Pyridine N-oxide Research Articles

Inhibition of Kornblum Reaction with Lithium Salts in SN2 Reactions of Sulfonates and a Nucleophile Containing a Pyridine N-Oxide Moiety: Convergent and Selective Synthesis of an MRGPRX2 Antagonist.

A critical step in the development of a convergent synthesis of an MRGPRX2 antagonist (1) was the SN2 reaction with a highly functionalized lactamide electrophile and a unique difluoropiperidine nucleophile containing a pyridine N-oxide moiety. Initial reactions with sulfonate leaving groups exhibited superb stereoselectivity, but yields were very low due to side reactions originated from competitive Kornblum reactions of the pyridine N-oxide and the sulfonates. Markedly improved reaction profiles were achieved by including stoichiometric lithium triflate. NMR data provided insights into how the lithium cation impacted the pyridine N-oxide through coordination and attenuating its nucleophilicity, leading to the inhibition of the undesired Kornblum reactions. Our approach is highly relevant to preservation of the N-oxide, a structural motif known to several marketed products and emerging as an important class in drug discovery in nucleophilic substitutions. Application of this method enabled the production of the target (1 and its HCl salt 1a) up to multikilogram scale with high selectivity and in much improved yield.

Photoinduced Copper-Catalyzed Cross-Coupling of Acylsilanes with Heteroarenes via Bimetallic Relay.

The transition metal-catalyzed direct coupling reactions involving electron-rich Fischer carbene species are largely underdeveloped and remain a big challenge. Here, a direct coupling reaction of azoles and azine N-oxides is reported with Fischer copper carbene species bearing an α-siloxy group i, which can be in situ generated from acylsilanes catalytically under photoirradiation and redox-neutral conditions. This coupling reaction between electron-rich α-siloxy Fischer Cu-carbene species with hard carbanion nucleophiles may undergo a bimetallic relay process, which is confirmed by the kinetic analysis and in situ NMR analysis. This reaction features mild conditions and remarkable heterocycle compatibility. Notably, this protocol tolerates a series of azole or azine N-oxide derivatives, including benzoxazole, benzothiazole, benzoimidazole, benzoisoxazole, oxazole, oxadiazole, triazolo[4,3-a]pyridine, purine, caffeine, pyridine N-oxide, quinoline N-oxide, pyrazine N-oxide, pyridazine N-oxide, etc. The synthetic value of this approach is demonstrated by the efficient synthesis of a histamine h4 receptor ligand and a marketed drug carbinoxamine.

N-Oxide Coordination to Mn(III) Chloride.

We report on the synthesis and characterization of Mn(III) chloride (MnIIICl3) complexes coordinated with N-oxide ylide ligands, namely trimethyl-N-oxide (Me3NO) and pyridine-N-oxide (PyNO). The compounds are reactive and, while isolable in the solid-state at room temperature, readily decompose into Mn(II). For example, "[MnIIICl3(ONMe3)n]" decomposes into the 2D polymeric network compound complex salt [MnII(µ-Cl)3MnII(µ-ONMe3)]n[MnII(µ-Cl)3]n·(Me3NO·HCl)3n (4). The reaction of MnIIICl3 with PyNO forms varied Mn(III) compounds with PyNO coordination and these react with hexamethylbenzene (HMB) to form the chlorinated organic product 1-cloromethyl-2,3,4,5,6-pentamethylbenzene (8). In contrast to N-oxide coordination to Mn(III), the reaction between [MnIIICl3(OPPh3)2] and 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) resulted in electron transfer-forming d5 manganate of the [TEMPO] cation instead of TEMPO-Mn(III) adducts. The reactivity affected by N-oxide coordination is discussed through comparisons with other L-MnIIICl3 complexes within the context of reduction potential.

Recent Advances in Synthetic Methods by Photocatalytic Single-Electron Transfer Chemistry of Pyridine N-Oxides.

