Copper-catalyzed Coupling Reaction Research Articles

Copper-Catalyzed Multicomponent Coupling Reaction of Primary Aromatic Amines, Rongalite, and Alkynes: Access to N-Aryl Propargylamines.

In this work, a practical copper-catalyzed multicomponent coupling reaction of primary aromatic amines, rongalite, and alkynes for the direct synthesis of N-aryl propargylamines has been developed. This method could overcome the substrate limitation in A3 coupling reactions of primary aromatic amines, formaldehyde, and alkynes. Mechanistic studies revealed that rongalite acts as not only the active C1 unit but also the accelerator to activate the in situ-generated N-arylmethanimines for the coupling reaction with alkynes. This coupling reaction is highly efficient and features a broad substrate scope, as well as utility with scale-up synthesis and converting the corresponding product N-aryl propargylamines into useful heterocyclic skeletons.

An Alternative Approach to Synthesize Sildenafil via Improved Copper-Catalyzed Cyclization.

A facile synthetic pathway for sildenafil has been developed. This approach is characterized by a ligand-free Ullmann-type copper-catalyzed coupling reaction to construct sildenafil and its derivative, pyrrazolo[4,3-d]pyrimidin-7-one ring, with yields of 79% and 82%, respectively, in a convergent fashion by connecting key building blocks halo-pyrazole moiety 16c with 2-ethoxybenzamidine and 2-ethoxy-5-[(4-methylpiperazin-1-yl)sulfonyl]benzamidine in a one-pot reaction. Thus, this approach circumvents the need to use nitric/sulfuric acid for nitration, a costly Pd-catalyst for reduction, and coupling agents encountered in the reported processes.

Tuning C-N Ullmann coupling with anion-exchanged ionic liquid-functionalized nanoparticle catalysts

Modern organic chemistry demands efficient and sustainable synthetic methods. Copper-catalyzed Ullmann coupling reactions, adept at constructing biaryl and aryl-heteroaryl motifs, have gained significant traction. However, traditional methods suffer from limitations. Nanoparticle catalysts, particularly copper nanoparticles (CuNPs), offer improved efficiency, but their performance is hampered by agglomeration and leaching. Hybrid supports incorporating ionic liquids (ILs) address this issue by providing a polar environment stabilizing CuNPs and enhancing catalytic activity and selectivity. This study investigates the impact of anion exchange in ionic liquids on the catalytic performance of C-N Ullmann couplings. Anion exchange modifies interionic interactions, hydrogen bonding, and dipolar properties, ultimately influencing the reaction's outcome. We synthesized CuNPs impregnated in silica supports functionalized with a triazolium-based ionic liquid possessing different anions (BF4−, PF6−, NTf2−) to elucidate the effect of anion exchange.Characterization techniques like FT-IR, XPS, TGA, and XPS confirmed successfully incorporating the triazole group and varying anions onto the material. TEM analysis showed the presence of CuNPs (4.5–5.7 nm) impregnated on the triazole functionalized silica supports.Catalytic studies yielded fascinating insights into the impact of different anions on conversion and selectivity. Iodide (I−) promoted higher conversion (100%), while tetrafluoroborate (BF4−) offered superior selectivity (57%). Computational studies provided valuable explanations, shedding light on the reactivity of the nanostructures and the interaction mechanism between substrates and the nanocatalyst. The theoretical results suggest that coordinative covalent bonds and highly polarized interactions govern the substrate interaction, with the aniline path achieving higher stabilization.Furthermore, the choice of anion influences the reactivity, substrate stabilization, and spin density distribution. These properties directly correlate with the conversion and selectivity observed in the catalytic studies.

Copper-catalyzed room-temperature cross-dehydrogenative coupling of secondary amides with terminal alkynes: a chemoselective synthesis of ynamides.

A copper-catalyzed aerobic oxidative cross-dehydrogenative coupling reaction between secondary amides and terminal alkynes has been developed. With the aid of ligands and 3 Å molecular sieves, ynamides can be efficiently synthesized at room temperature and conveniently scaled up. A legitimate mechanism involving nitrogen-centred radicals and copper trivalent intermediates has been proposed.

