Pyridine N-oxide Research Articles

Asymmetric synthesis of (S)-14-methyl-1-octadecene, the sex pheromone of Lyonetia clerkella Linnaeus

Abstract Lyonetia clerkella Linnaeus is one of the notorious pests that are found in orchards. A new and efficient asymmetric synthesis of the sex pheromone of this pest has been developed. Central to this approach were 4-(dimethylamino)pyridine N-oxide (DMAPO)/Boc2O-mediated N-acylation, Evans’chiral auxiliaries and the coupling of chiral tosylate with n-propyl magnesium bromide. Furthermore, we have demonstrated the scalability of the new acylation.

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%.

Mechanistic study on MeReVO(edt)Im catalysis for the oxygen atom transfer from pyridine oxide to Ph3As: Kinetics and computational study

The oxorhenium(V) monomer (CH3Re(V)O(edt)(Im) (where edt = 1,2 ethanedithiolate, Im= Imidazole) catalyzes the oxygen atom transfer reaction from pyridine N-oxide and substituted pyridine N-oxide to triphenylarsine (Ph3As). The kinetic results have shown that the reaction rate is first order with respect to the catalyst and pyridine N-oxide concentrations, and first order with respect to [Ph3As] at low concentration and zero order at high [Ph3As]. Also, the reaction is zero order with respect to the imidazole concentration. Therefore, rate law is R = k [Re-Im] [PyNO][Ph3As] at low Ph3As concentration and the rate law is R = k [Re-Im] [PyNO] at high Ph3As concentration. The electronic effect of the oxidant was investigated by studying the reaction rate constants of different substituted pyridine NOxide. The correlation of the rate constant values with σ is linear with reaction constant ρ = -2.4. A negative value indicates that the rate increases with electron-donating substituents. The effect of electron donor substituent on the reaction rate is mainly due to the enhancement of the binding of pyridine N-oxide to the ReVO in the first step of the proposed mechanism. The oxidation of ReVO to ReVIIO2 and release of the pyridine step is not highly sensitive to the nature of the substituent on the pyridine. The computational study indicates that the oxidation of ReVO to ReVIIO2 and release of the pyridine step is insensitive to the nature of the substituent on the pyridine with the average estimated activation barrier ≈ 9 kcal/mol and its less than the estimated activation barrier in the absence of imidazole (≈ 11.5 kcal/mol). This result support that the imidazole act as nucleophile to assist the oxidation of ReVO to ReVIIO2 step.

Controllable Pyridine N-Oxidation-Nucleophilic Dechlorination Process for Enhanced Dechlorination of Chloropyridines: The Cooperation of HCO4- and HO2.

Dechlorination of chloropyridines can eliminate their detrimental environmental effects. However, traditional dechlorination technology cannot efficiently break the C-Cl bond of chloropyridines, which is restricted by the uncontrollable nonselective species. Hence, we propose the carbonate species-activated hydrogen peroxide (carbonate species/H2O2) process wherein the selective oxidant (peroxymonocarbonate ion, HCO4-) and selective reductant (hydroperoxide anion, HO2-) controllably coexist by manipulation of reaction pH. Taking 2-chloropyridine (Cl-Py) as an example, HCO4- first induces Cl-Py into pyridine N-oxidation intermediates, which then suffer from the nucleophilic dechlorination by HO2-. The obtained dechlorination efficiencies in the carbonate species/H2O2 process (32.5-84.5%) based on the cooperation of HCO4- and HO2- are significantly higher than those in the HO2--mediated sodium hydroxide/hydrogen peroxide process (0-43.8%). Theoretical calculations confirm that pyridine N-oxidation of Cl-Py can effectively lower the energy barrier of the dechlorination process. Moreover, the carbonate species/H2O2 process exhibits superior anti-interference performance and low electric energy consumption. Furthermore, Cl-Py is completely detoxified via the carbonate species/H2O2 process. More importantly, the carbonate species/H2O2 process is applicable for efficient dehalogenation of halogenated pyridines and pyrazines. This work offers a simple and useful strategy to enhance the dehalogenation efficiency of halogenated organics and sheds new insights into the application of the carbonate species/H2O2 process in practical environmental remediation.

