Ullmann-type Coupling Reactions Research Articles

Synthesis and Mechanistic Study of Naphthalimide Derivative Formation via Cu-Mediated Ullmann-Type Reactions.

Cu-mediated Ullmann-type coupling reactions are fundamental to organic synthesis, garnering significant academic and industrial interest since their inception. Optimizing reaction parameters, particularly temperature control, is crucial for maximizing efficiency while maintaining high yields. Bidentate ligands, such as amino acids, have demonstrated potential in facilitating these reactions at lower temperatures (<100 °C). This study explores the Cu-catalyzed Ullmann-type coupling of naphthalimide derivatives with amino acid substitutions. Naphthalimide dyes, known for their diverse applications in bioimaging, solar cells, medicine, and sensors, were selected for their potent anticancer properties. The synthesized compounds were characterized by using 1H NMR, ESI-MS, and melting point analyses. Compounds with significant steric hindrance exhibited lower yields, leading to the development of a novel catalytic system employing l-carnosine as a bidentate ligand, which significantly improved yields. Mechanistic insights, derived from density functional theory calculations, identified "L-complex 3" as the most stable and reactive intermediate during oxidative addition to aryl halides. The oxidative addition transition state "OX1-TS" was found to be the most favorable, with a relatively low energy barrier of 6.13 kcal/mol, suggesting that this step, despite being the rate-limiting stage, is energetically accessible. In contrast, reductive elimination was facilitated by a Cu(III) penta-coordinated intermediate, with a barrier of just 8.34 kcal/mol, making it a more straightforward process. Theoretical findings aligned closely with experimental data, reinforcing the oxidative addition/reductive elimination pathway as the operative mechanism for this reaction.

Copper(II)-Catalyzed Amination of Aryl Chlorides in Aqueous Ammonia.

Anilines are ubiquitous in bio-active compounds and their synthesis can be achieved via metal-catalyzed cross-coupling reactions involving aryl halides. We describe an unusual, yet simple, CuII-catalyzed system for the amination of aryl chlorides in pure aqueous ammonia with 2.5 mol % catalyst loading under non-inert conditions. Different from previous systems, the reaction proceeds even without an additional organic solvent. Copper(II) sulfate in combination with 4,7-dimethoxy-1,10-phenanthroline enabled the amination of several aryl chlorides containing electron-neutral, -donating and -withdrawing groups to the corresponding anilines with good to excellent yields. The upscaling potential of the procedure has been shown by the synthesis at 50 mmol scale. The reaction proceeds as one of the rare cases of a CuII-assisted coupling, in contrast to the typical CuI-CuIII intermediates postulated for most Ullmann-type coupling reactions. The copper(II) center allows for a nucleophilic substitution pathway, enabled by the deprotonation of coordinated ammonia.

Expression of concern: Copper nanoparticle anchored biguanidine-modified Zr-UiO-66 MOFs: a competent heterogeneous and reusable nanocatalyst in Buchwald-Hartwig and Ullmann type coupling reactions.

Expression of concern for 'Copper nanoparticle anchored biguanidine-modified Zr-UiO-66 MOFs: a competent heterogeneous and reusable nanocatalyst in Buchwald-Hartwig and Ullmann type coupling reactions' by Hojat Veisi et al., RSC Adv., 2021, 11, 22278-22286, https://doi.org/10.1039/D1RA02634H.

An eco-friendly convenient approach for the synthesis of guar gum integrated copper nanoparticles: Investigation of its catalytic activity in the C[sbnd]N Ullmann coupling reactions and study of its anti-human kidney cancer effects

