Copper-catalyzed Reaction Research Articles

Importance of the CuAAC Reaction in the Synthesis of Platinum Complexes with 1,4-Disubstituted-1H-1,2,3-triazoles: A Review of Their Anticancer Activity

Despite multiple advances in treatment and prevention, cancer remains one of the leading causes of death worldwide. Chemotherapy remains the most effective method for cancer treatment. However, commercial chemotherapeutic drugs have limited efficacy, severe side effects, and acquired resistance. Therefore, the scientific community has devoted a great effort to designing new, more effective, and cheaper drugs. In this sense, copper-catalyzed azide-alkyne cycloaddition reactions (CuAAC) provide 1,4-disubstituted 1H-1,2,3-triazoles in high yields without forming by-products. This reaction allows the easy, efficient, functional, ordered, rapid, selective, and specific joining of small molecules, giving rise to more complex molecules. The CuACC reaction simplifies the synthesis processes, accelerating the discovery of new chemotherapeutic agents by allowing the joining of commercial platinum drugs, slightly altering their structure, or creating new molecules with improved properties. This work shows the importance of CuAAC reactions in the search for new metallodrugs with possible anticancer activity.

Length and Sequence-Selective Polymer Synthesis Templated by a Combination of Covalent and Noncovalent Base-Pairing Interactions.

Information can be encoded and stored in sequences of monomer units organized in linear synthetic polymers. Replication of sequence information is of fundamental importance in biology; however, it represents a challenge for synthetic polymer chemistry. A combination of covalent and noncovalent base pairs has been used to achieve high-fidelity templated synthesis of synthetic polymers that encode information as a sequence of different side-chain recognition units. Dialkyne building blocks were attached to the template by using ester base pairs, and diazide building blocks were attached to the template by using H-bond base pairs. Copper-catalyzed azide-alkyne cycloaddition reactions were used to zip up the copy strand on the template, and the resulting duplex was cleaved by hydrolyzing the covalent ester base pairs. By using recognition-encoded melamine oligomers with either three phosphine oxide or three 4-nitrophenol recognition units to form the noncovalent base pairs, exceptionally high affinities of the diazides for the template were achieved, allowing the templated polymerization step to be carried out at low concentrations, which promoted on-template intramolecular reactions relative to competing intermolecular processes. Two different templates, a 7-mer and an 11-mer, were used in the three-step reaction sequence to obtain the sequence-complementary copy strands with minimal amounts of side reaction.

Application of RET Approach for Ratiometric Response Enhancement of ICT Fluorescent Hg2+ Probe based on Crown-containing Styrylpyridinium Dye.

Styrylpyridinium dye bearing azadithia-15-crown-5 ether receptor group SP and 4-alkoxy-1,8-naphthalimide fluorophore were linked using copper-catalyzed azide-alkyne cycloaddition click reaction to afford dyad compound NI-SP. Chemosensor NI-SP exhibited selective ratiometric fluorescent response to the presence of Hg2+ in aqueous solution due to the interplay between resonance energy transfer (RET) and intramolecular charge transfer (ICT) processes occurred upon excitation. The observed switching of the ratio of emission intensities in the blue and red channels R was higher than in the case of monochromophoric styrylpyridine derivative SP showing ratiometric response based on ICT mechanism only. Biological studies revealed that NI-SP penetrates into human lung adenocarcinoma A549 cells and accumulates in cytoplasm and lysosomes. When cells were pre-incubated with mercury (II) perchlorate, the ratio R was increased 2.6 times, which enables detection of intracellular Hg2+ ions and their quantitative analysis in the 0.7-6.0 μM concentration range.

Copper-Catalyzed Sonogashira-Type Coupling Reaction of Vinylacetylene ortho-Carborane with Boronic Acid in the Synthesis of Luminophores with Phosphorescent Emission

Copper-Catalyzed Sonogashira-Type Coupling Reaction of Vinylacetylene ortho-Carborane with Boronic Acid in the Synthesis of Luminophores with Phosphorescent Emission

Efficient Synthesis of Benzoselenazoles and Benzothiazoles by an Ullmann Coupling of Dihalobenzenes with Acyl Iso(seleno/thio) cyanate–Malononitrile Adducts

AbstractWe describe a simple and efficient method for the synthesis of various benzoselenazoles and benzothiazoles by the Ullman coupling reaction of dihalobenzenes with acyl iso(seleno/thio)cyanate–malononitrile adducts in the presence of a copper catalyst with K2CO3 as a base at room temperature, without the help of additional ligands. Notable features of this protocol include the use of mild copper-catalyzed reaction conditions, simple and readily available raw materials, easy purification with the help of a solvent, and the synthesis of 17 new benzoselenazole and benzothiazole compounds.

