Copper-mediated Reaction Research Articles

Front Cover Picture: Cu(I) Mediated Azidation of Halobenzenes, and Cu Catalysed Selective Azide Reduction to Corresponding Amines (Adv. Synth. Catal. 17/2022)

The front cover image illustrates the complex mixture of a selective copper-mediated reaction of a bromobenzene bearing a bromoalkanoyl chain to an amine-azide. It proceeds stepwise via a bis-azide intermediate and produces copper nanostructures simultaneously, which grow on the PTFE stirring bar. The copper in the reaction mixture is responsible for the aryl azide reduction, and the mild protocol is broadly applicable for bromobenzenes with electron withdrawing groups. Furthermore, the copper nanostructures can mediate azide-alkyne click reactions. Details can be found in the Research Article by Max Roemer and co-workers (M. Roemer, I. Luck, N. Proschogo, Adv. Synth. Catal. 2022, 364, XXXX–XXXX; DOI: 10.1002/adsc.202200594)

Cu(I) Mediated Azidation of Halobenzenes, and Cu Catalysed Selective Azide Reduction to Corresponding Amines

AbstractAryl amines are synthesized from halobenzenes via copper mediated reactions employing sodium azide under mild conditions in ethanol/water. The reaction proceeds stepwise via the aryl azide, which is reduced to the corresponding amine in‐situ. The methodology allows syntheses of amines from corresponding para‐, meta‐ and ortho‐bromobenzenes bearing electron withdrawing groups. Bifunctional halobenzenes bearing alkanoyl chains with terminal bromides are selectively transformed, generating an aniline and an aliphatic azide, as this azide position is stable to reduction. A one‐pot multistep sequence for preparation of the target amines was designed. The azide formation is mediated by CuI while elemental Cu is generated simultaneously, which is deposited onto the employed PTFE stirring bar used in the reaction. The Cu films were quantified and analysed by SEM/EDS. The Cu, either deposited or in solution, is responsible for the azide reduction, possibly involving nitrene intermediates. An application of the modified stirring bars as a heterogeneous catalyst for a click reaction is demonstrated.magnified image

Catalytic Direct Cyanomethylenation of C(sp3)-H Bonds via a One-Step Double C-C Bond Formation.

An elegant and catalytic procedure for the one-step cyanomethylenation of C(sp3)-H bonds adjacent to benzazoles and ketones is described herein using DMF as a C-1 unit and TMSCN as the cyanide source. The copper-mediated reaction between DMF and TMSCN gives a cyanomethylene radical intermediate that reacts with 2-alkylbenzazoles or alkylketones to furnish desired cyanomethylenated compounds under palladium catalysis. Subsequent interconversion of cyanomethylenated products makes the protocol synthetically attractive.

Synthesis of phenoxathiins using an iron-catalysed C-H thioarylation.

Phenoxathiins are an important class of sulfur-containing heterocycle, found as the core component in numerous pharmaceutically active agents and materials. Despite this importance, there are relatively few methods for the synthesis of these heterocycles that avoid complex starting materials, harsh conditions or precious transition metals. We report a two-step synthesis of phenoxathiins from phenols using iron and copper-mediated reactions. The first step involves the accelerated ortho-thioarylation of phenols using N-(2-bromophenylthio)succinimide, catalysed by the Lewis acid, iron(III) triflimide and the Lewis base, bis(4-methoxyphenyl)sulfane. In the second step, the thioarylated products were converted to a series of phenoxathiins using a copper-mediated, Ullmann-type, C-O bond forming cyclisation reaction. The synthetic utility of this two-step approach for the preparation of biologically relevant phenoxathiins was demonstrated using natural product-based phenols.

Probe and dye design through copper-mediated reactions of N-arylhydroxylamines.

A phthalimide probe (P1) possessing a hydroxylamine group on the benzene ring has been prepared for fluorescence sensing of copper ions. The detection is based on the reaction between hydroxylamine and copper ions, resulting in two fluorescent products through hydroxyl rearrangement and dehydroxylation reactions. P1 shows a specific and sensitive fluorescence response towards copper ions with a limit of detection (LOD) of 1.11 nM (N = 3). The copper impurities from the industrial sources of the "click" ligand (tris(benzyltriazolylmethyl)amine (TBTA)) have been successfully examined using P1. This is the first case to utilize the reaction between hydroxylamine and copper ions. More importantly, the copper mediated hydroxyl rearrangement reaction opens a way to prepare a new sort of excited state intramolecular proton transfer (ESIPT) dye with ultra-small size and bright green fluorescence under physiological conditions.

