Oxidation Of Tertiary Amines Research Articles

Synthesis of spiroindolenines through a one-pot multistep process mediated by visible light.

Spiro-heterocyclic indolenines are privileged scaffolds widely present in numerous indole alkaloids. Here, we develop a novel approach for the one-pot multistep synthesis of different spiro[indole-isoquinolines]. The protocol proposed involves the visible light mediated oxidation of N-aryl tertiary amines using bromochloroform with the generation of a reactive iminium species, which reacts with an isocyanide and an electron-rich aniline in a three-component Ugi-type reaction to give an α-aminoamidine. This compound might undergo an additional visible light-mediated oxidation to furnish a second iminium intermediate, which acts as electrophile in an intramolecular electrophilic aromatic substitution giving the final spiro-indolenine. The scope of the process has been investigated with respect to all three components. Simple operations, mild conditions, and good yields make this strategy a convenient and sustainable way to obtain novel spiro-indolenine derivatives.

Asymmetric N-oxidation catalyzed by bisguanidinium dinuclear oxodiperoxomolybdosulfate

N-oxides play a pivotal role in natural products and emerging drug design, while also serving as valuable ligand scaffolds in organometallic chemistry. Among heteroatom oxidations, the conversion of amines to N-oxides is a critical and challenging facet. We present here a highly enantioselective N-oxidation methodology for both cyclic and acyclic amines. The method employs an ion-pair catalyst comprising a chiral bisguanidinium [BG]2+ cation and an achiral oxodiperoxomolybdosulfate anion [(µ-SO4)2Mo2O2(µ-O2)2(O2)2]2-. Notably, the bisguanidinium cation undergoes modification through silyl group incorporation and is elucidated by X-ray crystallography. Our findings underscore the crucial role of the side chain in the determination of the chiral pocket size, allowing for the oxidation of diverse tertiary amines with enantioselectivities. Comprehensive mechanistic investigations are conducted to explain the catalytic system’s efficacy in achieving dynamic kinetic resolution (DKR) with high efficiency.

Diastereoselective [3 + 2] Cycloaddition between Tertiary Amine N-Oxides and Substituted Alkenes to Access 7-Azanorbornanes.

We have developed a diastereoselective synthesis of 43 novel 7-azanorbornanes using tertiary amine N-oxides and substituted alkenes. Our method uses an efficient [3 + 2] cycloaddition, starting from either commercially available or easily accessible precursors to generate yields up to 97% and diastereomeric ratios up to >20:1. Density functional theory (DFT) calculations were performed, suggesting that the observed diastereoselectivity is likely due to steric considerations.

Novel chromatic reaction based on the redox reaction between tertiary aromatic amines and gold(Ⅲ) or cerium(Ⅳ)

Abstract Herein, a novel chromatic reaction based on the oxidative self-coupling of tertiary aromatic amines and driven by a redox reaction with gold(III) or cerium(IV) is developed. The dimers resulting from the oxidation of tertiary aromatic amines with gold(III) or cerium(IV) show colors depending on their chemical structures. Substituting a hydrogen atom on the aromatic ring with a methyl or methoxy group induces a bathochromic shift in the color developed via oxidation. This redox reaction is highly selective for gold(III) and cerium(IV) because of their high redox potentials and complexation abilities with tertiary aromatic amines, thus suggesting the development of a selective analytical method for gold(III) and cerium(IV). Cyclic voltammograms and ultraviolet–visible light absorption spectra confirm that the oxidative coupling of tertiary aromatic amines develops color. The addition of reductants, such as l-ascorbic acid, degrades the color of the resultant colored species, thus indicating that the quinoid structure of the colored species caused color development. Thus, the developed redox reaction of tertiary aromatic amines with gold(III) or cerium(IV) provides a new chromogenic platform for determining gold(III), cerium(IV), and ascorbic acid.

Synthesis of Aromatic N-Oxides Using Electrochemically Generated Peroxodicarbonate.

