Cu-catalyzed Reaction Research Articles

Base-Promoted Coupling of HFIP in Cu-Catalyzed Asymmetric Ring Opening of Cyclic Diaryliodoniums.

We report a Cu-catalyzed asymmetric ring-opening reaction of cyclic diaryliodoniums with 1,1,1,3,3,3-hexafluoroisopropanol (HFIP), enabling the construction of axially chiral biaryl compounds containing HFIP ether. HFIP is highly polar and exceptionally stable; thus, it is commonly used as a solvent due to its poor nucleophilicity. However, its use as a nucleophilic reagent has been rare. In this study, we successfully employed HFIP as a nucleophilic coupling partner in a Cu-catalyzed asymmetric ring-opening experiment of cyclic diaryliodoniums.

Overcoming Copper Reduction Limitation in Asymmetric Substitution: Aryl-Radical-Enabled Enantioconvergent Cyanation of Alkyl Iodides.

Cu-catalyzed enantioconvergent cross-coupling of alkyl halides has emerged as a powerful strategy for synthesizing enantioenriched molecules. However, this approach is intrinsically limited by the weak reducing power of copper(I) species, which restricts the scope of compatible nucleophiles and necessitates extensive ligand optimization or the use of complex chiral scaffolds. To overcome these challenges, we introduce an aryl-radical-enabled strategy that decouples the alkyl halide activation step from the chiral Cu center. We demonstrate that merging aryl-radical-enabled iodine abstraction with Cu-catalyzed asymmetric radical functionalization enables the conversion of racemic α-iodoamides to enantioenriched alkyl nitrile products with good yield and enantioselectivity. The rational design of chiral ligands identified a new class of carboxamide-containing BOX ligands. Mechanistic studies support an aryl-radical-enabled pathway and the unique hydrogen-bonding ability in the newly designed BOX ligands. This aryl-radical-enabled asymmetric substitution reaction has the potential to significantly expand the scope of Cu-catalyzed enantioconvergent cross-coupling reactions.

Impact of Side Chains in 1-n-Alkylimidazolium Ionomers on Cu-Catalyzed Electrochemical CO2 Reduction.

This study presents the impact of the side chains in 1-n-alkylimidazolium ionomers with varying side chain lengths (CnH2n+1 where n = 1, 4, 10, 16) on Cu-catalyzed electrochemical CO2 reduction reaction (CO2RR). Longer side chains suppress the H2 and CH4 formation, with the n-hexadecyl ionomer (n = 16) showing the greatest reduction in kinetics by up to 56.5% and 60.0%, respectively. On the other hand, C2H4 production demonstrates optimal Faradaic efficiency with the n-decyl ionomer (n = 10), a substantial increase of 59.9% compared to its methyl analog (n = 1). Through a combination of density functional theory calculations and material characterization, it is revealed that the engineering of the side chains effectively modulates the thermodynamic stability of key intermediates, thus influencing the selectivity of both CO2RR and hydrogen evolution reaction. Moreover, ionomer engineering enables industrially relevant partial current density of -209.5 mA cm-2 and a Faradaic efficiency of 52.4% for C2H4 production at 3.95 V, even with a moderately active Cu catalyst, outperforming previous benchmarks and allowing for further improvement through catalyst engineering. This study underscores the critical role of ionomers in CO2RR, providing insights into their optimal design for sustainable chemicalsynthesis.

Roles of Nonadiabatic Processes, Reaction Mechanism, and Selectivity in Cu-Catalyzed [2 + 2] Photocycloaddition of Norbornene and Acetone to Oxetane.