By adoption of the enabling technology of modern photoredox catalysis and photochemistry, the generation of reactive and versatile pyridine N-oxy radicals can be facilely achieved from single-electron oxidation of pyridine N-oxides. This Synopsis highlights recent methodologies mediated by pyridine N-oxy radicals in developing (1) pyridine N-oxide-based hydrogen atom transfer catalysts for C(sp3)-H functionalizations and (2) β-oxyvinyl radical-mediated cascade reactions. In addition, recent research revealed that direct photoexcitation of pyridine N-oxides allowed for the generation of alkyl carbon radicals from alkylboronic acids.

C3 Selective Hydroxylation of Pyridines via Photochemical Valence Isomerization of Pyridine N-Oxides.

The C-H hydroxylation of the pyridine C3 position is a highly desirable transformation but remains a great challenge due to the inherent electronic properties of this heterocycle core which bring difficulties in chemical reactivity and regioselectivity. Herein we present an efficient method for formal C3 selective hydroxylation of pyridines via photochemical valence isomerization of pyridine N-oxides. This metal-free transformation features operational simplicity and compatibility with a diverse array of functional groups, and the resulting hydroxylated products are amenable to further elaboration to synthetically useful building blocks. The synthetic utility of this strategy is further demonstrated in the effective late-stage functionalization of pyridine-containing medicinally relevant molecules and versatile derivatizations of 3-pyridinols.

Is There an Adduct of Pyridine N-Oxide and Boron Trifluoride in the Gaseous State? Gas Electron Diffraction vs Mass Spectrometry.

A study of saturated vapor over the pyridine N-oxide-boron trifluoride (PyO-BF3) adduct was carried out at T = 448(5) K by a synchronous gas electron diffraction/mass spectrometry (GED/MS) experiment. Due to the absence of ions in the mass spectrum, indicating the presence of a structure with an O-B dative bond, several models of vapor composition were tested by the GED method. It was found that the dominant molecular form (up to 100%) in vapor is the PyO-BF3 adduct. Using the DFT/M06-2X/aug-cc-pVTZ method, geometric optimization of the molecular ion [PyO-BF3]+ was carried out, which showed its intrinsic instability and dissociation into a [PyO]+ cation and a BF3 molecule. This study certainly demonstrates the significant advantage of the GED method to determine the qualitative and quantitative gas-phase composition of dative-bonded adducts and other noncovalent complexes as well, whereas the interpretation of mass spectra may be ambiguous due to the possible intrinsic instability of ions containing a dative bond. The nature of the O-B bond is discussed in terms of the natural bond orbitals (NBOs) and the quantum theory of atoms in molecules (QTAIM). A comparison of structural and energetic parameters for PyO-BF3 and the previously studied BF3 adducts allows the theoretical comprehension of the nature of the O-B bond to be extended and to explain the different thermal stabilities of these compounds.

Neutral guest binding by meso‑3,5-bis(trifluoromethyl)phenyl two-wall calix[4]pyrrole: N-oxide recognition features and unique acetonitrile binding mode

Two-wall calix[4]pyrroles bearing two aryl substituents at diametrically opposed meso-positions have been well explored toward the recognition and sensing of anionic substrates. However, their ability to form stable complexes with neutral guests remains underexplored. Herein, we report the heterocyclic N-oxides (such as pyridine N-oxide (PNO), 4-methylpyridine N-oxide (MPNO), and 4-phenylpyridine N-oxide (PPNO)) binding features of meso-3,5-bis(trifluoromethyl)phenyl two-wall calix[4]pyrrole 1. Single crystal X-ray diffraction analysis of the PNO complex of 1 revealed the formation of two types of closely resembled 1/1 complexes within the same crystal, wherein the calix[4]pyrrole core adopted a cone-like conformation and the PNO was bound to the cleft delineated by two aromatic walls adopting pseudo-edge-to-face (PETF) geometry. MPNO formed only one type of 1/1 complex with receptor 1 having PETF geometry in the solid state. Solution phase interaction of 1 with PNO, MPNO, and PPNO was investigated by 1H NMR spectroscopic titrations carried out in CD3CN. On the other hand, X-ray diffraction analysis of single crystals of 1, grown from CH3CN solution, unveiled the formation of a 1/2 host-acetonitrile solvate containing an unstable arrangement of CH3CN dimer displaying a unique CH3CN coordination mode in the solid state. Furthermore, a unique 1D supramolecular chain of CH3CN was stabilized within the narrow channel in the crystal lattice of 1•(CH3CN)2.