Pyridine Iodine(I) Cations: Kinetic Trapping as a Sulfonate Complexes.

Seven pyridine iodine(I) sulfonate complexes were prepared and isolated at low temperatures and characterized by X-ray diffraction analysis. The inherently instable pyridine iodine(I) cations are stabilized by an oxygen of sulfonate anions via the I⋅⋅⋅O halogen bond. In these complexes, the iodine atom of the pyridine iodine(I) cation acts as an electron acceptor and the sulfonate oxygen as the electron donor. These complexes are stable enough in the crystalline state, yet decompose rapidly under ambient conditions, also being unstable in solution. The (pyridine)N-I bond lengths [2.140(3)-2.197(2) Å] and the I⋅⋅⋅O halogen bonds [2.345(6)-2.227(3) Å] are analogous to (imide)N-I⋅⋅⋅O-N-pyridine uncharged halogen-bonded complexes formed from N-haloimides and pyridine N-oxides, thus confirming the existence of elusive pyridine iodine(I) cation.

Divergent synthesis of cyclopentenyl- & 1,5-divinyl-ketones via gold-catalyzed oxidative coupling of 1,3-enynes with various olefins

Two divergent synthetic routes were developed to synthesize cyclopentenyl- & 1,5-divinyl-ketones through gold catalyzed reaction of 1,3-enynes with different types of olefins with the addition of pyridine N-oxide. A formal [3 + 2] cycloaddition occurred in the reaction of aryl olefins by using 1,3-enynes as the C3 reactants, while the C1 reactivity thereof was exhibited in the reaction with alkyl olefins to provide 1,5-divinyl ketone products.

Synthesis of 2-(pyridylvinyl)chromen-4-ones and their N-oxide analogs for assessment of their biological activities as anticancer agents.

2-Styrylchromones have been shown to possess a broad spectrum of biological activities. Replacing the carbon atom in 2-styrylchromones with a nitrogen atom in the benzene rings forms 2-(pyridylvinyl)chromen-4-ones (aza-2-styrylchromones). We have synthesized a series of novel 2-(pyridylvinyl)chromen-4-ones and their pyridine N-oxides to evaluate them as potential anticancer agents against human non-small-cell lung cancer cells (A549). Among the 18 synthesized molecules, compounds 18 and 8a exhibited comparable inhibitory effects to 5-fluorouracil and showed no toxicity against normal cells.

Selectivity in Catalytic Asymmetric Formal [3 + 3] Annulation of 2-Enoyl-pyridine N-Oxide with Benzyl Methyl Ketone

The asymmetric formal [3 + 3] annulation process of (E)-2-(3-phenylacryloyl)pyridine N-oxide with benzyl methyl ketone was investigated. The possibility of a stereoselective outcome was checked using salts of natural amino acids, as well as chiral bifunctional derivatives containing amino groups and thiourea or squaramide fragments as organocatalysts. Different types of organocatalysts applied led to opposite enantiomers of 2-(3-oxo-4,5-diphenyl-cyclohex-1-en-yl)pyridine 1-oxide (up to 60% ee). Spectroscopic analysis of the isolated product and analysis of the reaction course was carried out, taking into account the obtained regio- and stereoselectivity. In order to verify the postulated results, calculations of the energy of the intermediate reaction products and the final product using the Kohn–Sham Density Functional Theory (KS-DFT) were made.

Multi-objective optimization of simultaneous oxidative desulfurization and denitrogenation of model fuel