Azaindole based fluorescent chemosensors for detecting Fe(II/III) ions and molecular logic gate implementation

A series of tridentate polypyridyl N^N^N/N^C^N-coordinating ligands (R1, L1, L2) were synthesized by copper-catalyzed Ullmann coupling (C–N bond-forming) reaction in moderate yields (∼50 %). Two charged ligands, L3 and L4 were also synthesized by methylation of L1 and L2 in moderate yields (∼45 %). These ligands were characterized by a set of analytical techniques including NMR, HRMS and single-crystal XRD. The electrochemical and photophysical properties of these ligands were examined using cyclic voltammetry, UV–vis absorption and luminescence spectroscopies. Theoretical calculations in the level of DFT and TD-DFT were also performed for the detailed studies of the optoelectronic properties of these compounds. These ligands displayed either an admixture of singlet ligand-centered (1LC) and singlet charge-transfer (1CT) transitions or pure 1LC/1CT luminescence in some cases. Ligands R1 and L1 which were highly emissive were further used as selective chemosensors for the detection of Fe(II)/(III) with a “turn-off” fluorescence behavior in a binding stoichiometry of 2:1 = ligand: M(II/III) [M = Fe(II)/Fe(III)] and a limit of detection up to 0.87–1.19 ppm level. L1 was also realized for the successful construction of the molecular logic gate.

Application of 1,4-pentanediol as a renewable solvent for copper-catalyzed Ullmann-type coupling reactions

It was demonstrated that 1,4-pentanediol as a biomass-originated polar protic solvent could be utilized as an alternative reaction medium for copper-catalyzed Ullmann-type coupling reactions of aryl iodides and various amines under mild conditions. The effect of the copper source, the base, the water, and the γ-valerolactone content of the reaction mixture on the reaction performance was investigated. Eighteen cross-coupling products were isolated with yields of 11–69 %, and high purity (>98 %). Two O-arylated products, 4-phenoxypentan-1-ol and 5-phenoxypentan-2-ol were characterized. The recycling of the solvents after product isolation was also demonstrated. These results represent an example that proves that biomass-derived safer solvents can be utilized in common, industrially important transformations.

A sustainable avenue for the synthesis of propargylamines and benzofurans using a Cu-functionalized MIL-101(Cr) as a reusable heterogeneous catalyst

A heterogeneous copper-catalyzed A3 coupling reaction of aldehydes, amines, and alkynes for the synthesis of propargylamines and benzofurans has been developed. Here, the modified metal–organic framework MIL-101(Cr)-SB-Cu complex was chosen as the heterogeneous copper catalyst and prepared via post-synthetic modification of amino-functionalized MIL-101(Cr). The structure, morphology, thermal stability, and copper content of the catalyst were determined by FT-IR, PXRD, SEM, TEM, EDX, TGA, XPS, and ICP-OES. The catalyst shows high catalytic activity for the aforementioned reactions under solvent-free reaction conditions. High yields, low catalyst loading, easy catalyst recovery and reusability with not much shrink in catalytic activity, and a good yield of 82% in gram-scale synthesis are some of the benefits of this protocol that drove it towards sustainability.

Cu-Catalyzed Polychloromethylamination of Styrenes through C(sp3 )-H Bond Cleavage.

A copper-catalyzed three-component coupling reaction has been developed allowing the rapid building of valuable complex highly functionalized β-polychloromethyl amines from simple styrenes, arylamines, and dichloromethane/chloroform. Using aryldiazonium salts as a radical initiator, a series of corresponding products are obtained with moderate to good yields under a carbon dioxide or nitrogen atmosphere (50 psi). In addition, good functional group tolerance can be observed.

Cu/Oxalic Diamide-Catalyzed Coupling of Terminal Alkynes with Aryl Halides.

N1-(2,6-Dimethylphenyl)-N2-(pyridin-2-ylmethyl)oxalamide (DMPPO) was revealed to be a more effective ligand for copper-catalyzed coupling reaction of (hetero)aryl halides with 1-alkynes than previously reported ones. Only 3 mol % CuCl and DMPPO are required to make the coupling complete at 100 °C (for bromides) and 80 °C (for iodides). Both (hetero)aryl and alkyl substituted 1-alkynes worked well under these conditions, leading to the formation of internal alkynes in great diversity.

Photoinduced copper-catalyzed enantioselective coupling reactions.