Copper Catalysts Anchored on Cysteine-Functionalized Polydopamine-Coated Magnetite Particles: A Versatile Platform for Enhanced Coupling Reactions.

Cysteine plays a crucial role in the development of an efficient copper-catalyst system, where its thiol group serves as a strong anchoring site for metal coordination. By immobilizing copper onto cysteine-modified, polydopamine-coated magnetite particles, this advanced catalytic platform exhibits exceptional stability and catalytic activity. Chemical modification of the polydopamine (PDA) surface with cysteine enhances copper salt immobilization, leading to the formation of the Fe3O4@PDA-Cys@Cu platform. This system was evaluated in palladium-free, copper-catalyzed Sonogashira coupling reactions, effectively catalyzing the coupling of terminal acetylenes with aryl halides. Additionally, the Fe3O4@PDA-Cys@Cu platform was employed in click reactions, confirming the enhanced catalytic efficiency due to increased copper content. The reusability of the platform was further investigated, demonstrating improved performance, especially in recyclability tests in click reaction, making it a promising candidate for sustainable heterogeneous catalysis.

Copper-Catalyzed Enantioselective Dehydro-Diels-Alder Reaction: Atom-Economical Synthesis of Axially Chiral Carbazoles.

The dehydro-Diels-Alder (DDA) reaction is a powerful method for the construction of aromatic compounds. However, the enantioselective DDA reaction has been rarely developed, probably due to the competitive thermal reaction. Herein, we report a copper-catalyzed enantioselective DDA reaction through vinyl cation pathway. The reaction leads to the atom-economical synthesis of axially chiral phenyl and indolyl carbazoles in generally excellent yields with good to excellent atroposelectivities. This methodology represents the first example of non-noble metal-catalyzed enantioselective DDA reaction. Notably, new chiral ligand and organocatalyst derived from the constructed axially chiral carbazole are demonstrated to be useful in asymmetric catalysis.

Site-Selective Zwitterionic Poly(caprolactone-carboxybetaine)-Growth Hormone Receptor Antagonist Conjugate: Synthesis and Biological Evaluation.

Zwitterionic polymers have been found to be biocompatible alternatives to poly(ethylene glycol) (PEG) for conjugation to proteins. This work reports the site-selective conjugation of poly(caprolactone-carboxybetaine) (pCLZ) to human growth hormone receptor antagonist (GHA) B2036-alkyne and investigation of safety, activity, and pharmacokinetics. Azide-end-functionalized pCLZs were synthesized and conjugated to GHA B2036-alkyne via copper-catalyzed click reaction. The resulting inhibitory bioactivity concentration responses in Ba/F3-GHR cells were compared to those of PEGylated GHA B2036. IgG and IgM antibody production was tested in mice, and no measurable antibody or cytokine production was detected for the pCLZ conjugate. Using 18F-labeled PET/CT imaging, the pCLZ conjugate showed an increase in circulation time compared to that of GHA B2036. Acute toxicity of the polymer was investigated in vivo and found to be nontoxic. Ex vivo degradation of the polymer on the conjugate was investigated. The results suggest that pCLZ-GHA is a potentially safe alternative to PEG-GHA.

6-Hydroxy Picolinohydrazides Promoted Cu(I)-Catalyzed Hydroxylation Reaction in Water: Machine-Learning Accelerated Ligands Design and Reaction Optimization.

Hydroxylated (hetero)arenes are privileged motifs in natural products, materials, small-molecule pharmaceuticals and serve as versatile intermediates in synthetic organic chemistry. Herein, we report an efficient Cu(I)/6-hydroxy picolinohydrazide-catalyzed hydroxylation reaction of (hetero)aryl halides (Br, Cl) in water. By establishing machine learning (ML) models, the design of ligands and optimization of reaction conditions were effectively accelerated. The N-(1,3-dimethyl-9H- carbazol-9-yl)-6-hydroxypicolinamide (L32, 6-HPA-DMCA) demonstrated high efficiency for (hetero)aryl bromides, promoting hydroxylation reactions with a minimal catalyst loading of 0.01 mol % (100 ppm) at 80 °C to reach 10000 TON; for substrates containing sensitive functional groups, the catalyst loading needs to be increased to 3.0 mol % under near-room temperature conditions. N-(2,7-Di-tert-butyl-9H-carbazol-9-yl)-6-hydroxypicolinamide (L42, 6-HPA-DTBCA) displayed superior reaction activity for chloride substrates, enabling hydroxylation reactions at 100 °C with 2-3 mol % catalyst loading. These represent the state of art for both lowest catalyst loading and temperature in the copper-catalyzed hydroxylation reactions. Furthermore, this method features a sustainable and environmentally friendly solvent system, accommodates a wide range of substrates, and shows potential for developing robust and scalable synthesis processes for key pharmaceutical intermediates.