Electrochemically generated green platform oxidizers like peroxodicarbonate (PODIC) constitute a game-changing technology in terms of sustainable chemistry while serving as an alternative counterreaction in the electrochemical hydrogen evolution. Peroxodicarbonate avoids the storage and shipping of concentrated hydrogen peroxide solution. We herein disclose an efficient method for the N-oxidation of quinolines, pyridines, and complex tertiary amines. The use of phenoyloxy succinimide (POSI) is the decisive factor for obtaining N-oxides (28 examples) in isolated yields of up to 98%.

Synthesis of a trivalent copper complex for efficient degradation of antibiotic ofloxacin

Copper-based catalysts have been widely used in heterogeneous advanced oxidation processes (AOPs) to degrade emerging contaminants, with trivalent copper species (Cu(III)) often identified as crucial intermediates. However, the current understanding of the reactivity and potential oxidation mechanism associated with such reactive species remains quite limited. In the present study, a stable Cu(III) complex was synthesized, and its reactivity towards a typical fluoroquinolone antibiotic, ofloxacin (OFX), was comprehensively investigated. The results revealed that Cu(III) itself functioned as the primary oxidizing agent instead of secondary hydroxyl radicals generated during OFX decomposition, which exhibited high reactivity over a wide pH range (3.0–9.0) with molar ratio of Cu(III) to OFX between 1:2 and 3:1. Interestingly, prevalent constituents of natural water, including (bi)carbonate (0–10 mM), chloride (0–10 mM), nitrate (0–10 mM) and humic acid (0–30 mg/L), displayed minimal influence on the oxidation efficiency of Cu(III). Piperazine moiety was identified as the primary reaction site, and three different pathways including tertiary amine oxidation, hydroxylation, and N-demethylation process were proposed. The detailed oxidation mechanisms were further illustrated by density functional theory (DFT) calculations. This study contributes to the theoretical foundation for investigating the mechanism of Cu(III)-mediated oxidation of antibiotics.

Mechanistic Studies on Oxygen-Insertion into Osmium(III)–Carbon Bond via High-Valent Oxido-Osmium(V) Complex

Abstract An osmium(III)-metalacycle complex consisting of 2-phenylpyridine is converted to the 2-phenoxidopyridine-osmium(III) complex upon treatment with a tertiary amine N-oxide, where a high-valent oxido-osmium(V) complex is proposed as a key reactive intermediate (H. Sugimoto et al. Organometallics, 2021, 40, 102–106). To gain insight into the reaction mechanism, substituent effects of 2-phenylpyridine moiety on the oxygen atom insertion reaction are examined using a series of 2-(4-X-phenyl)pyridines. All the cyclometalated complexes react with the tertiary amine N-oxide to produce the phenoxido-osmium(III) complexes. Kinetic analyses are conducted on the adduct formation process and the oxygen insertion reaction. In the former process, the binding constant of the amine N-oxide to the osmium(III) center is not influenced by electron withdrawing nature of the substituent X, but decrease of the reaction rate is observed in the latter process as electron withdrawing nature of X increases. Furthermore, the electronic effects of the amine N-oxides are examined using p-substituted N,N-dimethylaniline N-oxide (p-Y-C6H4N(O)(Me)2) to find that reaction rates increase as the electron withdrawing nature of Y increases. These results are consistent with the proposed mechanism in which the C–O bond formation involves conversion of the osmium(III)-N-oxide adduct to its oxido-osmium(V) species as the active oxidant.