Fe-Catalyzed Fluoroalkyl(hetero)arylation of Vinyl Azaarenes: Rapid and Modular Synthesis of Unsymmetrical 1,1-Bis(hetero)arylalkanes.

In contrast to transition-metal-catalyzed difunctionalization of activated alkenes, selective alkylarylation of vinyl azaarenes is underdeveloped. Consequently, the lack of modular and rapid syntheses of 1,1-bis(hetero)arylalkanes limits their exploration in medicinal chemistry. Herein we report a protocol using commercially available iron salts, bisphosphine ligands, fluoroalkyl halides, and Grignard reagents that enables the selective 1,2-fluoroalkyl(hetero)arylation of vinyl azaarenes. We demonstrate the versatility and robustness of the method through the selective synthesis of a range of unsymmetrical 1,1-bis(hetero)arylalkenes, including pyridine N-oxides, triazoles, pyrazines, carbazoles, indazoles, and 1,2-azaborines. Mechanistic insights from experimental and computational investigations support a radical pathway and provide insights into the role of non-covalent interactions in iron catalysis.

A Promising Approach to Target Colorectal Cancer Using Hybrid Triarylmethanes.

Aiming to create an innovative series of anti-colorectal cancer agents, we designed in this work hybrid triarylmethane compounds. Three hybrid triarylmethanes and their corresponding N-oxide analogues were successfully synthesized using an efficient procedure that involved connecting two triarylmethane molecules, through mono-, bi-, and triethylene glycol fragments. In our pursuit to develop more soluble molecules, we synthesized a hybrid triarylmethane featuring a lysine-based spacer through a convergent strategy involving 7 steps. All hybrid compounds were assessed for their antiproliferative activity on human HT-29 and HCT116 colorectal cancer (CRC) cell lines. Three pyridine N-oxide analogs demonstrated notable antiproliferative potential among the set of tested compounds, with IC50 values ranging from 18 to 24 μM on both human CRC cell lines analyzed. A cytotoxicity study conducted on murine fibroblasts revealed that these three active compounds were not toxic at the IC50 values, indicating their suitability for further drug development. A docking study was conducted on two representative compounds, one for each series and protein kinase B (AKT) was identified as a potential target of their in anti-cancer effects. A computational drug-likeness study predicted favourable oral and intestinal absorption efficiency.

Modulation of Electron Push-Pull by Redox Non-Innocent Additives for Long Cycle Life Zinc Anode.

Application of an aqueous Zn-ion battery is plagued by a water-induced hydrogen evolution reaction (HER), resulting in local pH variations and an unstable electrode-electrolyte interface (EEI) with uncontrolled Zn plating and side reactions. Here, 4-methyl pyridine N-oxide (PNO) is introduced as a redox non-innocent additive that comprises a hydrophilic bipolar N+-O- ion pair as a coordinating ligand for Zn and a hydrophobic ─CH3 group at the para position of the pyridine ring that reduces water activity at the EEI, thereby enhancing stability. The N+-O- moiety of PNO possesses the unique functionality of an efficient push electron donor and pull electron acceptor, thus maintaining the desired pH during charging/discharging. Intriguingly, replacing ─CH3 (electron pushing +I effect) by ─CF3 group (electron pulling ─I effect), however, does not improve the reversibility; instead, it degrades the cell performance. The electrolyte with 2m ZnSO4 + 15mm PNO enables symmetric cell Zn plating/stripping for a remarkable > 10 000h at 0.5mA cm-2 and exhibits coulombic efficiency (CE) ≈99.61% at 0.8mA cm-2 in Zn/Cu asymmetric cell. This work showcases the immense interplay of the electron push-pull of the additives on the cycling.