Recent Developments in Copper-Catalyzed Annulations for Synthesis of Spirooxindoles.

Spirooxindoles represent a special scaffold for pharmaceuticals and natural products, and significant advancements have been achieved in their synthesis in recent years. Among these, transition metal catalysis, particularly copper catalysis, has emerged as an efficient and reliable method for the synthesis of spirooxindoles. Based on different reaction types, two distinct substrate types have been summarized and classified by us for constructing spirooxindole scaffolds via intramolecular and intermolecular annulations. This review outlines the latest advancements in copper-catalyzed cyclization reactions for synthesizing spirooxindoles and provides detailed insights into the types of annulation reactions and their possible reaction mechanisms.

Synthesis of new 1,2,3-triazole-linked pyrimidines by click reaction

A mild and efficient synthesis of 1,4-disubstituted 1,2,3-triazole linked pyrimidines is reported using click reactions. These compounds were prepared by the reaction of 4-propargyl substituted 5-iodo-6-methyl-2(methylthio) pyrimidine with aryl and benzyl azides via copper-catalyzed azide-alkyne cycloaddition reactions in the presence of sodium ascorbate, as a reducing agent. Furthermore, the synthesized compounds were screened against the two bacterial strains pseudomonas aeruginosa and saphylococcus aureus.

Copper-Catalyzed Carbomagnesiation of 1-Halocyclopropenes.

We report a versatile copper-catalyzed carbomagnesiation reaction of poly- and fully substituted 1-halocyclopropenyl esters. By fine-tuning the regioselectivity of the addition, we were able to access configurationally stable fully substituted cyclopropyl carbenoid intermediates. These intermediates were subsequently trapped with electrophiles to furnish stereodefined poly- and fully substituted halocyclopropyl esters. The regioselectivity of the addition was found to be dependent on the nature of the sp2 substituents.

Modular Synthesis of gem-Difluorotetrahydrocarbazolone Scaffolds via Copper-Catalyzed Cascade Reaction of Bromodifluoroacetyl Indoles and Olefins.

A novel and efficient modular synthesis of gem-difluorotetrahydrocarbazolone scaffolds via copper-catalyzed radical cascade cyclization of bromodifluoroacetyl indoles and olefins has been reported. This operationally simple protocol provides straightforward and practical access to a series of privileged gem-difluorotetrahydrocarbazolone scaffolds from readily available starting materials, with the feature of broad functional group tolerance and mild reaction conditions. Moreover, the method could be used for the late-stage functionalization of bioactive molecules, which opens up the possibility for practical applications.

Alkyne-rich patchy polymer colloids prepared by surfactant-free emulsion polymerization

While free radical polymerization methods are employed frequently to prepare sub-micron polymer particles, we hypothesized that surfactant-free emulsion polymerization (SFEP)11Surfactant-free emulsion polymerization methodology may prove beneficial for obtaining functional polymer particles by solution polymerization methods that preclude the need for conventional surfactants. To test the effectiveness of SFEP for the preparation of functional colloids, solution polymerization of several monomers, including propargyl acrylate (PA),22Propargyl acrylate. styrene (Sty)33Styrene. and tert-butyl acrylate (t-BA),44Tert-butyl acrylate. was performed over a range of monomer ratios and reaction scales. Electron microscopy and infrared spectroscopy were employed to evaluate the outcome of SFEP for particle size, shape, surface anisotropy, and chemical composition. Combining this characterization with optimized SFEP synthesis, we found that spherical polymer particles—homopolymers of PA as well as copolymers—were obtained in the 60–300 nm diameter size range. Successful inclusion of PA enabled the use of the particles in copper-catalyzed azide-alkyne cycloaddition reactions (CuAAc).55Copper-catalyzed azide-alkyne cycloaddition Moreover, electron microscopy characterization with backscattering revealed chemical and shape anisotropies on copolymer particles indicative of monomer phase-separation during particle formation. Overall, the SFEP methodology represents a straightforward, one-pot, bottom-up approach to yield a library of functional polymer particles, while avoiding undesirable aspects associated with conventional surfactants.

Coplanar Atropochiral 5H-Cyclopenta[2,1-b:3,4-b']dipyridine Ligands: Synthesis and Applications in Asymmetric Ring-Opening Reaction.