Tertiary amine oxides as perovskite nanocrystal ligands and components of polymeric nanocomposites

AbstractAs a class of semiconductor nanocrystals that exhibit high photoluminescence quantum yield (PLQY) at tunable wavelengths, perovskite nanocrystals (PNCs) are attractive candidates for optoelectronic and light‐emitting devices. However, attempts to optimize PNC integration into such applications suffer from PNC instability and loss of PL over time. Here, we describe the impact of organic and polymeric N‐oxides when used in conjunction with PNCs, whereby a significant increase in PNC quantum yield is observed in solution, and stable PL emission is obtained in polymeric nanocomposites. Specifically, when using aliphatic N‐oxides in ligand exchange with CsPbBr3 PNCs in solution, a substantial boost in PNC brightness is observed (~40% or more PLQY increase), followed by an alteration of the perovskite chemistry. When N‐oxide substituents are positioned pendent to a poly(n‐butyl methacrylate) backbone, the optically clear flexible nanocomposite films obtained have bright PL emission and maintain optical clarity for months. X‐ray diffraction is useful for characterizing the PNC crystalline structure following exposure to aliphatic N‐oxides, while electron microscopy (EM) and small‐angle X‐ray scattering (SAXS) measurements of the PNC‐polymer nanocomposites show this polymeric N‐oxide platform to cleanly disperse PNCs in flexible polymer films.

Insights into electrogenerated intermediates and rapid screening of electrochemical reactions by surface-modified carbon fiber paper redox spray ionization mass spectrometry

The combination of electrochemistry and mass spectrometry is a powerful analytical tool for studying redox reaction mechanisms and identifying products or intermediates. However, the previously reported devices all require bespoke fabrication and are too complicated to be assembled and used by others. Crucially, the long ion transport distance and small spray volumes make it difficult to capture the short-lived intermediates. We present a practical mass spectrometric method in which surface-modified carbon fiber paper is innovatively applied to detect electrogenerated intermediates. Treating carbon fiber paper with dilute nitric acid removes its surface impurities, enhancing the capability of electro-redox. Electrospray ionization and redox reaction occur simultaneously on the tip of the paper. Transient electro-redox species generate and transfer into gas phase as soon as the appearance of spray. Rapid transport of quantities of electrogenerated ions to the mass spectrometer inlet makes it possible for mass spectrometric identification on the millisecond scale. The short-lived radical cations and iminium ions were successfully captured, reflecting the starting step of the cross-dehydrogenation coupling reaction. The real-time oxidation and online functionalization reactions of tertiary amines were achieved using this device without additional oxidants and electrolytes. In this way we could achieve in-depth mechanistic understanding and rapid screening of serial reactions.

An Overview of α‐Aminoalkyl Radical Mediated Halogen‐Atom Transfer

AbstractThe merging of photocatalysis with halogen‐atom transfer (XAT) processes has proven to be a versatile tool for the generation of carbon‐centered radicals in organic synthesis. XAT processes are unique in that they generate radicals without requiring the use of strong reductants necessary for the traditional single electron transfer (SET) activation of halides. Pathways to achieve XAT in synthetic applications can be categorized into three major sections: i) heteroatom‐based activators, ii) metal‐based activators, and iii) carbon‐based activators among which α‐aminoalkyl radicals have taken the center stage. Access to these α‐aminoalkyl radicals as XAT reagents has gained significant attention in the past few years due to the robustness of the reactions, the simplicity of the reagents required, and the broadness of their applications. Generation of these α‐aminoalkyl radicals is simply achieved through the single electron oxidation of tertiary amines, which after deprotonation at the α‐position generates the α‐aminoalkyl radicals. Due to the wide scope of tertiary amines available and the tunable nucleophilicity of α‐aminoalkyl radical formed, this strategy has become an attractive alternative to heteroatom/metal‐based radicals for XAT. In this minireview, we focus our attention on recent (2020–2023) developments and uses of this robust technology to mediate XAT processes.

Tumor permeable self-delivery nanodrug targeting mitochondria for enhanced chemotherapy

Drug self-delivery systems (DSDSs) have been extensively exploited to enhance drug loading capacity and avoid excipient-related toxicity issues. However, deficient tumor targeting, inferior tumor permeability, prominent burst release, and nonspecific subcellular distribution remain major obstacles. Herein, we reported a ROS-responsive amphiphilic prodrug (CPT-S-NO) synthesized by the conjugation of zwitterionic tertiary amine-oxide (TAO) moiety and hydrophobic camptothecin (CPT) through a thioether linkage, which formed a nanoparticulate DSDS in an aqueous solution. CPT-S-NO, compared with CPT-11 and the water-soluble TAO-modified CPT prodrug (CPT-NO), exhibited prolonged blood circulation, enhanced tumor accumulation, deep tumor penetration, efficient mitochondrial targeting, and ROS-activated drug release to induce mitochondrial dysfunction, corporately conducing to the superior antitumor efficacy in vivo. This TAO decoration strategy promises potential applications in designing multipotent DSDSs for various drugs.