Copper-Mediated Conversion of Alkynes into Nitriles via Iodotriazoles.

We disclose our studies on a copper-mediated reaction of alkynes with trimethylsilyl azide to afford nitriles, and proposed a reaction mechanism, which involves an iodoalkyne and an iodotriazole as intermediates.

Radiofluorination of oxazole-carboxamides for preclinical PET neuroimaging of GSK-3

Glycogen synthase kinase 3 (GSK-3) is an enzyme that is dysregulated in oncology, neurodegeneration, neuroinflammation and several mental health illnesses. As such, GSK-3 is a long-sought after target for positron emission tomography (PET) imaging and therapeutic intervention. Herein, we report on the development and radiofluorination of two oxazole-4-carboxamides, including one bearing a non-activated aromatic ring. Both compounds demonstrated excellent selectivity in a kinase screen and inhibit GSK-3 with high affinity. [18F]OCM-49 was synthesized from [18F]fluoride using a copper-mediated reaction of an aryl boronic acid precursor, while [18F]OCM-50 used a trimethylammonium triflate precursor, and both radiotracers were translated for preclinical PET imaging in rodents. Due to superior radiochemical yields and brain uptake (peak standardized uptake value of ∼2.0), [18F]OCM-50 was further evaluated in non-human primate and also showed good brain uptake and rapid clearance. Further studies to consider clinical translation of both radiotracers are underway.

Advances in Carbon–Element Bond Construction under Chan–Lam Cross-Coupling Conditions: A Second Decade

AbstractCopper-mediated carbon–heteroatom bond-forming reactions involving a wide range of substrates have been in the spotlight for many organic chemists. This review highlights developments between 2010 and 2019 in both stoichiometric and catalytic copper-mediated reactions, and also examples of nickel-mediated reactions, under modified Chan–Lam cross-coupling conditions using various nucleophiles; examples include chemo- and regioselective N-arylations or O-arylations. The utilization of various nucleophiles as coupling partners together with reaction optimization (including the choice of copper source, ligands, base, and other additives), limitations, scope, and mechanisms are examined; these have benefitted the development of efficient and milder methods. The synthesis of medicinally valuable or pharmaceutically important nitrogen heterocycles, including isotope-labeled compounds, is also included. Chan–Lam coupling reaction can now form twelve different C–element bonds, making it one of the most diverse and mild reactions known in organic chemistry.1 Introduction2 Construction of C–N and C–O Bonds2.1 C–N Bond Formation2.1.1 Original Discovery via Stoichiometric Copper-Mediated C–N Bond Formation2.1.2 Copper-Catalyzed C–N Bond Formation2.1.3 Coupling with Azides, Sulfoximines, and Sulfonediimines as Nitrogen­ Nucleophiles2.1.4 Coupling with N,N-Dialkylhydroxylamines2.1.5 Enolate Coupling with sp3-Carbon Nucleophiles2.1.6 Nickel-Catalyzed Chan–Lam Coupling2.1.7 Coupling with Amino Acids2.1.8 Coupling with Alkylboron Reagents2.1.9 Coupling with Electron-Deficient Heteroarylamines2.1.10 Selective C–N Bond Formation for the Synthesis of Heterocycle-Containing Compounds2.1.11 Using Sulfonato-imino Copper(II) Complexes2.2 C–O Bond Formation2.2.1 Coupling with (Hetero)arylboron Reagents2.2.2 Coupling with Alkyl- and Alkenylboron Reagents3 C–Element (Element = S, P, C, F, Cl, Br, I, Se, Te, At) Bond Forma tion under Modified Chan–Lam Conditions4 Conclusions

Copper-Mediated Synthesis of (E)-1-Azido and (Z)-1,2-Diazido Alkenes from 1-Alkene-1,2-diboronic Esters: An Approach to Mono- and 1,2-Di-(1,2,3-Triazolyl)-Alkenes and Fused Bis-(1,2,3-Triazolo)-Pyrazines.

