Oxidative N-dealkylation Research Articles

Preclinical evaluation of [18F]SYN1 and [18F]SYN2, novel radiotracers for PET myocardial perfusion imaging

BackgroundPositron emission tomography (PET) is now an established diagnostic method for myocardial perfusion imaging (MPI) in coronary artery disease, which is the main cause of death globally. The available tracers show several limitations, therefore, the 18F-labelled tracer is in high demand nowadays. The preclinical studies on normal Wistar rats aimed to characterise two potential, novel radiotracers, [18F]SYN1 and [18F]SYN2, to evaluate which is a better candidate for PET MPI cardiotracer.ResultsThe dynamic microPET images showed rapid myocardial uptake for both tracers. However, the uptake was higher and also stable for [18F]SYN2, with an average standardized uptake value of 3.8. The biodistribution studies confirmed that [18F]SYN2 uptake in the cardiac muscle was high and stable (3.02%ID/g at 15 min and 2.79%ID/g at 6 h) compared to [18F]SYN1 (1.84%ID/g at 15 min and 0.32%ID/g at 6 h). The critical organs determined in dosimetry studies were the small intestine and the kidneys. The estimated effective dose for humans was 0.00714 mSv/MBq for [18F]SYN1 and 0.0109 mSv/MBq for [18F]SYN2. The tested dose level of 2 mg/kg was considered to be the No Observed Adverse Effect Level (NOAEL) for both candidates. The better results were achieved for [18F]SYN2, therefore, further preclinical studies were conducted only for this tracer. Radioligand binding assays showed significant responses in 3 from 68 assays: muscarinic acetylcholine M1 and M2 receptors and potassium channel hERG. The compound was mostly metabolised via an oxidative N-dealkylation, while the fluor substituent was not separated from the molecule.Conclusion[18F]SYN2 showed a favourable pharmacodynamic and pharmacokinetic profile, which enabled a clear visualization of the heart in microPET. The compound was well-tolerated in studies in normal rats with moderate radiation exposure. The results encourage further exploration of [18F]SYN2 in clinical studies.

Mucolytic Drugs Ambroxol and Bromhexine: Transformation under Aqueous Chlorination Conditions.

Bromhexine and ambroxol are among the mucolytic drugs most widely used to treat acute and chronic respiratory diseases. Entering the municipal wastewater and undergoing transformations during disinfection with active chlorine, these compounds can produce nitrogen- and bromine-containing disinfection by-products (DBPs) that are dangerous for aquatic ecosystems. In the present study, primary and deep degradation products of ambroxol and bromhexine obtained in model aquatic chlorination experiments were studied via the combination of high-performance liquid and gas chromatography with high-resolution mass spectrometry. It was shown that at the initial stages, the reactions of cyclization, hydroxylation, chlorination, electrophilic ipso-substitution of bromine atoms with chlorine, and oxidative N-dealkylation occur. Along with known metabolites, a number of novel primary DBPs were tentatively identified based on their elemental compositions and tandem mass spectra. Deep degradation of bromhexine and ambroxol gives twenty-four identified volatile and semi-volatile compounds of six classes, among which trihalomethanes account for more than 50%. The specific class of bromhexine- and ambroxol-related DBPs are bromine-containing haloanilines. Seven of them, including methoxy derivatives, were first discovered in the present study. One more novel class of DBPs associated with bromhexine and ambroxol is represented by halogenated indazoles formed through dealkylation of the primary transformation products containing pyrazoline or tetrahydropyrimidine cycle in their structure.