We carried out this research was in order to evaluate the potency of guar gum (GG) hydrogel to conduct CuO NPs synthesis by adopting an eco-friendly approach as well as to study its role as catalyst and in relieving cancerous cell lines. In this context, we accomplished the CuO NPs/GG synthesis by employing a simple one-step approach and identified its characters through UV–Visible (UV–Vis) spectroscopy, X-ray diffraction (XRD), transmission electronic microscopy (TEM), scanning electron microscopy (SEM), energy dispersive X-rays spectroscopy (EDS), elemental mapping and ICP-OES analysis. XRD and TEM results of CuO NPs/GG showed the face centered cubic (fcc) structures and predominantly spherical shaped with a size of 20–30 nm. After the characterization, the prepared CuO NPs/GG nanocatalyst was used as catalyst in the N-arylation of amines (indole and imidazoles) through C(aryl)-N chemical bond arrangement from the related aryl halides (I, Br, Cl) by Ullmann-type coupling reactions. It is worth mentioning that the novel catalyst has the potential of being recycled seven times without much change in activity. Furthermore, the anti-kidney cancer properties of CuO NPs/GG nanocomposite were assessed by MTT assay about the cytotoxicity and anti-human on normal (HUVEC) and human kidney cell lines i.e. ACHN, CaKi-2 and HEC293. The corresponding IC50 values were 18.5, 17.2, and 15.6 µg/mL, respectively. The viability of malignant human kidney cell line reduced dose-dependently in the presence of the nano bio-composite. After clinical study, CuO NPs/GG nano bio-composite can be utilized as an efficient drug in the treatment of human kidney cancer in human.

Ullmann-Type N-, S-, and O-Arylation Using a Well-Defined 7-Azaindole-N-oxide (7-AINO)-Based Copper(II) Catalyst: Scope and Application to Drug Synthesis.

An air-stable, robust, and well-defined copper(II)-7-azaindole-N-oxide-based catalyst [Cu2II(7-AINO)4] (abbreviated as Cu(II)-7-AINO) has been demonstrated as an efficient catalyst for various Ullmann-type coupling reactions. This easily prepared and cost-effective catalyst facilitates the arylation and heteroarylation of diverse N-, S-, and O-nucleophiles, including azoles, aminoazoles, (hetero)arylthiols, and phenols. Notably, they also exhibit substantial compatibility with a wide range of functional groups. Furthermore, the catalyst demonstrates significant selectivity for -NH sites of aminoazoles and -SH sites of aminothiophenols over -NH2 sites in both cases, enhancing its versatility. Exploiting the catalyst's chemo- and regioselective properties, we have successfully demonstrated the applicability of our methodology in synthesizing various drug molecules. Specifically, Epirizole analogue, Nilotinib, and Vortioxetine were successfully synthesized using our protocol.

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.

Substitution Effects in Aryl Halides and Amides into the Reaction Mechanism of Ullmann-Type Coupling Reactions.

In this article, we present a comprehensive computational investigation into the reaction mechanism of N-arylation of substituted aryl halides through Ullmann-type coupling reactions. Our computational findings, obtained through DFT ωB97X-D/6-311G(d,p) and ωB97X-D/LanL2DZ calculations, reveal a direct relation between the previously reported experimental reaction yields and the activation energy of haloarene activation, which constitutes the rate-limiting step in the overall coupling process. A detailed analysis of the reaction mechanism employing the Activation Strain Model indicates that the strain in the substituted iodoanilines is the primary contributor to the energy barrier, representing an average of 80% of the total strain energy. Additional analysis based on conceptual Density Functional Theory (DFT) suggests that the nucleophilicity of the nitrogen in the lactam is directly linked to the activation energies. These results provide valuable insights into the factors influencing energetic barriers and, consequently, reaction yields. These insights enable the rational modification of reactants to optimize the N-arylation process.

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.

Cu-catalyzed, ligand free syntheses of arylaminopyrimidines in aqueous solution and insilico investigation of their druglikeliness properties