Oxetane has been extensively studied for its applications in medicinal chemistry and as a reactive intermediate in synthesis. Experiments report a Cu-catalyzed [2 + 2] photocycloaddition of acetone and norbornene to oxetane, which is proposed to deviate from the conventional Paternò-Büchi reaction. However, its mechanism at the atomic level is not clear. In this study, we used a combination of multistate complete active space second-order perturbation theory (MS-CASPT2) and density functional theory to systematically investigate the reaction mechanism and elucidate the factors contributing to the diastereomeric selectivity. Initially, the formation of the TpCu(Norb) complex is achieved by strong interaction between tris(pyrazolyl)borate Cu(I) (TpCu) and norbornene in the ground state (S0). Upon photoexcitation, TpCu(Norb) eventually decays to the T1 state, in which TpCu(Norb) attacks acetone to initiate subsequent reactions and produces final endo- or exo-oxetane products. All these reactions initially involve the C-C bond formation in the T1 state thereto leading to a ring-opening intermediate. This intermediate then undergoes a nonradiative transition to the S0 state, producing a five-membered ring intermediate, from which the C-O bond is formed, leading to the experimentally dominant exo-product. In contrast, the endo-oxetane formation requires a rearrangement process after the C-C bond is formed because of the large steric effects. As a consequence, the different reaction pathways generating exo- and endo-products exhibit large differences in the free-energy barriers, which results in a diastereomeric selectivity observed experimentally. Additionally, the nonradiative transition is found to play an important role in facilitating these reaction steps. The present computational study provides valuable mechanistic insights into Cu-catalyzed photocycloaddition reactions.

Selective electroreduction of CO2 to C2+ products on cobalt decorated copper catalysts

Cu-catalyzed electrochemical CO2 reduction reaction (CO2RR) to multi-carbon (C2+) products is often plagued by low selectivity because the adsorption energies of different reaction intermediates are in a linear scaling relationship. Development of Cu-based bimetallic catalysts has been considered as an attractive strategy to address this issue; however, conventional bimetallic catalysts often avoid metals with strong CO adsorption energies to prevent surface poisoning. Herein, we demonstrated that limiting the amount of Co in CuCo bimetallic catalysts can enhance C2+ product selectivity. Specifically, we synthesized a series of CuCox catalysts with trace amounts of Co (0.07-1.8 at%) decorated on the surface of Cu nanowires using a simple dip coating method. Our results revealed a volcano-shaped correlation between Co loading and C2+ selectivity, with the CuCo0.4% catalyst exhibiting a 2-fold increase in C2+ selectivity compared to the Cu nanowire sample. In situ Raman and Infrared spectroscopies suggested that an optimal amount of Co could stabilize the Cu oxide/hydroxide species under the CO2RR condition and promote the adsorption of CO, thus enhancing the C2+ selectivity. This work expands the potential for developing Cu-based bimetallic catalysts for CO2RR.

Synthesis of 3-Aminoazaindazoles via Cu-Catalyzed Cross Coupling of Isocyanides.

Nitrogen-containing heterocycles are commonly encountered in drug discovery, but the synthesis of such ring structures is not always efficient. Fused heterocyclic rings, in particular, can be challenging to synthesize. Herein, we report a highly convergent synthesis of 3-aminoazaindazoles via a Cu-catalyzed reaction between isocyanides and 3-halo-2-hydrazineylpyridines (and analogues). Reaction optimization through high-throughput experimentation (HTE) identified a novel set of exogenous ligand-free Cu conditions utilizing a cheap and readily available catalyst. The reaction displays high functional group tolerance and has the potential to be highly enabling for medicinal chemistry efforts. A putative mechanism is described as well as preliminary mechanistic experiments.

Copper catalyzed cycloaddition for the synthesis of non isomerisable 2′ and 3′-regioisomers of arg-tRNAarg

In this report, non-isomerisable analogs of arginine tRNA (Arg-triazole-tRNA) have been synthesized as tools to study tRNA-dependent aminoacyl-transferases. The synthesis involves the incorporation of 1,4 substituted-1,2,3 triazole ring to mimic the ester bond that connects the amino acid to the terminal adenosine in the natural substrate. The synthetic procedure includes (i) a coupling between 2′- or 3′-azido-adenosine derivatives and a cytidine phosphoramidite to access dinucleotide molecules, (ii) Cu-catalyzed cycloaddition reactions between 2′- or 3′-azido dinucleotide in the presence of an alkyne molecule mimicking the arginine, providing the corresponding Arg-triazole-dinucleotides, (iii) enzymatic phosphorylation of the 5′-end extremity of the Arg-triazole-dinucleotides with a polynucleotide kinase, and (iv) enzymatic ligation of the 5′-phosphorylated dinucleotides with a 23-nt RNA micro helix that mimics the acceptor arm of arg-tRNA or with a full tRNAarg. Characterization of nucleoside and nucleotide compounds involved MS spectrometry, 1H, 13C and 31P NMR analysis. This strategy allows to obtain the pair of the two stable regioisomers of arg-tRNA analogs (2′ and 3′) which are instrumental to explore the regiospecificity of arginyl transferases enzyme. In our study, a first binding assay of the arg-tRNA micro helix with the Arginyl-tRNA-protein transferase 1 (ATE1) was performed by gel shift assays.

