazine and pyrene moieties as an efficient organocatalyst

Materials with high specific surface area and bearing abundant basic sites at their pore surface are very demanding as heterogeneous catalyst for the eco-friendly base catalyzed reactions. Here we have developed a new secondary amine linked triazine and pyrene containing microporous organic polymer (TrzPyPOP) through a simple polycondensation reaction between tetramine1,4-bis(4,6-diamino-s-triazin-2-yl)-benzene (SL-1) and monoaldehyde pyrene-1-carboxaldehyde. This new porous organic polymer TrzPyPOP is very rich in N-content with high BET surface area (1016 m2 g−1). High surface area and N-rich surface basic sites have been explored in its potential as heterogeneous organocatalyst for the synthesis of dihydropyrimidones via Biginelli condensation involving three-component coupling reaction. Only a very little amount of catalyst was effective for the synthesis of dihydropyrimidones derivatives (yields = 88–99 %) together with high recycling efficiency under the optimum reaction conditions.