Kinetic and Mechanistic Pathway of Electron Transfer Reactions: Pyridine Oxidation by Peroxomonophosphoric Acid in Acidic Aqueous Medium

Abstract: The kinetic and mechanistic pathways of pyridine oxidation by peroxomonophosphate has been studied in an acidic aqueous medium. Reactions of peroxomonophosphoric acid are the least exploited kinetically. This reaction has been attempted to understand the role of oxidation of pyridine and the reactivity pattern of peroxomonophosphate. The reaction has been second order and First-order concerning the oxidant and substrate, respectively. The reaction rate showed a decreasing effect with increasing hydrogen ion concentration. Considering peroxomonophosphate reactions as non-chain reactions and all the results, a feasible mechanism for the reaction has been suggested. The calculated energy of activation and entropy of activation has been observed conventionally to be 80 ± 5 kJ mol-1 and – 45 ± 6 JK-1 mol-1. The oxidation product was pyridine-N-oxide in this reaction.

Designing strategically functionalized hybrid porous polymers with octavinylsilsesquioxane/dibenzo[g,p]chrysene/benzo[c]-1,2,5-thiadiazole units for rapid removal of Rhodamine B dye from water

Because of their large surface area and persistent pores that have exceptional adsorption capabilities, porous organic/inorganic polymers (POIPs) with octavinylsilsesquioxane (OVS) units have attracted much interest recently. In this study aimed at removing Rhodamine B (RhB) from wastewater, we utilized OVS nanoparticles synthesized through the Heck coupling process to produce two distinct types: OVS-DBC-PO and OVS-DBC-BT POIPs. OVS and a variety of chemical compounds containing Br, such as tetrabromodibenzo[g,p]chrysene (DBC-Br4), 2,6-bis(4-bromophenyl)pyridine 1-oxide (PO-Br2), and 4,7-dibromobenzo[c][1,2,5]thiadiazole (BT-Br2) were involved in the reactions. Thermogravimetric analysis (TGA) results revealed that the high thermal decomposition temperature (Td10) of OVS-DBC-PO and OVS-DBC-BT POIPs were 447 °C and 543 °C, respectively. Additionally, the OVS-POIPs demonstrated significant porosity, with the OVS-DBC-BT POIP exhibiting the highest specific BET surface area (SABET) of 386 m2 g−1. OVS-DBC-PO and OVS-DBC-BT POIPs exhibit exceptional porosity character. Based on dye adsorption measurements, RhB interacts with functional groups on the OVS-POIP samples' surface and penetrates their pores, enhancing the number of contact sites and the effectiveness of adsorption. Both OVS-DBC-PO and OVS-DBC-BT POIPs demonstrated maximum adsorption capacities of 65 and 66 mg g−1, respectively, at a pH of 4 and a temperature of 25 °C. As a result, OVS-DBC-PO and OVS-DBC-BT POIP materials could be viewed as efficient absorbents for removing RhB from aqueous solutions and this study presents a novel way of making POIPs, which are adsorbents used in the filtration and treatment of water.

The Geometry and Nature of C─I···O─N Interactions in Perfluoroiodobenzene-Pyridine N-oxide Halogen-Bonded Complexes.

The N─Oxide oxygen in the 111 C─I···⁻O─N+ halogen bond (XB) complexes, formed by five perfluoroiodobenzene XB donors and 32 pyridine N-oxides (PyNO) XB acceptors, exhibits three XB modes: bidentate, tridentate, and monodentate. Their C─I···O XB angles range from 148° to 180°, reflecting the iodine σ-hole's structure-guiding influence. The I···⁻O─N+ angles range from 87° to 152°. On the contrary, the I···⁻O─N+ angles have a narrower range from 107° to 125° in stronger monodentate N─I···⁻O─N+ XBs of N-iodoimides and PyNOs. The C─I···⁻O─N+ systems exhibit a larger variation in I···⁻O─N+ angles due to weaker XB donor perfluoroiodoaromatics forming weak I···O XBs, which allows wider access to electron-rich N-O group regions. Density Functional Theory analysis shows that I···O interactions are attractive even when the I···⁻O─N+ angle is ≈80°. Correlation analysis of structural parameters showed that weak I···O XBs in perfluoroiodobenzene-PyNO complexes affect the C─I bond via n(O)→σ*(C─I) donation less than the N─I bond via n(O)→σ*(N─I) donation in very strong I···O XBs of N-iodoimide-PyNO complexes. This implies that PyNOs' oxygen self-tunes its XB acceptor property, dependent on the XB donor σ-hole strength affecting the bonding denticity, geometry, and interaction energies.