Oxidative N-Dealkylation of N,N-Dimethylanilines by Non-Heme Manganese Catalysts

Non-heme manganese(II) complexes [(IndH)MnIICl2] (1) and [(N4Py*)MnII(CH3CN)](ClO4)2 (2) with tridentate isoindoline and pentadentate polypyridyl ligands (IndH = 1,3-bis(2′-pyridylimino)isoindoline; N4Py* = N,N-bis(2-pyridylmethyl)-1,2- di(2-pyridyl)ethylamine) proved to be suitable to catalyze the oxidative demethylation of N,N-dimethylaniline (DMA) with various oxidants such as tert-butyl hydroperoxide (TBHP), peracetic acid (PAA), and meta-chloroperoxybenzoic acid (mCPBA), resulting N-methylaniline (MA) as a main product with N-methylformanilide (MFA) as a result of a free-radical chain process under air. The effect of electron-donating and electron-withdrawing substituents on the aromatic ring on the relative reactivity of the substrates and on the product composition (MA/MFA) was also studied and showed a significant impact on the catalytic N-demethylation reaction. Based on the Hammett correlation with ρ = −0.38 (PAA), −0.45 (mCPBA), and −0.63 (TBHP) for 1 and ρ = −0.38 (PAA) and −0.37 (mCPBA) for 2, an electrophilic intermediate is suggested as the key oxidant. Furthermore, the spectral investigation (UV-Vis) resulted in direct evidence for the formation of a high-valent oxomanganese(IV) and a transient radical cation intermediate, p-Me-DMA•+, suggesting that the initial step in the manganese-catalyzed oxidations is a fast electron-transfer between the amine and the high valent oxometal species. The mechanisms of the subsequent steps are discussed.

Absorption, Metabolism, and Excretion of ACT-1004-1239, a First-In-Class CXCR7 Antagonist: In Vitro, Preclinical, and Clinical Data.

ACT-1004-1239 is a potent, selective, first-in-class CXCR7 antagonist, which shows a favorable preclinical and clinical profile. Here we report the metabolites and the metabolic pathways of ACT-1004-1239 identified using results from in vitro and in vivo studies. Two complementary in vitro studies (incubation with human liver microsomes in the absence/presence of cytochrome P450- [CYP] specific chemical inhibitors and incubation with recombinant CYPs) were conducted to identify CYPs involved in ACT-1004-1239 metabolism. For the in vivo investigations, a microtracer approach was integrated in the first-in-human study to assess mass balance and absorption, distribution, metabolism, and excretion (ADME) characteristics of ACT-1004-1239. Six healthy male subjects received orally 100 mg non-radioactive ACT-1004-1239 together with 1 μCi 14C-ACT-1004-1239. Plasma, urine, and feces samples were collected up to 240 h post-dose and 14C-drug-related material was measured with accelerator mass spectrometry. This technique was also used to construct radiochromatograms of pooled human samples. Metabolite structure elucidation of human-relevant metabolites was performed using high performance liquid chromatography coupled with high resolution mass spectrometry and facilitated by the use of rat samples. CYP3A4 was identified as the major CYP catalyzing the formation of M1 in vitro. In humans, the cumulative recovery from urine and feces was 84.1% of the dose with the majority being eliminated via the feces (69.6%) and the rest via the urine (14.5%). In human plasma, two major circulating metabolites were identified, i.e., M1 and M23. Elimination via M1 was the only elimination pathway that contributed to ≥25% of ACT-1004-1239 elimination. M1 was identified as a secondary amine metabolite following oxidative N-dealkylation of the parent. M23 was identified as a difluorophenyl isoxazole carboxylic acid metabolite following central amide bond hydrolysis of the parent. Other metabolites observed in humans were A1, A2, and A3. Metabolite A1 was identified as an analog of M1 after oxidative defluorination, whereas both, A2 and A3, were identified as a reduced analog of M1 and parent, respectively, after addition of two hydrogen atoms at the isoxazole ring. In conclusion, CYP3A4 contributes to a relevant extent to ACT-1004-1239 disposition and two major circulating metabolites were observed in humans. Clinical Trial Registration: (https://clinicaltrials.gov/ct2/show/NCT03869320) ClinicalTrials.gov Identifier NCT03869320.

Metabolic N-Dealkylation and N-Oxidation as Elucidators of the Role of Alkylamino Moieties in Drugs Acting at Various Receptors.