A ligand free Cu(NO3)2·3H2O catalyzed synthetic protocol for arylaminopyrimidines starting from chloropyrimidines and aliphatic/aromatic amines in aqueous medium is being reported here. The procedure is quite general and was successful to deliver 22 numbers of arylaminopyrimidines including 5 novel compounds in good to excellent yield (54–97 %). The reaction protocol doesn't require dry solvents and inert atmosphere, and in comparison to existing reports, it worked under mild reaction temperature (80 °C). The developed methodology offers first application of ligand free Ullmann type coupling reactions for the synthesis of arylaminopyrimidine-2,4(1H,3H)-diones and arylaminopyrimidines. The aqueous medium containing the catalyst system can be reusable up to third run without significant decline in productivity. All the 22 synthesized compounds were computed to investigate their druglikeliness properties using SwissADME tool. 18 of those were found to obey all the criteria set for druglikeliness properties and 5 of those fulfilling completely the requirements of all the six parameters of bioavailability radar viz. lipophilicity, molecular weight, polarity, solubility, flexibility and saturation to be orally bioavailable. While all the compounds were predicted to have high gastrointestinal (GI) absorption, 16 of those have blood brain barrier (BBB) penetration ability.

Regioselective Functionalization of Arenes Using Iron Triflimide Catalysis

AbstractHere we present our development of the super Lewis acid, iron(III) triflimide as an activating agent of N-halo- and N-thioaryl succinimides for the regioselective functionalization of arenes. We also describe how the iron(III)-catalyzed halogenation reactions were further exploited by combination with copper(I)-catalyzed Ullmann-type coupling reactions for the development of one-pot, multistep processes, including intermolecular aryl C–H amination. This Account also illustrates intramolecular versions of these one-pot processes for the preparation of benzannulated heterocycles, as well as the application of these methods for the synthesis of biologically active compounds and natural products.1 Introduction2 Iron(III)-Catalyzed Halogenation of Arenes3 One-Pot Intermolecular Aryl C–H Amination4 One-Pot Intramolecular C–N, C–O, and C–S Bond-Forming Processes5 Iron(III)-Catalyzed Thioarylation of Arenes6 Synthesis of Phenoxathiins and Phenothiazines Using Lewis Acid and Lewis Base Catalysis7 Conclusions

On-surface Synthesis: What Happens Behind the Scenes?

On-surface synthesis has become a powerful approach to produce low-dimensional carbon-based nanostructures with atomistic precision. A large variety of analytical tools and methods are available to provide efficient monitoring of on-surface reactions, among which, scanning probe microscopy (SPM) has proven to be particularly efficient to characterize reaction intermediates and products down to the atomic scale. Nevertheless, due to limited temporal resolution, difficulties to explore the full temperature range, and lack of identifying the chemical environment of all elements involved in on-surface processes, SPM is ideally complemented with temperature programmed X-ray photoelectron spectroscopy (TP-XPS). In this short review, we aim to unveil some of the capabilities of synchrotron based TP-XPS reporting on our own research on Ullmann-type on-surface coupling reactions.

Copper-catalyzed synthesis and anticancer activity evaluation of indolo[1,2-a]quinoline derivatives

A simple and effective one-pot synthesis of substituted indolo[1,2-a]quinolines has been developed. The desired products were obtained in up to 98% yield when substituted 2-methyindoles were treated with 2-iodobenzaldehyde in the presence of Cs2CO3, CuI and l-proline. Our mechanistic study confirmed that the reaction sequence involved an intermolecular Knoevenagel reaction followed by an intramolecular Ullmann-type coupling reaction. Moreover, some of the synthesized compounds were found to be active against human breast (MCF-7) and colorectal (HCT-116) cancer cells with IC50 values of 27.96 μM and in the range of 6.21–46.91 μM, respectively.

Halogenated Anthracenes as Building Blocks for the On-Surface Synthesis of Covalent Polymers: Structure Prediction with the Lattice Monte Carlo Method

Functionalized polycyclic aromatic hydrocarbons (PAHs) have been recently recognized as promising building blocks for surface-assisted polymerization reactions producing low-dimensional covalent structures with tailorable properties. In this work, we used the lattice Monte Carlo (MC) simulation method to predict the structure of the labile metal–(halogenated)anthracene connections preceding the formation of covalent polymers in the Ullmann-type coupling reaction occurring on catalytically active metallic surfaces. To that purpose, a coarse-grained model of mono-, di-, and trisubstituted anthracene monomers and two-coordinate metal atoms was proposed, in which these components were adsorbed on a triangular lattice. The formation of metal–organic nodes cementing the resulting superstructures was assumed to be dependent on the directionality of the short-range interactions assigned differently to PAH molecules. Our extensive MC simulations performed for the complete set of 50 positional isomers predicted various organometallic intermediates with morphologies ranging from cyclic oligomers, chains, ladders, ribbons to aperiodic networks and others. These results were compared with the analogous findings obtained for the smaller naphthalene unit. The outcome of the theoretical studies reported herein can be helpful in designing low-dimensional covalent polymers with tunable architecture and functions.