Fine-tuning N-doped species of C catalysts for 98% current efficiency of electrocatalytic decarboxylation into hindered ether

Regulating the interaction between the substrate and electrode is crucial for maximizing catalytic performance. In this study, we developed a method for controlling the sintering temperature and introducing H2O2 post-treatment to modulate the N-doping of C catalysts, enhancing the interaction between the substrate and electrode to cause a radical reaction, thereby promoting electrocatalytic decarboxylation. When 10 g of feedstock was used, the electrocatalytic system exhibited 9.4- and 4.2-fold increases in productivity and current efficiency, respectively, compared with the conventional method. A systematic investigation combining experiments and theoretical calculations revealed that pyridine N-oxide units not only promote bridging adsorption of the substrate and the formation of a substrate-enriched electric layer but also the transfer of mass and electrons, generating more reactive carboxyl radicals. The electrocatalytic system delivers a current efficiency of 98%, which is exceptional compared to previously reported electrocatalysts. The system is in line with the development trend of the green chemical industry, combining flow reactors and photovoltaic technology. This study offers valuable insights and guidance for advancing electrocatalytic organic synthesis for future industrial applications.

Elucidating the Mechanism of Tetrahydrofuran-Diol Formation through Os(VI)-Catalyzed Oxidative Cyclization of 5,6-Dihydroxyalkenes Ligated by Citric Acid.

A computational study is reported here on the mechanism of tetrahydrofuran (THF)-diol formation from the Os(VI)-catalyzed oxidative cyclization of 5,6-dihydroxyalkene ligated with citric acid and in the presence of Bro̷nsted acid. Initiated by Os(VI) dioxo citrate formation, coordination of co-oxidant pyridine-N-oxide (PNO) and protonation of its oxo group generate the active catalyst. The catalytic cycle commences through successive steps, including dihydroxyalkene addition to the active catalyst in a concerted mechanism to form hexacoordinated alkoxy-protonated PNO-complexed Os(VI) bisglycolate as a turnover-limiting step (TLS), cyclization to Os(IV) THF-diolate, reoxidation to Os(VI) THF-diolate, and hydrolysis via a dissociative mechanism to furnish the THF-diol and regenerate the active species, sustaining the catalytic cycle through an Os(VI)/Os(IV) cycle. Despite the overall exergonic nature of catalytic cycle (ΔGrcycle = -45.0 kcal/mol), the TLS is accelerated by the formation of an open-valence 16-electron Os(VI) intermediate but decelerated by the undesired formation of a saturated/hexacoordinate 18-electron Os(VI) intermediate. Bro̷nsted acid plays crucial roles in the formation of Os(VI) citrate and the active catalyst, impediment of the second cycle, and the cyclization step. Additionally, besides its role as a co-oxidant, and in the presence of acid, PNO is found to assist the insertion of dihydroxyalkene and, importantly, in releasing the THF-diol to regenerate the active intermediate.

Pyridine N-oxides as hydrogen atom transfer reagents for site-selective photoinduced C(sp3)–H functionalization

Pyridine N-oxides as hydrogen atom transfer reagents for site-selective photoinduced C(sp3)–H functionalization

Synthesis and biological activities of pyridine N-oxide bearing 5-aminoisoxazoles as potential acetylcholinesterase and monoamine oxidase inhibitors for Alzheimerʼs disease