Metabolic reactions that occur at alkylamino moieties may provide insight into the roles of these moieties when they are parts of drug molecules that act at different receptors. N-dealkylation of N,N-dialkylamino moieties has been associated with retaining, attenuation or loss of pharmacologic activities of metabolites compared to their parent drugs. Further, N-dealkylation has resulted in clinically used drugs, activation of prodrugs, change of receptor selectivity, and providing potential for developing fully-fledged drugs. While both secondary and tertiary alkylamino moieties (open chain aliphatic or heterocyclic) are metabolized by CYP450 isozymes oxidative N-dealkylation, only tertiary alkylamino moieties are subject to metabolic N-oxidation by Flavin-containing monooxygenase (FMO) to give N-oxide products. In this review, two aspects will be examined after surveying the metabolism of representative alkylamino-moieties-containing drugs that act at various receptors (i) the pharmacologic activities and relevant physicochemical properties (basicity and polarity) of the metabolites with respect to their parent drugs and (ii) the role of alkylamino moieties on the molecular docking of drugs in receptors. Such information is illuminative in structure-based drug design considering that fully-fledged metabolite drugs and metabolite prodrugs have been, respectively, developed from N-desalkyl and N-oxide metabolites.

Visible light-induced oxidative N-dealkylation of alkylamines by a luminescent osmium(vi) nitrido complex.

N-Dealkylation of amines by metal oxo intermediates (M Created by potrace 1.16, written by Peter Selinger 2001-2019 ]]> O) is related to drug detoxification and DNA repair in biological systems. In this study, we report the first example of N-dealkylation of various alkylamines by a luminescent osmium(vi) nitrido complex induced by visible light.

In vitro phase I metabolism of three phenethylamines 25D-NBOMe, 25E-NBOMe and 25N-NBOMe using microsomal and microbial models.

Numerous 2,5-dimethoxy-N-benzylphenethylamines (NBOMe), carrying a variety of lipophilic substituents at the 4-position, are potent agonists at 5-hydroxytryptamine (5HT2A ) receptors and show hallucinogenic effects. The present study investigated the metabolism of 25D-NBOMe, 25E-NBOMe, and 25N-NBOMe using the microsomal model of pooled human liver microsomes (pHLM) and the microbial model of the fungi Cunninghamella elegans (C. elegans). Identification of metabolites was performed using liquid chromatography-high resolution-tandem mass spectrometry (LC-HR-MS/MS) with a quadrupole time-of-flight (QqToF) instrument. In total, 36 25D-NBOMe phase I metabolites, 26 25E-NBOMe phase I metabolites and 24 25N-NBOMe phase I metabolites were detected and identified in pHLM. Furthermore, 14 metabolites of 25D-NBOMe, 11 25E-NBOMe metabolites, and nine 25N-NBOMe metabolites could be found in C. elegans. The main biotransformation steps observed were oxidative deamination, oxidative N-dealkylation also in combination with hydroxylation, oxidative O-demethylation possibly combined with hydroxylation, oxidation of secondary alcohols, mono- and dihydroxylation, oxidation of primary alcohols, and carboxylation of primary alcohols. Additionally, oxidative di-O-demethylation for 25E-NBOMe and reduction of the aromatic nitro group and N-acetylation of the primary aromatic amine for 25N-NBOMe took place. The resulting 25N-NBOMe metabolites were unique for NBOMe compounds. For all NBOMes investigated, the corresponding 2,5-dimethoxyphenethylamine (2C-X) metabolite was detected. This study reports for the first time 25X-NBOMe N-oxide metabolites and hydroxylamine metabolites, which were identified for 25D-NBOMe and 25N-NBOMe and all three investigated NBOMes, respectively. C. elegans was capable of generating all main biotransformation steps observed in pHLM and might therefore be an interesting model for further studies of new psychoactive substances (NPS) metabolism.