A stereoselective and convenient route has been demonstrated to access (Z)-1,2-diazido alkenes from the corresponding 1,2-diboronic esters via a copper-mediated reaction with sodium azide. Alternately, mono-functionalization was regioselectively carried out with trimethylsilyl azide as an azidation reactant. The in situ conversion of bis-azides to the corresponding bis-triazoles can be readily achieved in the presence of copper sulfate and sodium ascorbate, while the modification of the catalytic system opened a new convenient route to bis-triazolo-pyrazines, a new class of fused heterocycles.

Imaging niacin trafficking with positron emission tomography reveals in vivo monocarboxylate transporter distribution

IntroductionA sufficient dietary intake of the vitamin niacin is essential for normal cellular function. Niacin is transported into the cells by the monocarboxylate transporters: sodium-dependent monocarboxylate transporter (SMCT1 and SMCT2) and monocarboxylate transporter (MCT1). Despite the importance of niacin in biological systems, surprisingly, its in vivo biodistribution and trafficking in living organisms has not been reported. The availability of niacin radiolabelled with the short-lived positron emitting radionuclide carbon-11 ([11C]niacin) would enable the quantitative in vivo study of this endogenous micronutrient trafficking using in vivo PET molecular imaging. Methods[11C]Niacin was synthesised via a simple one-step, one-pot reaction in a fully automated system using cyclotron-produced carbon dioxide ([11C]CO2) and 3-pyridineboronic acid ester via a copper-mediated reaction. [11C]Niacin was administered intravenously in healthy anaesthetised mice placed in a high-resolution nanoScan PET/CT scanner. To further characterize in vivo [11C]niacin distribution in vivo, mice were challenged with either niacin or AZD3965, a potent and selective MCT1 inhibitor. To examine niacin gastrointestinal absorption and body distribution in vivo, no-carrier-added (NCA) and carrier-added (CA) [11C]niacin formulations were administered orally. ResultsTotal synthesis time including HPLC purification was 25 ± 1 min from end of [11C]CO2 delivery. [11C]Niacin was obtained with a decay corrected radiochemical yield of 17 ± 2%.We report a rapid radioactivity accumulation in the kidney, heart, eyes and liver of intravenously administered [11C]niacin which is consistent with the known in vivo SMCTs and MCT1 transporter tissue expression. Pre-administration of non-radioactive niacin decreased kidney-, heart-, ocular- and liver-uptake and increased urinary excretion of [11C]niacin. Pre-administration of AZD3965 selectively decreased [11C]niacin uptake in MCT1-expressing organs such as heart and retina.Following oral administration of NCA [11C]niacin, a high level of radioactivity accumulated in the intestines. CA abolished the intestinal accumulation of [11C]niacin resulting in a preferential distribution to all tissues expressing niacin transporters and the excretory organs. ConclusionsHere, we describe the efficient preparation of [11C]niacin as PET imaging agent for probing the trafficking of nutrient demand in healthy rodents by intravenous and oral administration, providing a translatable technique to enable the future exploration of niacin trafficking in humans and to assess its application as a research tool for metabolic disorders (dyslipidaemia) and cancer.

Direct Alkoxycarbonylation of Heteroarenes via Cu-Mediated Trichloromethylation and In Situ Alcoholysis.

We report an efficient approach for direct alkoxycarbonylation of furans as well as other heteroarenes via a one-step copper-mediated reaction of three components (i.e., heteroarene, alcohol, and CHCl3). The copper additive was confirmed to simultaneously promote the reaction in three pathways: oxidant cracking, single electron transfer, and alcoholysis. By means of this protocol, various functionalized furancarboxylates and other heteroarenecarboxylates were facilely obtained in moderate to good yields.

Chiral Chalcogen Bond Donors Based on the 4,4'-Bipyridine Scaffold.

Organocatalysis through chalcogen bonding (ChB) is in its infancy, as its proof-of-principle was only reported in 2016. Herein, we report the design and synthesis of new chiral ChB donors, as well as the catalytic activity evaluation of the 5,5′-dibromo-2,2′-dichloro-3-((perfluorophenyl)selanyl)-4,4′-bipyridine as organocatalyst. The latter is based on the use of two electron-withdrawing groups, a pentafluorophenyl ring and a tetrahalo-4,4′-bipyridine skeleton, as substituents at the selenium center. Atropisomery of the tetrahalo-4,4′-bipyridine motif provides a chiral environment to these new ChB donors. Their synthesis was achieved through either selective lithium exchange and trapping or a site-selective copper-mediated reaction. Pure enantiomers of the 3-selanyl-4,4′-bipyridine were obtained by high performance liquid chromatography enantioseparation on specific chiral stationary phase, and their absolute configuration was assigned by comparison of the measured and calculated electronic circular dichroism spectra. The capability of the selenium compound to participate in σ-hole-based interactions in solution was studied by 19F NMR. Even if no asymmetric induction has been observed so far, the new selenium motif proved to be catalytically active in the reduction of 2-phenylquinoline by Hantzsch ester.

