Nitrogen Heterocycles Research Articles

γ-Hydroxy-γ-butyrolactams as 1,2-bis-electrophiles in a Brønsted/Lewis acid-free synthesis of condensed nitrogen heterocycles

Here, we describe the one-pot assembly of imidazo[1,2-a]pyridine and quinoxaline heterocyclic cores by the electrophilic tandem cyclization between 3,5-diaryl substituted 5-hydroxy-3-pyrrolin-2-ones and the corresponding nitrogen bis-nucleophiles.

Modular synthesis of cyclic β-difluoroamines.

Fluorine-containing saturated nitrogen heterocycles are very attractive structures in medicinal and biological chemistry because fluorine can be used to tune conformation as well as key properties such as basicity and bioavailability. At present cyclic fluorinated amines are accessed using hazardous reagents such as DAST or by lengthy synthesis routes. Here we report a modular two-step synthesis of cyclic β-fluoroalkyl amines using a photoredox-catalysed cyclisation/hydrogen atom transfer reaction of bromodifluoroethylamines.

Structural chemistry of penta- and hexanitrato thorium(iv) complexes isolated using N–H donors

Fifteen Th(iv)–nitrate compounds, consisting of [Th(NO3)5(H2O)2]1− or [Th(NO3)6]2− units, were isolated from aqueous solution using a series of N–H heterocycles.

Harnessing the 1,3-azadiene-anhydride reaction for the regioselective and stereocontrolled synthesis of lactam-fused bromotetrahydropyrans by bromoetherification of lactam-tethered trisubstituted tertiary alkenols.

Halo-cycloetherification of lactam-tethered alkenols enables the construction of oxygen-heterocycles that are fused to nitrogen heterocycles via intramolecular halonium-induced nucleophilic addition. Specifically, tetrahydropyrans (THPs) that are fused to a nitrogen heterocycle constitute the core of several bioactive molecules, including tachykinin receptor antagonists and alpha-1 adrenergic antagonists. Although the literature is replete with successful examples of the halo-cycloetherification of simple mono- or disubstituted primary alkenols, methods for the modular, efficient, regioselective, and stereocontrolled intramolecular haloetherification of sterically encumbered trisubstituted tertiary alkenols are rare. Here, we describe a simple intramolecular bromoetherification strategy that meets these benchmarks and proceeds with exclusive 6-endo regioselectivity. The transformation employs mild and water-tolerant conditions, which bodes well for late-stage diversification. The hindered ethers contain four contiguous stereocenters as well as one halogen-bearing tetrasubstituted stereocenter.

Unveiling Amaryllidaceae alkaloids: from biosynthesis to antiviral potential - a review.

Covering: 2017 to 2023 (now)Amaryllidaceae alkaloids (AAs) are a unique class of specialized metabolites containing heterocyclic nitrogen bridging that play a distinct role in higher plants. Irrespective of their diverse structures, most AAs are biosynthesized via intramolecular oxidative coupling. The complex organization of biosynthetic pathways is constantly enlightened by new insights owing to the advancement of natural product chemistry, synthetic organic chemistry, biochemistry, systems and synthetic biology tools and applications. These promote novel compound identification, trace-level metabolite quantification, synthesis, and characterization of enzymes engaged in AA catalysis, enabling the recognition of biosynthetic pathways. A complete understanding of the pathway benefits biotechnological applications in the long run. This review emphasizes the structural diversity of the AA specialized metabolites involved in biogenesis although the process is not entirely defined yet. Moreover, this work underscores the pivotal role of synthetic and enantioselective studies in justifying biosynthetic conclusions. Their prospective candidacy as lead constituents for antiviral drug discovery has also been established. However, a complete understanding of the pathway requires further interdisciplinary efforts in which antiviral studies address the structure-activity relationship. This review presents current knowledge on the topic.