Kinetics and Degradation Mechanism of Adrenaline Derivative CpQ in Diluted Aqueous Solutions

The degradation kinetics of an adrenaline (epinephrine) derivative, CpQ, was studied in solution in the pH range of 1-12 at 40-80 °C by high-performance liquid chromatography and ultraviolet-visible spectroscopy. The pH-rate profile exhibits a bell-shaped curve with two sigmoidal regions in the specific acid-catalyzed and specific base-catalyzed regions. The pH range of maximum stability was 2.5-4.5 with the main degradation pathway being the oxidative N-dealkylation of the aliphatic amino moiety followed by fast interconversion of the resulting fragments to stable degradation products. The autoxidation reaction was slower than the reaction of the oxygen reactive species. The chiral center underwent R to S racemization by a polar reaction mechanism under acidic conditions with a rate minimum at pH 4. The rates of degradation of the R and S enantiomers were similar across all pHs. CpQ degradation in the presence of hydrogen peroxide at 40 °C was significantly faster, and the extent of increases with pH. Metal ions bind to CpQ and catalyze its hydrolysis in the order Fe3+ > Fe2+ > Mg2+ > Mn2+ > Ti3+ > Sr2+ > Zn2+, with a rate enhancement of ≤1 order of magnitude at the studied pH values of 1 and 5. There was no buffer catalysis observed in the hydrolysis of the studied compound for maleate and phosphate but significant buffer catalysis in the case of citrate and malate.

Optimization of pharmacokinetic properties by modification of a carbazole-based cannabinoid receptor subtype 2 (CB2) ligand

Recently, the development of the fluorinated PET tracer [18F]1a for imaging of CB2 receptors in the central nervous system was reported. [18F]1a showed high CB2 affinity and selectivity over the CB1 subtype, but rapid biotransformation in mice. In addition to the amide hydrolysis, oxidative N-dealkylation and carbazole oxidation were postulated as main metabolic pathways. Based on these results, novel carbazole derivatives with additional 6-substituents (23a, 24a), modified hydrogenation state (26a) and enlarged fluoroalkyl substituent (13a, 13b) were synthesized and pharmacologically evaluated. The key step in the synthesis of substituted carbazoles 23a, 24a and 26a was a Fischer indole synthesis. Nucleophilic substitution of tosylated lactate 5 by carbazole anion provided the fluoroisopropyl derivatives 13a and 13b. Partial hydrogenation of the aromatic carbazole system (26a) was not tolerated by the CB2 receptor. A methylsulfonyl moiety in 6-position (24a) led to considerably reduced CB2 affinity, whereas a 6-methoxy moiety (23a) was well tolerated. An additional methyl moiety in the fluoroethyl side chain of 1a resulted in fluoroisopropyl derivatives 13 with unchanged high CB2 affinity and CB2: CB1 selectivity. Compared with the fluoroethyl derivative 1a, the carbazole N-atom of the fluoroisopropyl derivative 13a (Ki(CB2) = 2.9 nM) is better shielded against the attack of CYP enzymes as formation of N-oxides was not observed and N-dealkylation took place to a less amount.

Synthesis and Profiling of a Novel Potent Selective Inhibitor of CHK1 Kinase Possessing Unusual N-trifluoromethylpyrazole Pharmacophore Resistant to Metabolic N-dealkylation.