Petroleum fractions are accompanied with sulfur and nitrogen compounds, and nitrogen compounds tend to compete for the catalyst active sites, reducing desulfurization efficiency. They can be removed by oxidative desulfurization and denitrogenation, wherein the sulfur and nitrogen compounds are converted into corresponding oxides with higher polarity than their parent forms, thus favoring their extractive or adsorptive removal from the oil phase. The introduction of ultrasound into the oxidation system can significantly improve the process efficiency and oxidation kinetics through strong cavitation phenomena involving physical and chemical effects. In this work, ultrasound-assisted simultaneous oxidation of pyridine and dibenzothiophene (DBT) contained in a model fuel was performed. Response surface methodology (RSM) was employed to study the effect of six parameters, viz., catalyst dose (5–12.5 g/L), reaction time (5–60 min), ultrasonic amplitude (10–60 %), volume of hydrogen peroxide (0.5–2 mL), volume of acetic acid (0.5–2 mL) and reaction temperature (40–60 °C) on the conversion of DBT and pyridine. A face-centered central composite design was employed as the RSM tool, and the effect of the parameters and their interactions on the two responses was investigated. The two responses were simultaneously optimized via desirability functions and overlaying individual contour plots. The results revealed that sonication significantly enhanced the conversion of both compounds. All six factors significantly influenced the oxidation of pyridine, while DBT conversion was mainly affected by four factors. The desirability for the process under consideration ranged from 0.85 to 0.89, and at the optimum conditions, 100 % conversion of pyridine and 46.06 % conversion of DBT were obtained. Two-staged oxidation of the fuel at optimum conditions resulted in 100 and 93.7 % conversion of pyridine and DBT, respectively.

Efficient utilization of photoelectron-hole at semiconductor-microbe interface for pyridine degradation with assistance of external electric field

In this study, enhanced pyridine bio-photodegradation with assistance of electricity was achieved. Meanwhile, photoelectron-hole played a vital role in accelerating pyridine biomineralization. The significant separation of photoelectron-hole was achieved with an external electric field, which provided sufficient electron donors and acceptors for pyridine biodegradation. The enhanced electron transport system activity also revealed the full utilization of photoelectron-hole by microbes at semiconductor-microbe interface with assistance of electricity. Microbial community analysis confirmed the enrichment of functional species related to pyridine biodegradation and electron transfer. Microbial function analysis and microbial co-occurrence networks analysis indicated that upregulated functional genes and positive interactions of different species were the important reasons for enhanced pyridine bio-photodegradation with external electric field. A possible mechanism of enhanced pyridine biodegradation was proposed, i.e., more photoelectrons and holes of semiconductors were utilized by microbes to accelerate reduction and oxidation of pyridine with the assistance of electrical stimulation. The excellent performance of the photoelectrical biodegradation system showed a potential alternative for recalcitrant organic wastewater treatment.

Synthesis of 2-acyl benzofurans and indoles based on nucleophile-intercepted Meyer–Schuster rearrangement of o-hydroxyphenyl and o-aminophenyl propargylic alcohols

A new type of nucleophile-intercepted Meyer–Schuster rearrangement mediated by pyridine N-oxide under metal-free conditions using a catalytic amount of acid is disclosed. It enables synthesis of 2-acyl benzofurans and indoles in 56–>99% yields.

Generation and capture of naphthoquinonynes: a new frontier in the development of trypanocidal quinones via aryne chemistry.

The regioselective synthesis of functionalized naphthoquinones via the formation and capture of naphthoquinonynes has been used to prepare trypanocidal compounds. The target compounds are functionalized on the aromatic ring, leaving the quinoidal ring intact. Using this technique, eighteen functionalized naphthoquinones were succesfull obtained, divided in two main groups: the first scope using N-nucleophiles, and the second scope using pyridine N-oxides, with yields up to 74%. Evaluation against bloodstream trypomastigotes of T. cruzi has identified fourteen compounds that are more potent than benznidazole (Bz); for instance, compounds 29b-I and 30b, with IC50/24 h values of 10.5 and 10.1 μM, respectively, are approximately 10-fold more active than Bz. This study provides the first examples of the application of naphthoquinonyne chemistry for the synthesis of new compounds with potent trypanocidal activities.

Enhanced binding of methyl alkylammonium cations through preorganization of a water-soluble calix[4]pyrrole.