3 + 2] Cycloadditions of Tertiary Amine N-Oxides and Silyl Imines as an Innovative Route to 1,2-Diamines.

We have developed a one-pot synthetic method for producing 1,2-diamines from easily prepared and commercially available precursors through a formal umpolung process. Our method utilizes an efficient [3 + 2] cycloaddition as the key step in forming substituted 1,2-diamines in moderate to high yields. These resulting compounds can undergo subsequent transformations, demonstrating their utility as synthetic building blocks for more complex scaffolds. Finally, we propose a reasonable mechanism for this transformation using density functional theory modeling, justifying the experimental observations.

Screening of Zwitterionic Liposomes with Red Blood Cell‐Hitchhiking and Tumor Cell‐Active Transporting Capability for Efficient Tumor Entrance

AbstractThe active transport of nanoparticles into the solid tumor through cell transcytosis has shown great promise in cancer nanomedicine, but it is challenging to develop efficient active transporting nanomedicines with the potential for clinical translation. Here, a type of tertiary amine oxide (TAO)‐containing zwitterionic liposomal nanocarriers is developed that can hitchhike red blood cells (RBCs) to tumor blood vessels and enter solid tumors through transcytosis. To boost the active‐transporting capability, a library of the TAO liposomes (TAOLs) with different chemical structures and particle sizes is constructed and screened by their stability and active transporting capability. Two types of TAOLs are identified that can induce efficient tumor cell transcytosis through rapid macropinocytosis and endoplasmic reticulum/Golgi‐involved exocytosis. It is found that these zwitterionic TAOLs can hitchhike RBCs to gain long blood circulation, get off the cell at the tumor site, effectively enter the tumor through transcytosis, and infiltrate the whole tumor. The chemotherapeutic drug‐loaded liposomes can stop the tumor progression of mice bearing human hepatocellular carcinoma HepG2 cells, exhibiting superior antitumor activity compared to the traditional liposomal drug. This study demonstrates a strategy to construct effective active transporting liposomal nanomedicines for efficient tumor entrance.

Oxidative cyanation of tertiary amines for facile synthesis of tetrahydroisoquinolines with quaternary centers

A facile and efficient synthesis of tetrahydroisoquinolines with quaternary centers has been successfully realized by orchestrating a sequential process consisted of N-bromosuccinimide oxidation and cyanation of tertiary amines. This compatible combination protocol enables one-pot synthesis of α-cyano tetrahydroisoquinolines containing a quaternary center with up to 99% yield.

Amine Oxidation by Electrochemically Generated Peroxodicarbonate

AbstractThe N-oxidation of tertiary amines was achieved by using electrochemically generated peroxodicarbonate solutions as sustainable oxidizers. The presence of EDTA and 2,2,2-trifluoroacetophenone as a mediator was found to be crucial for converting water-insoluble substrates. Various tertiary amines were converted into their corresponding N-oxides in yields of up to 98%. The scope includes economically important surfactants and potential platform oxidizers.

Perovskite as recyclable heterogeneous photocatalyst for synthesis of bis-1,3-dicarbonyl compounds

An efficient and simple synthetic approach has been developed for the synthesis of bis-1,3-dicarbonyl compounds via visible light-mediated oxidation of tertiary amines in the presence of CsPbBr3 perovskite. This heterogeneous photocatalyst exhibits highly catalytic activity and broad applicability to a variety of substrates. It can be recycled by simple centrifugal filtration and reused several times without obvious decrease of activity.