Design, synthesis and photophysical properties of novel star-shaped truxene-based heterocycles utilizing ring-closing metathesis, Clauson-Kaas, Van Leusen and Ullmann-type reactions as key tools.

Design, synthesis and properties of polycyclic aromatic hydrocarbons (PAHs) has historically attracted a considerable interdisciplinary interest from both fundamental as well as applied viewpoint on account of their wonderful optoelectronic properties. The scientific interest in two-dimensional star-shaped PAHs particularly in truxene architectures arises because of their high thermal stability, exceptional solubility and ease with which they can be constructed and modified. Therefore, bearing in mind a wide range of applications of truxene and its congeners, herein we reveal three novel distinctly different routes for the generation of C3-symmetric pyrrole-based truxene architectures by means of cyclotrimerization, ring-closing metathesis (RCM), Clauson–Kaas and Ullmann-type coupling reactions as key steps. Moreover, we have also assembled some other interesting heterocyclic systems possessing oxazole, imidazole, benzimidazole, and benzoxazole in the framework of truxene. Additionally, the preliminary photophysical properties (absorption and emission) for these versatile systems has been revealed.

Copper nanoparticle anchored biguanidine-modified Zr-UiO-66 MOFs: a competent heterogeneous and reusable nanocatalyst in Buchwald-Hartwig and Ullmann type coupling reactions.

We have designed a functionalized metal–organic framework (MOF) of UiO topology as a support, with an extremely high surface area, adjustable pore sizes and stable crystalline coordination polymeric structure and implanted copper (Cu) nanoparticles thereon. The core three dimensional Zr-derived MOF (UiO-66-NH2) was modified with a biguanidine moiety following a covalent post-functionalization approach. The morphological and physicochemical features of the material were determined using analytical methods such as FT-IR, SEM, TEM, EDX, atomic mapping, XRD and ICP-OES. The SEM and XRD results justified the unaffected morphology of Zr-MOF after structural modifications. The as-synthesized UiO-66-biguanidine/Cu nanocomposite was catalytically explored in the aryl and heteroaryl Buchwald–Hartwig C–N and Ullmann type C–O cross coupling reactions with excellent yields. A library of biaryl amine and biaryl ethers was synthesized over the catalyst under mild and green conditions. Furthermore, the catalyst was isolated by centrifugation and recycled 11 times with no significant copper leaching or change in its activity.

Nucleation of Tiny Silver Nanoparticles by Using a Tetrafacial Organic Molecular Barrel: Potential Use in Visible-Light-Triggered Photocatalysis.

Coordination-driven self-assembly of discrete molecular architectures of diverse shapes and sizes has been well studied in the last three decades. Use of dynamic imine bonds for designing analogous metal-free architectures has become a growing challenge recently. This article reports an organic molecular barrel (OB4R ) as a potential template for nucleation and stabilization of very tiny (<1.5 nm) Ag nanoparticles (AgNPs). Imine bond condensation of a rigid tetra-aldehyde with a flexible diamine followed by imine-bond reduction yielded the discrete tetragonal organic barrel (OB4R ). The presence of a molecular pocket ornamented with eight diamine moieties gives the potential for encapsulation of silver(I). The organic barrel was finally used as a molecular vessel for the controlled nucleation of silver nanoparticles (AgNPs) with fine size tuning through binding of AgI ions in the confined space of the barrel followed by reduction. Transmission electron microscopy (TEM) analysis of the Ag0 @OB4R composite revealed that the mean particle size is 1.44±0.16 nm. The composite material has approximately 52 wt % silver loading. The barrel-supported ultrafine AgNPs [Ag0 @OB4R ] are found to be an efficient photocatalyst for facile Ullmann-type aryl-amination coupling of haloarenes at ambient temperature without using any additives. The catalyst was stable for several cycles of reuse without any agglomeration. The new composite Ag0 @OB4R represents the first example of discrete organic barrel-supported AgNPs employed as a photocatalyst in Ullmann-type coupling reactions at room temperature.