The introduction of nitrogen-containing heterocyclic compounds (NHC) and Cu2+ in Co-MOF further improves the removal of dibenzothiophene from model fuels

NHC/Co-MOF-Cu2+ composite adsorbent materials were prepared through the in-situ synthesis of nitrogenous heterocyclic compounds (NHC) on Co-containing metal–organic framework (Co-MOF) using terephthalaldehyde (C8H6O2) and p-Phenylenediamine (C6H8N2) at room temperature. Subsequently, further modification with Cu2+ was carried out. These materials were then utilized for the removal of dibenzothiophene (DBT) from simulated gasoline. The samples were analyzed using scanning electron microscopy (SEM), X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), Fourier transform infrared spectroscopy (FT-IR) and other methods. The results indicated the uniform attachment of NHC and Cu2+ metal particles onto Co-MOF, confirming the successful synthesis of NHC/Co-MOF-Cu2+ adsorption materials. The introduction of Cu2+ enhanced the π-complexation between NHC/Co-MOF-Cu2+ and DBT. The introduction of NHC brought heteroatoms and ring structures to the composite, increasing the electron cloud density of the NHC/Co-MOF-Cu2+ composite and thereby amplifying the π-complexation with DBT. The adsorption capacity of NHC/Co-MOF-Cu2+ for DBT (150.4 mg/g) is significantly larger than that of Co-MOF (102.5 mg/g). The adsorption process of NHC/Co-MOF-Cu2+ for DBT followed the pseudo-second-order kinetic model and Langmuir model. Additionally, the adsorption process was found to be spontaneous and exothermic. Over five consecutive adsorption–desorption cycles, the efficiency of NHC/Co-MOF-Cu2+ decreased by only 10 %, indicating its excellent regeneration performance.

Method Development for Quantitative Analysis of Polycyclic Aromatic Hydrocarbons, Nitrogen Heterocycles and Sulfur Heterocycles in Crude Oils Using Quadrupole Time-of-Flight Mass Spectrometry

An oil spill is a catastrophic event that results in various toxic polycyclic aromatic hydrocarbons (PAHs) entering the environment. Polycyclic aromatic nitrogen heterocycles (PANHs) are more toxic to the environment than their parent PAHs. The high cost and paucity of available PANH standards, the lower abundance of PANHs relative to PAHs, and the difficult separation due to co-elution with PAHs have all contributed to the scarcity of related published literature on the determination of these compounds. To overcome these challenges, a new quantitative method has been successfully developed and validated for the inclusion of 113 polycyclic aromatic carbon (PAC) compounds in a single injection. The 113 compounds consist of PAHs, nitrogen heterocycles, sulfur heterocycles, and alkylated equivalents. Distinct separation of the PANHs and their alkylated counterparts (APANHs) from PAHs was achieved using a gas chromatography quadrupole time-of-flight (GC-QToF) mass spectrometer. The instrument resolved compounds by the high-resolution extraction of monoisotopic masses, allowing response correction factors (RCFs) to be determined from available PANH standards and to calculate concentrations from PAH calibration standards. The developed method was applicable to crude oil samples, generating concentrations of PANHs and relevant information on compound stability for use in oil spill forensics investigation. Development of this practical PAC method provides a powerful tool for screening toxic contaminants, assessing environmental impact, and monitoring recovery following an oil spill.

Experimental and DFT study on the effect of typical component interaction on nitrogen conversion during pyrolysis of food waste

Pyrolysis technology is an effective way to realize the reduction and recycling of food waste (FW), but the generation of N-containing substances has a great impact on the quality of pyrolysis products and the environment. The present study mainly focused on the effect of typical component interaction on nitrogen conversion during the pyrolysis of FW, which was investigated by TG-FTIR, GC-MS, and DFT calculation. The experimental results show that during pyrolysis at 500 ℃, compared with soybean protein pyrolysis, co-pyrolysis of soybean protein with rice starch reduces the production of NH3 and HCN in the pyrolysis gas and reduces the production of nitriles in the pyrolysis oil, while the production of N-containing heterocycles and amides in the pyrolysis oil increases. Soybean protein and rice starch promote the immobilization of N in pyrolysis oil through Maillard reaction and produce Maillard reaction products (MRPs). MRPs can be converted to nitrogenous heterocycles by ring formation reactions, and to amides by continued cleavage, which results in the increased yields of N-containing heterocycles and amides in the pyrolysis oil.