Controlling One- or Two-Electron Oxidation for Selective Amine Functionalization by Alternating Current Frequency.

Here, we report a unique electrosynthetic method that enables the selective one-electron oxidation of tertiary amines to generate α-amino radical intermediates over two-electron oxidation to iminium cations, providing easy access to arylation products by simply applying an optimal alternating current (AC) frequency. More importantly, we have discovered an electrochemical descriptor from cyclic voltammetry studies to predict the optimal AC frequency for various amine substrates, circumventing the time-consuming trial-and-error methods for optimizing reaction conditions. This new development in AC electrolysis provides an alternative strategy to solving challenging chemoselectivity problems in synthetic organic chemistry.

A Facile Oxidation of Tertiary Amines to Lactams by Using Sodium Chlorite: Process Improvement by Precise pH Adjustment with CO2

AbstractBy using cheap and innocuous sodium chlorite, a series of tertiary amines have been oxidized to the corresponding lactams with good selectivity and high yield. In this method, neither transition-metal catalyst nor oxidant was used. In the oxidation step, the pH of the sodium chlorite was precisely adjusted to pH around 6 using CO2, such pH is a compromise between oxidative properties, chemical stability, and unwanted precipitation. In addition, buffer salts are not necessary, which allows this oxidation reaction to be performed under safe and environmentally benign conditions.

W/HAP catalysed N-oxidation of tertiary amines with H2O2 as an oxidant.

Synthesis of several N-oxides with tungsten exchanged hydroxyapatite (W/HAP) in the presence of 30% hydrogen peroxide (H2O2) as an oxidant is presented. A process with aqueous H2O2, a cheap and clean oxidant with an active catalyst is developed to reduce waste production and meet the requirements of green chemistry. Several tertiary amines have been efficiently oxidized to their corresponding N-oxides with excellent yields. The as-synthesized catalyst (W/HAP) is characterized using BET, FTIR, SEM, ICP-OES and XRD. Effect of catalyst loading , temperature and oxidants were studied. A kinetic model has been developed to determine the reaction rate at different temperatures and activation energy for the model reaction.Graphical abstractSynopsis. Synthesis of several N-oxides using tungsten exchanged hydroxyapatite (W/HAP) in the presence of 30% hydrogen peroxide (H2O2) as an oxidant is presented. A process with aqueous H2O2, a cheap and clean oxidant with an active catalyst is developed to reduce waste production and meet the requirements of green chemistry. Supplementary InformationThe online version contains supplementary material available at 10.1007/s12039-022-02038-0.

Flavin-Dependent Monooxygenase-Mediated 1,2-Oxazine Construction via Meisenheimer Rearrangement in the Biosynthesis of Paeciloxazine.

The [1,2]-Meisenheimer rearrangement is well known as the [1,2]-migration of an O-substituted hydroxylamine from a tertiary amine N-oxide, and it is frequently employed in organic synthesis to enforce adjacent carbon oxidation or install a 1,2-oxazine core, which is a prevalent structural feature and pharmacophore of many bioactive natural products. Although the [1,2]-Meisenheimer rearrangement was proposed to occur in the biosynthesis of a number of 1,2-oxazine-containing natural products, it has never been proved biosynthetically. Here, we identified the biosynthetic gene cluster of an insecticidal natural product, paeciloxazine (1), from Penicillium janthinellum and characterized a flavin-dependent monooxygenase, PaxA, as the first example that mediates the formation of a 1,2-oxazine moiety via Meisenheimer rearrangement. In vitro biochemical assays, site-directed mutations, docking and molecular dynamics simulations, and density functional theory calculations support the mechanism that PaxA first catalyzes N-oxidation to form an N-oxide intermediate, which undergoes [1,2]-Meisenheimer rearrangement with the assistance of an amino acid with proton transfer property. This study expands the repertoire of rearrangement reactions during the biosynthesis of natural products and provides a new strategy for discovering natural products with N-O tethers by genome mining.