We describe the synthesis of two tetra-α aryl-extended calix[4]pyrroles (C[4]Ps) 4a-b bearing four terminal carboxylic groups in their meso-propyl chains defining the lower rims. The synthesized C[4]Ps became soluble (1-3 mM) in water at pD = 10. We probed the interaction of 4a towards tetra-methylammonium (G1) chloride in water using 1H NMR spectroscopy. The C[4]P 4a includes G1 in the shallow aromatic cavity defined by the pyrrole rings in cone conformation forming a 1 : 1 complex G1⊂4a. Pyridine-N-oxide (PNO) binding in the larger polar aromatic cavity of 4a results in the quantitative self-assembly of the supramolecular receptor PNO@4a featuring the pyrrole rings preorganized in cone conformation. The PNO@4a receptor displays improved binding properties towards G1 than the parent C[4]P 4a. We thermodynamically characterized (1H NMR titrations and ITC experiments) the 1 : 1 complexes of PNO@4a with a series of tetra-alkylammonium salts, including biologically relevant examples. The PNO@4a supramolecular receptor displays significant affinity (log K = 3-4) but lacks selectivity in water binding of methyl trialkyl ammonium cations. Cation-π and coulombic interactions are the main intermolecular forces stabilizing the complexes. We also performed DFT calculations to gain some insights into the complexes' structures.

PyBroP-mediated nucleophilic addition of oxindoles with pyridine N-oxides to access 3-pyridyl-3,3-disubstituted oxindoles

An attractive topic of metal-free methods is to achieve oxindoles that bear an N-heteroaromatic group-substituted quaternary center at the 3-position.

Експериментальне дослідження гепатопротекторної дії комплексу n-оксид-2,6-диметил піридину з бурштиновою кислотою (Потейтіну) на моделі токсичного гепатиту, спричиненого тетрахлорметаном

Plant growth regulators (PGR), in particular, methyl derivatives of pyridine N-oxide, reduce the acute toxicity of pesticides, reduce the hepatotoxic effects of chlorpyrifos and ease the course of intoxication under long-term exposure. The role of the body’s defence systems under the combined effects of PGR and pesticides has not yet been sufficiently elucidated. The study of the protective effect of PGR Poteitin under the conditions of toxic damage to the liver by carbon tetrachloride (CCl4) will allow finding out the mechanisms of its combined action. The results of the research will be used to develop preventive measures for pesticide poisoning. Aim. Investigate the hepatoprotective properties of the 2.6-dimethylpyridine N-oxide complex with succinic acid (Poteitin) on the model of acute hepatitis caused by carbon tetrachloride. Materials and Methods. Acute hepatitis was modelled on male Wistar Han rats with subcutaneous injection of CCl4 (pure substance) in petroleum jelly oil (0.8 ml/100 g of body weight) for 2 days. Poteitin was administered at the doses of 23 and 0.23 mg/kg, reference substance Silybor 35 – at the dose of 5 mg/kg. Intact rats received petroleum jelly oil in the same volumes. Poteitin and Silybor were administered in a treatment-prophylactically regimen, orally 1 hour pre- and 2 hours post-CCl4. The activity of enzymes of cytolysis and cholestasis, indicators reflecting liver function, the content of lipid peroxidation (LP) products and antioxidant activity were determined in blood serum. Histological studies of liver tissue were carried out. The index of effectiveness of the protective effect of Poteitin was calculated The results were statistically processed using the one-way ANOVA followed by Fisher's LSD post-hoc test. Results and Discussion. CCl4 caused acute liver damage: increased activity of markers of cytolysis and cholestasis, decrease in a number of functional tests, activity of catalase, LP products accumulation, fatty and balloon dystrophy of hepatocytes, lympho-leukocyte infiltration. Poteitin on the background of CCl4 contributed to the normalization of the activity of markers of cytolysis and cholestasis, the restoration of functional indicators, reduced the content of LP products, increased the activity of catalase, and reduced liver damage. The protective effect of Poteitin was not inferior to Silybor. Conclusions. 1. Under the conditions of acute hepatitis, carbon tetrachloride causes moderate liver damage. 2. Poteitin at the doses of 23 and 0.23 mg/kg has a pronounced hepatoprotective effect: it normalizes the activity of enzymes of cytolysis and cholestasis, functional indicators – the level of glucose, cholesterol, total protein and bilirubin, urea; reduces the intensity of LP and activation of the antioxidant system. 3. The protective effect of Poteitin at both tested doses as cytolysis and cholestasis indicators, functional tests and morphostructural changes in the liver is comparable to the reference drug Silybor. The protective effect of Poteitin, determined by the intensity of LP, is greater than that of Silybor. Keywords: acute hepatitis, carbon tetrachloride, hepatoprotective effect, 2.6-dimethylpyridine N-oxide complex with succinic acid.