Checkpoint-mediated dependency of tumor cells can be deployed to selectively kill them without substantial toxicity to normal cells. Specifically, loss of CHK1, a serine threonine kinase involved in the surveillance of the G2-M checkpoint in the presence of replication stress inflicted by DNA-damaging drugs, has been reported to dramatically influence the viability of tumor cells. CHK1's pivotal role in maintaining genomic stability offers attractive opportunity for increasing the selectivity, effectivity, and reduced toxicity of chemotherapy. Some recently identified CHK1 inhibitors entered clinical trials in combination with DNA antimetabolites. Herein, we report synthesis and profiling of MU380, a nontrivial analogue of clinically profiled compound SCH900776 possessing the highly unusual N-trifluoromethylpyrazole motif, which was envisioned not to undergo metabolic oxidative dealkylation and thereby provide greater robustness to the compound. MU380 is a selective and potent inhibitor of CHK1 which sensitizes a variety of tumor cell lines to hydroxyurea or gemcitabine up to 10 times. MU380 shows extended inhibitory effects in cells, and unlike SCH900776, does not undergo in vivo N-dealkylation to the significantly less selective metabolite. Compared with SCH900776, MU380 in combination with GEM causes higher accumulation of DNA damage in tumor cells and subsequent enhanced cell death, and is more efficacious in the A2780 xenograft mouse model. Overall, MU380 represents a novel state-of-the-art CHK1 inhibitor with high potency, selectivity, and improved metabolic robustness to oxidative N-dealkylation. Mol Cancer Ther; 16(9); 1831-42. ©2017 AACR.

Synthesis of N-unsubstituted 1,2,3-triazoles via aerobic oxidative N-dealkylation using copper(II) acetate

A copper-catalyzed aerobic oxidative CN bond cleavage reaction was developed for the synthesis of 4-substituted-NH-1,2,3-triazoles. Diverse β-ketotriazoles derivatives, which are the starting materials for the aerobic oxidative CN bond cleavage reaction, were prepared from nine aryl and seven alkyl alkynes and α-azidoacetophenone by a copper(I)-catalyzed [3 + 2]cycloaddition reaction. The aerobic oxidation of α-(1,2,3-triazol-1-yl)acetophenones using a catalytic amount of copper(II) acetate in the presence oxygen under neutral conditions gave the title compounds in high yield.

Experimental and mechanistic insights into copper(ii)-dioxygen catalyzed oxidative N-dealkylation of N-(2-pyridylmethyl)phenylamine and its derivatives.

A di-(2-pyridylmethyl)phenylamine ((PyCH2)2NPh) supported Cu(ii)/O2 catalytic system was explored with the synthesis of pyridylmethyl-based compounds of carboxylate (PyCOOH), amide (PyC(O)NHPh), and imine (PyCH[double bond, length as m-dash]NPh) from the oxidative N-dealkylation of N-(2-pyridylmethyl)phenylamine (PyCH2NHPh) and its derivatives, by means of controlling the addition of a base and/or water to the reaction system under a dioxygen atmosphere at room temperature. Experimental studies showed that the imine and amide species could be precursors in succession in the way to the final oxidation state of carboxylates. A cyclic catalytic mechanism was proposed including the base triggered C-H bond activation of the 2-pyridylmethyl group (PyCH2-) and the intermolecular Cu-OOH α-hydrogen atom abstraction from the coordinated imine substrate (PyCH[double bond, length as m-dash]NPh).

Oxidative N-Dealkylation of Tertiary Amines with Tetraethylammonium Periodate Catalyzed by Metal Complexes

The oxidative N-dealkylation of tertiary amines, N,N-dimethylaniline and N,N-diethylaniline, catalyzed by some sterically hindered FeIII complexes and tetraethylammonium periodate as oxidant gave the corresponding N-dealkylated and mono-oxygenated products in good yields. The presence of electronegative atoms on the catalyst complexes influenced the product yield. The presence of H-atom abstractor 2,6-di-tert-butyl-4-methylphenol did not influence product formation, thereby suggesting that the reaction proceeded predominantly via a one-electron transfer mechanism rather than via hydrogen abstraction. Tetraethylammonium periodate favoured oxygen transfer to the substrate.

Substituted tetraphenyl porphyrin catalyzed oxidative N-dealkylation of tertiary amine using molecular oxygen

Oxidative N-dealkylation of NN-dimethylaniline catalyzed by substituted tetraaryl porphyrin complexes of iron and manganese with molecular oxygen, gave a mixture of dealkylated, monooxygenated and dimerised compounds as products. Presence of substituents on the catalyst effects nature and yield of products formed. One electron transfer route [E T) predominated over H-atom abstraction [HAT] in most of the reactions.