Surface-Confined Metal–Organic Precursors Comprising Naphthalene-Like Derivatives with Differently Distributed Halogen Substituents: A Monte Carlo Model

The on-surface synthesis of organic polymers has been recently recognized as a useful method to create low-dimensional covalently bonded structures with tailorable topology and functions. In this work, the Monte Carlo simulation method was used to study the metal–organic precursors of covalent polymers formed in the Ullmann-type coupling reaction of halogenated naphthalene derivatives. To this purpose, a coarse-grained model was proposed in which the monomers, represented by a pair of interconnected segments, and two-coordinate metal atoms (one segment) were adsorbed on a triangular lattice-mimicking (111) catalytically active crystalline surface. Different distributions of halogen atoms in the naphthalene molecules were modeled using the directional interactions assigned to these units, sustaining the resulting metal–tecton reversible links. Depending on the halogen content and distribution, the simulations predicted the creation of diverse supramolecular connections such as linear and cyclic aggregates and other more complex forms. Moreover, in the case of prochiral monomers, the calculations demonstrated basic structural differences between the enantiopure and racemic assemblies in which chiral separation or mixing was observed. The obtained results can be helpful in directing the surface-assisted polymerization reactions toward organic structures with predefined size, shape, symmetry, and connectivity.

CuIBiOI is an efficient novel catalyst in Ullmann-type CN[sbnd] couplings with wide scope—A rare non-photocatalyic application

Preparation of a new, mixed-cationic layered CuIBiOI was prepared and its non-photocatalytic catalytic properties were explored. This solid substance had BiOI-like, lamellar and deflected structure resulting from CuI ion incorporation in the Bi2O2 layers. The as-prepared substance was fully characterized by XRD, Raman, far IR, UVDR, XP spectroscopies, thermal (TG-DTG) and analytical (ICP-MS, SEM-EDX) methods, electron microscopies (SEM, TEM) as well as BET surface area measurements. By performing Ullmann-type CN coupling reactions between aryl halides and aqueous ammonia, its catalytic capabilities were tested. The effects of solvents, added base and catalyst loading as well as reaction time and reaction temperature were scrutinized, and a green way for the reaction was identified. The recyclability of the catalyst without the loss of activity and its general applicability for a wide range of aryl halides were also demonstrated.

Supramolecular Ordering and Reactions of a Chlorophenyl Porphyrin on Ag(111)

Surface-assisted Ullmann-type coupling reactions are a potential bottom-up approach for building tailored low-dimensional materials with novel physical and chemical properties. In this investigatio...

Enhancing Hydrogen Evolution Activity of Au(111) in Alkaline Media through Molecular Engineering of a 2D Polymer.

The electrochemical splitting of water holds promise for the storage of energy produced intermittently by renewable energy sources. The evolution of hydrogen currently relies on the use of platinum as a catalyst—which is scarce and expensive—and ongoing research is focused towards finding cheaper alternatives. In this context, 2D polymers grown as single layers on surfaces have emerged as porous materials with tunable chemical and electronic structures that can be used for improving the catalytic activity of metal surfaces. Here, we use designed organic molecules to fabricate covalent 2D architectures by an Ullmann‐type coupling reaction on Au(111). The polymer‐patterned gold electrode exhibits a hydrogen evolution reaction activity up to three times higher than that of bare gold. Through rational design of the polymer on the molecular level we engineered hydrogen evolution activity by an approach that can be easily extended to other electrocatalytic reactions.