Copper-catalyzed enantioselective coupling has been widely investigated, which allows rapid construction of various chiral molecules. Despite important advances via polar and radical mechanisms, exploring general and practical strategies for the regio-, enantio- and diastereoselective assembly of stereogenic centers is of significant value but remains highly problematic. The integration of photocatalysis with asymmetric copper catalysis could provide appealing access to the development of new reaction pathways and structurally diverse chiral compounds, and extend the boundaries of radical chemistry. This review summarizes recent advances in photoinduced copper-catalyzed enantioselective coupling reactions, and discusses the mechanistic aspects.

Synthesis of 1-Aminoisoquinolines and Their Application in a Host-Guest Doped Strategy To Construct Ultralong Room-Temperature Phosphorescence Materials for Bioimaging.

Organic ultralong room-temperature phosphorescence (RTP) materials have attracted great attention for their wide applications in optoelectronic devices and bioimaging. However, the development of these materials remains a challenging task, partially due to the lack of rational molecular design strategies and unclear luminescence mechanisms. Herein, we present a method for facile access to structurally diverse substituted 1-aminoisoquinoline derivatives through a copper-catalyzed one-pot three-component coupling reaction that provides a promising approach to rapidly assemble a library of 1-aminoisoquinolines for exploring the regularity of the host-guest doped system. A series of host-guest RTP materials with wide-ranging lifetimes from 4.4 to 299.3 ms were constructed by doping various substituted isoquinolines derivatives into benzophenone (BP). Furthermore, 4 r/BP nanoparticles could be used for in-vivo imaging with a signal-to-noise ratio value as high as 32, revealing the potential of the isoquinoline framework for the construction of high-performance RTP materials.

Development and Scale-Up of a Copper-Catalyzed Sulfamidation Coupling Reaction

Development and Scale-Up of a Copper-Catalyzed Sulfamidation Coupling Reaction

Copper-catalyzed oxidative cross-dehydrogenative coupling (CDC) reaction of alcohols with secondary phosphine oxides

A copper-catalyzed oxidative cross-dehydrogenative coupling (CDC) strategy of secondary phosphine oxides and alcohols for the synthesis of various phosphinate esters was proposed. Under the mild reaction conditions (CuCl2·2H2O/K2S2O8, at room temperature for 3–12 h under air), a variety of substrates were well-tolerated and afforded the desirable compounds in moderate to excellent yields.

Copper-Catalyzed Phosphorylation of N,N-Disubstituted Hydrazines: Synthesis of Multisubstituted Phosphorylhydrazides as Potential Anticancer Agents.

An efficient copper-catalyzed aerobic oxidative cross-dehydrogenative coupling reaction for the synthesis of multisubstituted phosphorylhydrazides from N,N-disubstituted hydrazines and hydrogen phosphoryl compounds is accomplished. The reaction proceeds under mild conditions without the addition of any external oxidants and bases. This work reported here represents a direct P(═O)-N-N bond formation with the advantages of being operationally simple, good functional group tolerance, and high atom and step economy. Furthermore, the selected compounds exhibit potential inhibitory activity against tumor cells, which can be used in the field of screening of anticancer agents as new chemical entities.

From A3/KA2 to AYA/KYA multicomponent coupling reactions with terminal ynamides as alkyne surrogates – a direct, green route to γ-amino-ynamides

A copper-catalysed three-component coupling reaction between a carbonyl derivative, a terminal ynamide and an amine has been developed for the one-pot construction of γ-amino-ynamides under mild and environmentally-friendly conditions.

Copper catalyzed decarboxylative coupling between coumarin 3-carboxylic acid and 4-thiazolidinones

An efficient copper-catalyzed decarboxylative cross coupling reaction of coumarin 3-carboxylic acid with 4-thiazolidinones has been developed. The described strategy operated smoothly via subsequent decarboxylation and radical addition in the presence of copper catalyst and oxidant. Various coumarinyl-4-thiazolidinone derivatives were obtained easily in moderate to good yield by employing this strategy. Substrate scope and optimization have been carried out appropriately. Optimization was carried out through various copper catalyst, oxidants, and additives.

Copper-Catalyzed Regioselective Coupling of Tosylhydrazones and 2-Pyridones: A Strategy for the Production of N-Alkylated Compounds.