Insight into the deamination mechanism of 6-cyclopropylamino guanosine analogs for anti-HIV drug design

Deamination is a crucial step in the transformation of 6-cyclopropylamino guanosine prodrug to its active form. A convenient method using capillary electrophoresis (CE) without sample labeling was developed to analyze the deamination of a series of d-/l-6-cyclopropylamino guanosine analogs by mouse liver homogenate, mouse liver microsome, and adenosine deaminase (ADA). A two-step process involving a 6-amino guanosine intermediate formed by oxidative N-dealkylation was demonstrated in the metabolism of 6-cyclopropylamino guanosine to 6-hydroxy guanosine. The results indicated that the transformation rates of different prodrugs to the active form varied greatly, which were closely correlated with the configuration of nucleosides and the structure of glycosyl groups. Most importantly, d-form analogs were metabolized much faster than their l-counterparts, thus clearly pointed out that compared to guanine, modification of glycosyl part might be a better choice for the development of L-guanosine analogs for the treatment of HIV.

Amine oxidative N-dealkylation via cupric hydroperoxide Cu-OOH homolytic cleavage followed by site-specific fenton chemistry.

Copper(II) hydroperoxide species are significant intermediates in processes such as fuel cells and (bio)chemical oxidations, all involving stepwise reduction of molecular oxygen. We previously reported a Cu(II)-OOH species that performs oxidative N-dealkylation on a dibenzylamino group that is appended to the 6-position of a pyridyl donor of a tripodal tetradentate ligand. To obtain insights into the mechanism of this process, reaction kinetics and products were determined employing ligand substrates with various para-substituent dibenzyl pairs (-H,-H; -H,-Cl; -H,-OMe, and -Cl,-OMe), or with partially or fully deuterated dibenzyl N-(CH2Ph)2 moieties. A series of ligand-copper(II) bis-perchlorate complexes were synthesized, characterized, and the X-ray structures of the -H,-OMe analogue were determined. The corresponding metastable Cu(II)-OOH species were generated by addition of H2O2/base in acetone at -90 °C. These convert (t1/2 ≈ 53 s) to oxidatively N-dealkylated products, producing para-substituted benzaldehydes. Based on the experimental observations and supporting DFT calculations, a reaction mechanism involving dibenzylamine H-atom abstraction or electron-transfer oxidation by the Cu(II)-OOH entity could be ruled out. It is concluded that the chemistry proceeds by rate limiting Cu-O homolytic cleavage of the Cu(II)-(OOH) species, followed by site-specific copper Fenton chemistry. As a process of broad interest in copper as well as iron oxidative (bio)chemistries, a detailed computational analysis was performed, indicating that a Cu(I)OOH species undergoes O-O homolytic cleavage to yield a hydroxyl radical and Cu(II)OH rather than heterolytic cleavage to yield water and a Cu(II)-O(•-) species.

(E)-α,β-unsaturated amides from tertiary amines, olefins and CO via Pd/Cu-catalyzed aerobic oxidative N-dealkylation.

A novel Pd/Cu-catalyzed chemoselective aerobic oxidative N-dealkylation/carbonylation reaction has been developed. Tertiary amines are utilized as a "reservoir" of "active" secondary amines in this transformation, which inhibits the formation of undesired by-products and the deactivation of the catalysts. This protocol allows for an efficient and straightforward construction of synthetically useful and bioactive (E)-α,β-unsaturated amide derivatives from easily available tertiary amines, olefins and CO.