Cu-catalyzed click reaction in synthesis of eugenol derivatives as potent antimalarial agents

Eugenol(1), a terpenoid found in Ocimum, has various biological activities. The present study aims at extraction, isolation of the plant secondary metabolite eugenol (1), it’s derivatisation and structure identification as bioactive molecules. Synthesis and antiplasmodial activity (in-vitro and in-vivo), of a series of fourteen novel eugenol-based 1,2,3-triazole derivatives was done in the present study. Derivatives 5a–5n showed good antimalarial activity against the strain Plasmodium falciparum NF54. Derivative 5 m, IC50 at 2.85 µM was found to be several times better than its precursor 1 (106.82 µM) whereas the derivative 5n showed three fold better activity than compound 1, in vitro. The structure-activity relationship of the synthesised compounds indicated that the presence of triazole ring in eugenol analogues is responsible for their good activity. Compound 5m, was further evaluated for in-vivo antimalarial activity which showed about 79% parasitemia suppression. It is the first report on antimalarial activity of triazole eugenol derivatives.

Efficient Solvent-Free Synthesis of Indolizines Using CuBr Catalyst from Pyridine, Acetophenone, and Electron-Deficient Alkenes.

Herein, we have developed a new approach for the synthesis of indolizine via Cu-catalyzed reaction of pyridine, acetophenone, and nitroolefin under mild conditions in high yields. This reaction involved the formation of C-N and C-C bonds and new indolizine compounds with high stereoselectivity and excellent functional group tolerance.

Effect of Particle Heterogeneity in Catalytic Copper-Containing Single-Chain Polymeric Nanoparticles Revealed by Single-Particle Kinetics.

Single-chain polymeric nanoparticles (SCPNs) have been extensively explored as a synthetic alternative to enzymes for catalytic applications. However, the inherent structural heterogeneity of SCPNs, arising from the dispersity of the polymer backbone and stochastic incorporation of different monomers as well as catalytic moieties, is expected to lead to variations in catalytic activity between individual particles. To understand the effect of structural heterogeneities on the catalytic performance of SCPNs, techniques are required that permit researchers to directly monitor SCPN activity at the single-polymer level. In this study, we introduce the use of single-molecule fluorescence microscopy to study the kinetics of Cu(I)-containing SCPNs towards depropargylation reactions. We developed Cu(I)-containing SCPNs that exhibit fast kinetics towards depropargylation and Cu-catalyzed azide-alkyne click reactions, making them suitable for single-particle kinetic studies. SCPNs were then immobilized on the surface of glass coverslips and the catalytic reactions were monitored at a single-particle level using total internal reflection fluorescence (TIRF) microscopy. Our studies revealed the interparticle turnover dispersity for Cu(I)-catalyzed depropargylations. In the future, our approach can be extended to different polymer designs which can give insights into the intrinsic heterogeneity of SCPN catalysis and can further aid in the rational development of SCPN-based catalysts.

Enhanced Carbon-Carbon Coupling at Interfaces with Abrupt Coordination Number Changes.

Cu-catalyzed electrochemical CO2 reduction reaction (CO2RR) produces multi-carbon (C2+) chemicals with considerable selectivities and activities, yet required high overpotentials impede its practical application. Here, we design interfaces with abrupt coordination number (CN) changes that greatly reduce the applied potential for achieving high C2+ Faradaic efficiency (FE). Encouraged by the mechanistic finding that the coupling between *CO and *CO(H) is the most probable C-C bond formation path, we use Cu2O- and Cu-phthalocyanine-derived Cu (OD-Cu and PD-Cu) to build the interface. Using operando X-ray absorption spectroscopy (XAS), we find that the Cu CN of OD-Cu is ~11, favoring CO* adsorption, while the PD-Cu has a COH*-favorable CN of ~4. Operando Raman spectroscopy revealed that the interfaces with abrupt CN changes promote *OCCOH formation. As a result, the designed catalyst achieves a C2+ FE of 85±2 % at 220 mA cm-2 in a zero-gap CO2 electrolyzer. An improvement of C2+ FE by 3 times is confirmed at the low potential regime where the current density is 60-140 mA cm-2, compared to bare OD-Cu. We report a 45-h stable CO2RR operation at 220 mA cm-2, producing a C2+ product FE of ~80 %.