The highly regioselective N-alkylation reaction of 2-pyridones was achieved through hydrazone chemistry, especially for substrates with bulky secondary alkyl groups. Described herein is a copper-catalyzed coupling reaction of pyridone derivatives with tosylhydrazones.

Copper-Catalyzed Decarboxylative Functionalization of Conjugated β,γ-Unsaturated Carboxylic Acids.

Copper-catalyzed decarboxylative coupling reactions of conjugated β,γ-unsaturated carboxylic acids have been achieved for allylic amination, alkylation, sulfonylation, and phosphinoylation. This approach was effective for a broad scope of amino, alkyl, sulfonyl, and phosphinoyl radical precursors as well as various conjugated β,γ-unsaturated carboxylic acids. These reactions also feature high regioselectivity, good functional group tolerance, and simple operation procedure. Mechanistic studies show that the reaction proceeds via copper-catalyzed electrophilic addition onto an olefin followed by decarboxylation, with radical intermediates involved. These insights present a modular and powerful strategy to access versatilely functionalized allyl-containing skeletons from readily available and stable carboxylic acids.

Theoretical investigation into the mechanism of copper-catalyzed Sonogashira coupling using trans-1,2-diamino cyclohexane ligand

The mechanism of copper-catalyzed Sonogashira coupling reaction employing trans-1,2-diamino cyclohexane ligand have been investigated with Density Functional Theory (DFT) method augmented with Conductor-like Polarizable Continuum Model (CPCM) solvation model. The cross-coupling reactions could be accelerated by employing chelating diamine ligands. Thus, we considered trans-1,2-diamino cyclohexane as the ligand for our study. These coupling reactions find its applicability in the synthesis of aryl acetylenes, the precursors for the various benzofuran derivatives which are present in many biologically important compounds. Considering various reaction pathways possible, it was found that diamine ligated copper (I) acetylide was the active state of the catalyst, which on further reaction with aryl halide undergoes a concerted oxidative addition – reductive elimination process giving the cross-coupled product aryl acetylene while regenerating the active catalytic species. Unlike the Pd-catalyzed Sonogashira cross-coupling, there occurs a concerted mechanism owing to the ease of bond formation between Csp2-Csp carbon atoms and instability of a Cu (III) metal center. This shows the mechanism of copper-catalyzed cross-couplings are quite different from that of Pd catalyzed reactions. The latter usually involves individual process involving oxidative addition and reductive elimination. The presences of various functional groups on the substrate molecules have a crucial role in determining the feasibility of the reaction. Henceforth, we have investigated the electronic effects of various functional groups in the substrate molecule on the activation barrier of the cross-coupling reaction.

Bis-Phenoxo-CuII2 Complexes: Formal Aromatic Hydroxylation via Aryl-CuIII Intermediate Species

Ullmann-type copper-mediated arylC-O bond formation has attracted the attention of the catalysis and organometallic communities, although the mechanism of these copper-catalyzed coupling reactions remains a subject of debate. We have designed well-defined triazamacrocyclic-based aryl-CuIII complexes as an ideal platform to study the C-heteroatom reductive elimination step with all kinds of nucleophiles, and in this work we focus our efforts on the straightforward synthesis of phenols by using H2O as nucleophile. Seven well-defined aryl-CuIII complexes featuring different ring size and different electronic properties have been reacted with water in basic conditions to produce final bis-phenoxo-CuII2 complexes, all of which are characterized by XRD. Mechanistic investigations indicate that the reaction takes place by an initial deprotonation of the NH group coordinated to CuIII center, subsequent reductive elimination with H2O as nucleophile to form phenoxo products, and finally air oxidation of the CuI produced to form the final bis-phenoxo-CuII2 complexes, whose enhanced stability acts as a thermodynamic sink and pushes the reaction forward. Furthermore, the corresponding triazamacrocyclic-CuI complexes react with O2 to undergo 1e− oxidation to CuII and subsequent C-H activation to form aryl-CuIII species, which follow the same fate towards bis-phenoxo-CuII2 complexes. This work further highlights the ability of the triazamacrocyclic-CuIII platform to undergo aryl-OH formation by reductive elimination with basic water, and also shows the facile formation of rare bis-phenoxo-CuII2 complexes.