Photochemical Difluoromethylation of Quinoxalin-2(1H)-ones with Difluoroacetic Anhydride and Pyridine N-Oxide.

A novel photochemical difluoromethylation of quinoxalin-2(1H)-ones under catalyst-free conditions was achieved with difluoroacetic anhydride and pyridine N-oxide. The green and mild reaction conditions as well as readily attainable difluoroacetic anhydride provide a useful protocol to prepare C3-difluoromethylated quinoxalin-2(1H)-ones.

Novel insights into the co-metabolism of pyridine with different carbon substrates: Performance, metabolism pathway and microbial community

Pyridine is a widely employed nitrogen-containing heterocyclic organic, and the discharge of pyridine wastewater poses substantial environmental challenges due to its recalcitrance and toxicity. Co-metabolic degradation emerged as a promising solution. In this study, readily degradable glucose and the structurally analogous phenol were used as co-metabolic substrates respectively, and the corresponding mechanisms were thoroughly explored. To treat 400 mg/L pyridine, all reactors achieved remarkably high removal efficiencies, surpassing 98.5%. And the co-metabolism reactors had much better pyridine-N removal performance. Batch experiments revealed that glucose supplementation bolstered nitrogen assimilation, thereby promoting the breakdown of pyridine, and resulting in the highest pyridine removal rate and pyridine-N removal efficiency. The high abundance of Saccharibacteria (15.54%) and the enrichment of GLU and glnA substantiated this finding. On the contrary, phenol delayed pyridine oxidation, potentially due to its higher affinity for phenol hydroxylase. Nevertheless, phenol proved valuable as a carbon source for denitrification, augmenting the elimination of pyridine-N. This was underscored by the abundant Thauera (30.77%) and Parcubacteria (7.21%) and the enriched denitrification enzymes (narH, narG, norB, norC, and nosZ, etc.). This study demonstrated that co-metabolic degradation can bolster the simultaneous conversion of pyridine and pyridine-N, and shed light on the underling mechanism.

Development of Highly Potent, G-Protein Pathway Biased, Selective, and Orally Bioavailable GPR84 Agonists.

Orphan G-protein-coupled receptor 84 (GPR84) is a receptor that has been linked to cancer, inflammatory, and fibrotic diseases. We have reported DL-175 as a biased agonist at GPR84 which showed differential signaling via Gαi/cAMP and β-arrestin, but which is rapidly metabolized. Herein, we describe an optimization of DL-175 through a systematic structure-activity relationship (SAR) analysis. This reveals that the replacement of the naphthalene group improved metabolic stability and the addition of a 5-hydroxy substituent to the pyridine N-oxide group, yielding compounds 68 (OX04528) and 69 (OX04529), enhanced the potency for cAMP signaling by 3 orders of magnitude to low picomolar values. Neither compound showed detectable effects on β-arrestin recruitment up to 80 μM. Thus, the new GPR84 agonists 68 and 69 displayed excellent potency, high G-protein signaling bias, and an appropriate in vivo pharmacokinetic profile that will allow investigation of GPR84 biased agonist activity in vivo.

Ligand-Enabled Palladium(II)-Catalyzed γ-C(sp3)-H Arylation of Primary Aliphatic Amines.

The Pd(II)/sulfoxide-2-hydroxypyridine catalytic system shows promising activity in C-H activation chemistry. In this study, we showcase how this catalytic system solves the problem of native primary amine-directed γ-C(sp3)-H arylation. Primary amines with different complexities are compatible with the established methodology, and the range of applicable substrates can be expanded to include pyridine, oxime ether, and pyridine N-oxide.

Chemo- and Regioselective Alkylation of Pyridine N-Oxides with Titanacyclopropanes.

While titanacyclopropanes are used to react mainly with ester, amide, and cyano to undergo cyclopropanation, herein they react preferentially with pyridine N-oxide to accomplish C2-H alkylation beyond these functionalities with double regioselectivity. After being pyridylated at the less hindered C-Ti bond, the remaining C-Ti bond of titanacyclopropanes can be further functionalized by various electrophiles, allowing facile introduction of complex alkyls onto the C2 of pyridines. Its synthetic potential has been demonstrated by late-stage diversification of drugs.