Room-Temperature Copper-Catalyzed Etherification of Aryl Bromides.

We disclose the development of a Cu-catalyzed C-O coupling method utilizing a new N1,N2-diarylbenzene-1,2-diamine ligand, L8. Under optimized reaction conditions, structurally diverse aryl and heteroaryl bromides underwent efficient coupling with a variety of alcohols at room temperature using an L8-based catalyst. Notably, the L8-derived catalyst exhibited enhanced activity when compared to the L4-based system previously disclosed for C-N coupling, namely the ability to functionalize aryl bromides containing acidic functional groups. Mechanistic studies demonstrate that C-O coupling utilizing L8 ⋅ Cu involves rate-limiting alkoxide transmetallation, resulting in a mechanism of C-O bond formation that is distinct from previously described Pd-, Cu-, or Ni-based systems. This lower energy pathway leads to rapid C-O bond formation; a 7-fold increase relative to what is seen with other ligands. The results presented in this report overcome limitations in previously described C-O coupling methods and introduce a new ligand that we anticipate may be useful in other Cu-catalyzed C-heteroatom bond-forming reactions.

Parallel additions of molybdenum and copper particles for boosted peroxydisulfate activation process: Performance, mechanism, and application

Molybdenum (Mo) has been certified as a benign cocatalyst in homogenous Fenton/Fenton-like reactions. To improve zero-valent copper (Cu) induced peroxydisulfate (PDS) reaction, Mo and Cu were parallelly added to enhance the activation of (PDS for metronidazole (MTZ) degradation in this work. The efficient MTZ elimination (96.01 %) was reached after 20 min by Cu/Mo/PDS process in terms of 0.10 g⋅L−1 PDS, 0.08 g⋅L−1 Cu, 0.30 g⋅L−1 Mo, and initial pH 6.5. This ternary system presented a broad pH adaptive capacity (pH 3.5–9.5) and well cycling effect (above 80 % after three cycles). The addition of Mo enhanced Cu(II)/Cu(I) circulation and PDS decomposition, and electrochemical test testified that could be attributed to the electron migration between Cu and Mo. The cycle of Cu(II)/Cu(I) triggered by the conversion of Mo0 and Mo4+ was further proved by X-ray photoelectron spectroscopy result. Singlet oxygen and sulfate radicals were identified as the dominant reactive substances by scavenger test, probe measurement, and electron paramagnetic resonance spectroscopy. By density functional theory calculation and mass spectrometry analyses, two possible decomposed pathways of MTZ were raised. At last, Mo and Cu powders were immobilized together by a simple physical mixing with methacrylate, which also showed the integrated catalytic property and good reusability. This work could advance the development of Cu-catalyzed Fenton-like reaction with inorganic co-catalysis in water purification.

Pimonidazole-alkyne conjugate for sensitive detection of hypoxia by Cu-catalyzed click reaction

Hypoxia is involved in various diseases, such as cancers. Pimonidazole has often been used as the gold-standard marker to visualize hypoxic regions. Pimonidazole labels hypoxic regions by forming a covalent bond with a neighboring protein under hypoxic conditions in the body, which is detected by immunohistochemistry performed on tissue sections. To date, some pimonidazole-fluorophore conjugates have been reported as fluorescent probes for hypoxia imaging that do not require immunostaining. They are superior to pimonidazole because immunostaining can produce high background signals. However, large fluorophores in the conjugates may alter the original biodistribution and reactivity. Here, we report a new hypoxia marker, Pimo-yne, as a pimonidazole-alkyne conjugate. Pimo-yne has a similar hypoxia detection capability as pimonidazole because the alkyne tag is small and can be detected by Cu-catalyzed click reaction with azide-tagged fluorescent dyes. We successfully visualized hypoxic regions in tumor tissue sections using Pimo-yne with reduced background signals. The detected regions overlapped well with those detected by pimonidazole immunohistochemistry. To further reduce the background, we employed a turn-on azide-tagged fluorescent dye.Graphical abstract