Copper-Mediated Deprotection of Thiazolidine and Selenazolidine Derivatives Applied to Native Chemical Ligation.

Cupric sulfate efficiently opens thiazolidine and selenazolidine rings, producing a protected N-terminal cysteine or selenocysteine derivative without the use of inert gas or solvent. This is a clear advantage over methods that use water-soluble palladium salts, which fail to react with the selenazolidine ring. This copper-mediated reaction proceeds with monovalent or divalent copper ions, and disulfide bond formation followed by ring-opening promotes the process. This copper-mediated reaction, which is compatible with the standard native chemical ligation conditions, was applied to the synthesis of the 77-mer CXCL14 protein.

External Oxidant-Dependent Reactivity Switch in Copper-Mediated Intramolecular Carboamination of Alkynes: Access to a Different Class of Fluorescent Ionic Nitrogen-Doped Polycyclic Aromatic Hydrocarbons.

An interesting case of external oxidant-controlled reactivity switch leading to a divergent set of ionic nitrogen-doped polycyclic aromatic hydrocarbons (N-doped PAHs), is presented here, which is quite unrecognized in copper-mediated reactions. In the current scenario, from the same pyridino-alkyne substrates, the use of the external oxidant PhI(OAc)2, in combination with Cu(OTf)2, gave N-doped spiro-PAHs via a dearomative 1,2-carboamination process; whereas, without the use of oxidant, an alkyne/azadiene [4 + 2]-cycloaddition cascade occurred to exclusively afford ionic N-doped PAHs. These newly synthesized N-doped PAHs further exhibit tunable emissions, as well as excellent quantum efficiencies.

Bio-based Catalysts from Biomass Issued after Decontamination of Effluents Rich in Copper—an Innovative Approach towards Greener Copper-based Catalysis

The abundance of Cu-contaminated effluents and the serious risk of contamination of the aquatic systems combine to provide strong motivating factors to tackle this environmental problem. The treatment of polluted effluents by rhizofiltration and biosorption is an interesting ecological alternative. Taking advantage of the remarkable ability of the selected plants to bioconcentrate copper into roots, these methods have been exploited for the decontamination of copperrich effluents. Herein, we present an overview on the utility of the resulted copper-rich biomass for the preparation of novel bio-sourced copper-based catalysts for copper-mediated reactions: from the bioaccumulation of copper in plant, to the preparation and full analysis of the new Eco-Cu catalysts, and their application in selected key reactions. The hydrolysis of a thiophosphate, an Ullmanntype coupling leading to N- and O-arylated compounds, and a CuAAC “click” reaction, all performed under green and environmentally friendly conditions, will be described.

Multicomponent click reaction catalyzed by organic surfactant-free copper sulfide (sf-CuS) nano/micro flowers

The azide-alkyne cycloaddition (Huisgen reaction) is one of the most powerful and widely used copper-mediated reactions. In many such reactions, use of metal or metal oxide nanoparticles as the catalyst is more appealing because of the increased catalytic activity attributed to the large surface to volume ratio. However, the nano/micro particles are synthesized often in the presence of long chain organic molecules as capping or stabilizing agents. These organic molecules cover the active centers and restrict or reduce their catalytic activity. Therefore, we have synthesized the copper sulfide (sf-CuS) nano/micro particles without having organic surfactant molecules as the capping agent. These particles with a flower-like architecture (micro flowers, mf) were obtained readily under the supersaturated condition at room temperature. In these particles, the surface was freely available for adsorption and desorption reactions. When utilized as a catalyst in multicomponent cycloaddition reactions, the sf-CuS mf exhibited excellent catalytic activity compared with some other nanoparticles with surfactants. This sf-CuS mf catalyzed the one-pot synthesis of 1,2,3-triazole and β-hydroxy-1,2,3-triazole effectively from a variety of benzyl bromide derivatives epoxides respectively. Both these reactions proceeded in the presence of azide and phenylacetylene in the water at room temperature. The catalyst was reusable, and there was no catalyst leaching observed during reactions. Synthesis of β-hydroxy triazoles and 1,2,3-triazoles under exceptionally mild conditions with high yields proved the sf-CuS mf as the catalyst as a robust and recyclable catalyst.