Bipyridines represent a class of ligands renowned for their versatility and efficacy in numerous transition metal-catalyzed reactions. Chiral bipyridine ligands are noted for their distinctive reactivity and stereoselectivity. In this work, we have designed and synthesized a class of bipyridine ligands endowed with an axially chiral scaffold. These ligands feature: (a) a precisely aligned coplanar bipyridine framework that is beneficial for metal chelation; (b) a spacious environment around the metal-bipyridine complexes, capable of hosting substrates with substantial steric bulk; (c) a chiral pocket induced by the axially chiral architecture. These atropochiral planar bipyridine ligands were successfully applied in copper-catalyzed ring-opening reactions of cyclic diaryliodoniums with bulky secondary amines, achieving high efficiency and stereoselectivity that were unsuccessful in our previous efforts.

Synthesis of Aryl Alkyl Thioethers via a Copper-Catalyzed Three-Component Reaction with DABSO, Aryldiazonium Salts, and Alkyl Bromides.

We developed a method for synthesizing aryl alkyl thioether compounds via a three-component reaction involving aryldiazonium salts, 1,4-diazabicyclo[2.2.2]octane bis(sulfur dioxide), and alkyl bromides. Optimal yields were achieved when a copper catalyst was used in conjunction with zinc and tetrabutylammonium bromide in an acetonitrile solvent at 130 °C for 10 h. This methodology demonstrates good functional group tolerance and enables the successful synthesis of various aryl alkyl thioethers with moderate to high yields.

Ligand-Enabled Copper-Catalyzed Ullmann-Type S-C Bond Formation to Access Sulfilimines.

A copper-catalyzed Ullmann-type cross-coupling reaction of sulfenamides with aryl iodides is developed. The key to success is the use of a 2-methylnaphthalen-1-amine-derived amide ligand, which enables the formation of an S-C bond to access functionalized sulfilimines in good to excellent yields at room temperature. This method has the advantages of mild conditions, a broad substrate scope, good functional group compatibility, and high chemoselectivity. The utility of this protocol is highlighted through late-stage modification of drug-relevant molecules and sulfilimine product derivatization.

Synthesis and BSA binding study of the Cu(II) complex and applications of it to enhance catalytic activity for C(Sp2)-H bond functionalization and for the synthesis of polyhydroquinolines

Among the various copper-catalyzed coupling reactions, C–S and C–N bond-forming reactions have carried off plentiful recognition due to their demand in the synthesis of molecules having biological and pharmaceutical impact. Organo-copper complex has an incontestable supremacy over the other catalytic complex due to its low cost and the use of readily accessible and stable ligands. As a consequence and in continuation of our explorative studies in this direction, an efficient and novel organo-copper complex has been synthesized and characterized by spectroscopic (NMR, FT-IR) and single crystal X-ray diffraction (XRD) methods. The synthesized stable metal complex has fascinating physical, chemical, biological and catalytic properties. In the chemical exploration refer to protein-metal interactions; we have often used Bovine Serum Albumin (BSA) protein. The synthesized copper complex has the potential to form coordinate bonds with functional groups present in BSA, together with amino acid residues and the protein backbone. The binding of metal complexes to BSA has outstanding imputation in medicinal chemistry. For enhancement of the catalytic activity of the organo-copper complex, we have evaluated it in carbon-hetero bond formation reactions where it proffered an influential tool for the establishment of C–S and C–N bonds.

Stereodivergency in Copper-Catalyzed Borylative Difunctionalizations: The Impact of Boron Coordination.

A reagent-controlled diastereodivergent copper-catalyzed borylative difunctionalization is reported. The formation of Lewis adducts that guide selectivity is commonly invoked in organic reaction mechanisms. Using density functional theory calculations, we identified BpinBdan as a sterically similar and less Lewis acidic alternative to B2pin2. Using a newly developed borylative aldol domino reaction as the proof-of-concept, we demonstrate a change in stereochemical outcome by a simple change of borylating reagent-B2pin2 affords the diastereomer associated with coordination control while BpinBdan overturns this mode of binding. We show that this strategy can be generalized to other scaffolds and, more importantly, that BpinBdan does not alter the diastereomeric outcome of the reaction when coordination is not involved. BpinBdan can be viewed as a mechanistic probe for coordination in future copper-catalyzed borylation reactions.

Copper-Catalyzed Oxyfluorosulfonylation of β,γ-Unsaturated Oximes with Sulfur Dioxide and Selectfluor for Isoxazoline-Functionalized Aliphatic Sulfonyl Fluorides.

In this report, we describe a copper-catalyzed cascade reaction involving oxygen radical-induced cyclization/SO2 insertion/fluorination of β,γ-unsaturated oximes with sulfur dioxide and Selectfluor under mild conditions for the synthesis of isoxazoline-functionalized aliphatic sulfonyl fluorides. The synthetic potential of these compounds has been evaluated through diverse SuFEx reactions.