A series of ten novel pyridine N-oxide-bearing 5-aminoisoxazoles was efficiently synthesized in moderate yields by reacting 2-(cyanomethyl)pyridine 1-oxide with α-chlorooximes, employing sodium ethoxide as a base. The synthesized compounds were verified with a variety of spectra. Subsequently, the inhibitory potency of compounds 4c, 4e, 4f, 4h, and 4i against AChE and BChE, primary targets in Alzheimer's disease, was assessed. In silico docking analyses were conducted to evaluate the interaction of compounds 4c, 4e, 4f, 4h, and 4i with AChE and MAO-B. Among the tested compounds, 4e and 4h demonstrated remarkable AChE inhibition, exhibiting IC50 values of (0.050 µM and 0.039 µM, respectively), comparable to the inhibition achieved by donepezil (IC50 = 0.020 µM). Additionally, compounds 4c, 4e, 4f, 4h, and 4i displayed potent MAO-A inhibition, with IC50 values of (0.203, 0.067, 0.083, 0.044, and 0.159 µM, respectively), surpassing the efficacy of moclobemide (IC50 = 6.061 µM). Compounds 4e, 4f, and 4h also inhibited MAO-B, with IC50 values of (0.076, 0.058, and 0.049 µM, respectively), close to the inhibitory effects of Selegiline (IC50 = 0.037 µM). Compound 4h emerged as a multi-target inhibitor, effectively inhibiting AChE, MAO-A, and MAO-B. These findings underscore the therapeutic potential of these novel compounds in the treatment of Alzheimer's disease, warranting further investigation into their clinical application.

Probing tungsten-alkylidyne cyclic polymer initiator decomposition pathways with oxidants

An OCO-pincer supported tungsten(VI) alkylidyne exhibits diverse reactivity depending on the identity of the oxidizing agent and the stoichiometry of the reaction. Oxidation reactions are studied with azo, nitroso, and oxo compounds. Benzo(c)cinnoline facilitates migratory insertion of the alkylidyne carbon in the pincer backbone forming a tethered tungsten (VI) alkylidene complex. Analogous azobenzene activates a CC bond in the tert—butyl group of the alkylidyne and results in a tungsten di-imido complex. Nitrosobenzene and pyridine N-oxide undergo oxygen atom transfer (OAT) reactions and result in tungsten oxo complexes. Reactions with nitrosobenzene are sensitive to stoichiometry; CC bond activation is observed in stoichiometric reactions, while only OAT occurs with excess nitrosobenzene.

Novel Pyridyl Macrocyclic Triarylmethanes: Synthesis by Ring-closing Metathesis and Chemical Analysis

Background:: Nowadays, macrocyclic compounds constitute a privileged source for the development of compounds with interesting biological properties. Ring-closing olefin me-tathesis has received great attention for the synthesis of small, medium, and larger ring systems. Methods:: In the present work, we described the synthesis of eight original pyridyl macrocyclic triarylmethanes using an efficient 3-step synthetic strategy. The bisalkylated 4,4'-(pyridin-X-ylmethylene) diphenols (X=2-4) were prepared by ring-closing metathesis as macrocyclization key step, using Grubbs second generation catalyst. Results:: The pyridyl macrocyclic triarylmethanes were obtained with moderate to good yields. The introduction of a pyridine N-oxide moiety before the macrocyclization proved to be interest-ing to afford a higher yield of the corresponding metathesis product. FT-IR, 1 H NMR, 13C NMR, and X-ray diffraction analysis have been used for the characterization of the synthesized compounds. Conclusion:: The synthetic strategy used here proposes an efficient alternative to prepare macro-cyclic triarylmethanes of different sizes.

Synthesis of 2-(Pyridin-2-yl)phenols and 2-(Pyridin-2-yl)anilines.

Herein, we report a new synthetic strategy for 2-(pyridin-2-yl)phenols and 2-(pyridin-2-yl)anilines catalyzed by a Pd/C-ethylene system. The starting materials, 2-(pyridin-2-yl)cyclohexan-1-ones, can be easily prepared by the reaction of substituted pyridine N-oxide and cyclohexanones. The most useful feature of this method is that both 2-(pyridin-2-yl)phenols and 2-(pyridin-2-yl)anilines are easily synthesized independently using the same compound as a starting material, simply by adding or not adding a nitrogen source.