Copper-mediated synthesis of N-vinyl ynamides from N-vinyl carbamates

Ynamides are versatile 3-atoms building blocks for organic synthesis as they participate in a variety of ionic, radical and pericyclic processes. Converting ynamides into 5-atom building blocks, such as the yet unreported N-vinyl ynamides, would open new avenues in this fascinating chemistry. We describe herein our efforts towards such goal and demonstrate that the cross-coupling between N-vinyl carbamates and bromo-alkynes using copper(I) thiophene carboxylate, 1,10-phenanthroline and tBuOK in DMSO is a reactive system with an improved profile compared to the classical ynamides syntheses. The advantages and limitations of this copper-mediated reaction are discussed.

The Disappearing Director: The Case of Directed N-Arylation via a Removable Hydroxyl Group.

A facile and broadly applicable method for the regiospecific N-arylation of benzotriazoles is reported. Copper-mediated reactions of diverse 1-hydroxy-1H-benzotriazoles with aryl boronic acids lead to 1-aryl-1H-benzotriazole 3-oxides. A N1-OH → N3 prototropy in the 1-hydroxy-1H-benzotriazoles is plausibly the underlying basis, where the tautomer is captured by the boronic acid, leading to C-N (not C-O) bond formation. Because the N-O bond in amine N-oxides and 1-hydroxy-1H-benzotriazoles can be easily reduced by diboron reagents such as (pinB)2 and B2(OH)4, exposure of the 1-aryl-1H-benzotriazole 3-oxides to B2(OH)4 then leads to facile reduction of the N-O bond resulting in diverse, regiospecifically-arylated benzotriazoles. Thus, the N-hydroxyl group in 1-hydroxy-1H-benzotriazoles acts as a disposable arylation director.

Copper-Mediated Reactions of Nitriles with Nitromethanes: Aza-Henry Reactions and Nitrile Hydrations.

In this study, the first aza-Henry reaction of nitriles with nitromethane in a CuI/Cs2CO3/DBU system is described. The process was conveniently and directly used for the synthesis of β-aminonitroalkenes 2a-x and tolerated aryl-, alkyl-, hetaryl-, alkenyl-, and alkynylnitriles. The resulting aminonitroalkenes 2 could be successfully transformed to the corresponding 2-nitroacetophenones, 2-amino-1-halonitroalkenes, 2-alkylaminonitroalkenes, or 3-nitropyridines. In the presence of H2O, the aza-Henry reaction turned the reaction path to the nitrile hydration to exclusively yield the amides 3a-s.

Radical Cyclization of Trichloroacetamides: Synthesis of Lactams

Trichloroacetamides can act as radical precursors to synthesize nitrogen-containing heterocycles in a variety of processes, mainly involving atom transfer radical cyclizations (ATRC), mediated by Cu(I) or Ru(II) catalysts, and the hydride reductive method, employing either Bu₃SnH or (Me₃Si)₃SiH, or recently NaBH₃CN. Additionally, amine-mediated single-electron transfer cyclizations, as well as radical processes promoted by Ni, Fe, Mn, Ti, and Ag, have been developed. 1 Introduction 2 Atom Transfer Radical Cyclizations (ATRC) 2.1 Copper-Mediated Reactions 2.2 Ruthenium(II)-Mediated Reactions 2.3 ATRC Promoted by Other Metals 3 Photocyclization Reactions 4 Reductive Cyclization via Single-Electron Transfer Processes 4.1 Ni/AcOH-Promoted Cyclizations 4.2 Titanocene(III)-Catalyzed Reactions 4.3 Silver Acetate Mediated Reactions 4.4 Amine-Mediated Single-Electron Transfer 5 Cyclization Involving M–H Hydrogen Atom Donors (M = Sn, Si, B) 5.1 Bu₃SnH-Mediated Reactions 5.2 (Me₃Si)₃SiH (TTMSS)-Mediated Reactions 5.3 Borohydride-Mediated Radical Cyclizations 6 Concluding Remarks