Development and synthesis of a novel salen-type ligand based on phenylalanine for Mizoroki-Heck, and S-arylation cross-coupling reactions

In this article, we introduced a novel salen-type ligand precursor and applied it in the Pd-catalyzed Mizoroki–Heck and Cu-catalyzed S-arylation cross-coupling reactions. For the preparation of this structure, (DL)-phenyl alanine was employed as a starting material. These ligand precursor and related catalytic system can be readily synthesised. Various aryl halides (-I, -Br) and alkenes were applied successfully in this protocol to give the corresponding Mizoroki-Heck cross-coupling and S-arylated products in high to excellent yields.

Cu-Catalyzed Tandem Oxidation-Intramolecular Cannizzaro Reaction of Biorenewables and Bioactive Molecules.

A tandem Cu-catalyzed oxidation-intramolecular Cannizzaro reaction leading to bioactive α-hydroxyesters from α-hydroxyketones is reported. The process uses oxygen as a sole oxidant to achieve the formation of glyoxals, which are efficiently converted in situ to important α-hydroxyesters. The mechanistic insights are provided by isotopic labeling and supported by DFT calculations. The transformation proved a robust synthetic tool to achieve the synthesis of human metabolites and hydroxyl esters of various biologically active steroid derivatives.

Cu-Catalyzed Direct Asymmetric Mannich Reaction of 2-Alkylazaarenes and Isatin-Derived Ketimines.

The first direct catalytic asymmetric Mannich reaction of 2-alkylazaarenes and ketimines was realized with a chiral Cu-bis(oxazoline) complex as the catalyst. The asymmetric addition of 2-alkylpyridines to isatin-derived ketimines proceeded smoothly to afford α,β-functionalized 2-substituted pyridines bearing 3-amino-3,3-disubstituted oxindole motifs with excellent results (≤99% yield, 99:1 dr, and 98% ee). The catalytic system was also extended to 2-alkylbenzothiazoles as nucleophiles for the asymmetric Mannich reaction of ketimines.

Cu-Catalyzed Direct Enantioselective Vinylogous Mannich Reaction between β,γ-Unsaturated Pyrazoleamides and Ketimines.

A catalytic asymmetric vinylogous Mannich-type reaction between β,γ-unsaturated amides and ketimines has been developed in excellent regio-, diastereo-, and enantioselectivities. The methodology provides an efficient approach to construct chiral homoallylic amines with a 3-amino-2-oxindole scaffold. Moreover, the transformations of the chiral products, including the removal of the pyrazole group or Boc group, the reduction of the C-C double bond, and Suzuki coupling, have been investigated.

Atroposelective Chan-Evans-Lam Amination.

The synthetic control of atropoisomerism along C-N bonds is a major challenge, and methods that allow C-N atroposelective bond formation are rare. This is a problem because each atropoisomer can feature starkly differentiated biological properties. Yet, among the three most practical and applicable classical amination methods available: 1) the Cu-catalyzed Ullmann-Goldberg reaction, 2) the Pd-catalyzed Buchwald-Hartwig reaction, and 3) the Cu-catalyzed Chan-Evans-Lam reaction, none has truly been rendered atroposelective at the newly formed C-N bond. The first ever Chan-Evans-Lam atroposelective amination is herein described with a simple copper catalyst and newly designed PyrOx chiral ligand. This method should find important applications in asymmetric synthesis, in particular for medicinal chemistry.

(3+2) Cycloaddition of Heteroaromatic N-Ylides with Sulfenes.

A (3+2) cycloaddition of heteroaromatic N-ylides with sulfenes, which are generated in situ from sulfonyl chlorides, has been developed. A variety of ylides were transformed into the corresponding sulfone-embedded N-fused heterocycles in high yields. Hexafluoroisopropyl mesylate was demonstrated to be a suitable reactant for quinolinium ylides. Furthermore, this cycloaddition could be performed with an ylide prepared by a Cu-catalyzed ylide transfer reaction in a one-pot manner, extending the substrate scope to an unisolable ylide.