Aerobic oxidative N-dealkylation of secondary amines in aqueous solution catalyzed by rhodium porphyrins

N-dealkylation demonstrates an important biochemical oxidation reaction by cytochrome P450 and other monooxygenases. In this article, catalytic oxidative N-dealkylation of secondary amines was achieved using rhodium(III) tetra (p-sulfonato-phenyl) porphyrin (( TSPP ) Rh III ) in aqueous solution with oxygen as the sole oxidant. Addition of benzaldehyde to trap primary amine product inhibited catalyst deactivation and dramatically increased reaction turnover numbers (TONs). Substrate scope examination suggested the reaction was performed with a preference for bulkier secondary amines. Kinetic study exhibited first-order kinetics with regard of ( TSPP ) Rh III catalyst. Results from the Hammett study gave a ρ value of -1.38, suggesting formation of an iminium ion intermediate in the rate determining step.

Unraveling the origins of catalyst degradation in non-heme iron-based alkane oxidation.

A series of potentially tetradentate and pentadentate ligands modelled on BPMEN has been prepared and their iron(II) bis(triflate) complexes have been isolated and characterised by spectroscopic and crystallographic techniques (BPMEN = N,N'-bis(pyridylmethyl)ethylenediamine). Changes to the BPMEN ligand have invariably led to complexes with different coordination modes or geometries and with inferior catalytic efficiencies for the oxidation of cyclohexane with H2O2. The reaction of an iron(II) complex containing a pentadentate BPMEN-type ligand with O2 has resulted in ligand degradation via oxidative N-dealkylation and the isolation of a bis(hydroxo)-bridged dinuclear iron(III) complex with a picolinate-type ligand.

Access to a Cu(II)-O-Cu(II) motif: spectroscopic properties, solution structure, and reactivity.

We report a complex with a rare Cu(II)-O-Cu(II) structural motif that is stable at room temperature, which allows its in-depth characterization by a variety of spectroscopic methods. Interest in such compounds is fueled by the recent discovery that a Cu(II)-O-Cu(II) species on the surface of Cu-ZSM-5 is capable of oxidizing methane to methanol, and this in turn ties into mechanistic discussions on the methane oxidation at the dicopper site within the particulate methane monooxygenase. For the synthesis of our Cu2O complex we have developed a novel, neutral ligand system, FurNeu, exhibiting two N-(N',N'-dimethylaminoethyl)(2-pyridylmethyl)amino binding pockets connected by a dibenzofuran spacer. The reaction of FurNeu with CuCl yielded [FurNeu](Cu2(μ-Cl))(CuCl2), 1, demonstrating the geometric potential of the ligand to stabilize Cu-X-Cu moieties. A Cu(I) precursor with weakly coordinating anions was chosen in the next step, namely [Cu(NCCH3)4]OTf, which led to the formation of [FurNeu](Cu(NCCH3))2(OTf)2, 3. Treatment of 3 with O2 or PhIO led to identical green solutions, whose UV-vis spectra were markedly different from the one displayed by [FurNeu](Cu)2(OTf)4, 4, prepared independently from FurNeu and Cu(OTf)2. Further investigations including PhIO consumption experiments, NMR and UV-vis spectroscopy, HR-ESI mass spectrometry, and protonation studies led to the identification of the green product as [FurNeu](Cu2(μ-O))(OTf)2, 5. DOSY NMR spectroscopy confirmed its monomeric character. Over longer periods of time 5 decomposes to give [Cu(picoloyl)2], formed through an oxidative N-dealkylation reaction followed by further oxidation of the ligand. Due to its slow decomposition reaction, all attempts to crystallize 5 failed. However, its structure in solution could be determined by EXAFS analysis in combination with DFT calculations, which revealed a Cu-O-Cu angle that amounts to 105.17°. Moreover, TDDFT calculations helped to rationalize the UV-vis absorptions of 5. The reactivity of complex 5 with 2,4-di-tert-butylphenol, DTBP, was also investigated; the initially formed biphenol product, TBBP, was found to further react in the presence of excessive O2 to yield 2,4,7,9-tetra-tert-butyloxepino[2,3-b]benzofuran, TBOBF, via an intermediate diphenoquinone. It turned out that 5, or its precursor 3, can even be employed as a catalyst for the oxidation of DTBP to TBBP or for the oxidation of TBBP to TBOBF.