Carbon and nitrogen product distribution in the electrochemical degradation of nitrogen-heterocyclic compounds

We report for the first time the carbon and nitrogen product distribution during the electrochemical oxidation (EO) of pyrazine and related N-heterocyclic compounds (NHCs) present in the hard-to-treat wastewater from a biofuel production process. The experimental study was carried out using a boron-doped diamond anode. Identified and quantified intermediate products included oxamic acid, formamide, oxalic acid, and formic acid. Analysis of the C and N yields as a function of the extent of carbon removal reveals the influence of the current- and mass transfer-control operating regimes on product distribution. Carbon monoxide, which was detected among the gaseous products, suggests a possible decarbonylation pathway in the current-controlled regime. An apparent nitrogen gas and ammonium yields correlated linearly with the carbon removal, while nitrate yields significantly increased in the mass transfer-controlled regime. Nitrate and apparent nitrogen gas appear to form directly from organic nitrogen intermediates, rather than from the ammonium that also forms in the process. The research gives new insights into the NHCs degradation pathways, product distribution, and final water composition as a function of operating regime in the EO of recalcitrant wastewater.

Sulfur- and Amine- Promoted Multielectron Autoredox Transformation of Nitromethane: Multicomponent Access to Thiourea Derivatives.

Thiourea derivatives are in-demand motifs in organic synthesis, medicinal chemistry and material science, yet redox methods for the synthesis that start from safe, simple, inexpensive and readily available feedstocks are scarce. In this article, we disclose the synthesis of these motifs using elemental sulfur and nitromethane as the starting materials. The method harnesses the multi-electron auto-redox property of nitromethane in the presence of sulfur and amines, delivering thiourea products without any added oxidant or reductant. Extension of this reaction to cyclizable amines and/or higher homologues of nitromethane led to a wide range of nitrogen heterocycles and thioamides. Operationally simple, the reactions are scalable, tolerate a wide range of functional groups, and can be employed for the direct functionalization of natural products. Mechanistically, the nitro group was found to act as an oxidant leaving group, being reduced to ammonia whereas sulfur, along with the role of a sulfur building block for the thiocarbonyl group, behaved as a complementary reductant, being oxidized to sulfate.

Sequential One-Pot Synthesis of β-Amino-γ-keto-malonates from Nitro-Substituted Donor–Acceptor Cyclopropanes

AbstractA sequential one-pot procedure has been developed to access β-amino-γ-keto-malonates from nitro-substituted donor–acceptor cyclopropanes and four different nitrogen heterocycles. The reaction proceeds through in situ generation of aroylmethylidene malonates from 1-aryl-2-nitrocyclopropanes via Kornblum-type ring-opening oxidation using DMSO and subsequent aza-Michael addition with the nitrogen heterocycles. To prove the synthetic utility of the resulting products, one of them was transformed into a pyridazinone derivative.

Tandem Addition/Cyclization/Halogenation Reaction of Difluoromethylated N-Acylhydrazones with Allyltrimethylsilanes.

As novel difluoromethyl building blocks, difluoromethylated N-acylhydrazones react with allyltrimethylsilanes and the halogen source via a tandem addition/cyclization/halogenation strategy, which produces various difluoromethylpyrazoline compounds in good yields. The method features mild reaction conditions, broad substrate scopes, and a transition metal-free process with easy operation. It also proves that difluoromethylated N-acylhydrazones are useful difluoromethyl building blocks for the construction of difluoromethylated nitrogen heterocycles.

Coffee charcoal as a green catalyst for oxidative dehydrogenation

Nitrogen heterocyclic (N-heterocyclic) compounds are extensively present in natural products and active drug molecules. However, their synthesis typically requires the use of noble metal catalysts and harsh conditions. In this study, we report a novel approach using coffee charcoal as a green catalyst for the mildly mechanically driven oxidative dehydrogenation of N-heterocyclic compounds. A one-step strategy was employed to construct a microporous coffee charcoal catalyst with C defects, in-situ co-doping of multi-atoms (N, O), and abundant modification of functional groups (–OH and –COOH). Under room temperature and with H2O as solvent, the coffee charcoal catalyst demonstrates a high yield of approximately 94 % and allows for gram-scale reactions with H2O being the only by-product. Moreover, the catalyst exhibits excellent reusability, maintaining its activity for over 13 cycles. Results indicate that the defects and atom doping can enhance the adsorption of O2, which is then activated to singlet oxygen (1O2) through the conversion of –OH functional groups on the catalyst’s surface. The singlet oxygen (1O2) can strengthen the oxidative dehydrogenation of N-heterocyclic compounds. Furthermore, the mechanically driven technique both activates the reaction interface and supplies the necessary reactive energy, thus providing a comprehensive explanation for the mild reaction conditions observed. In conclusion, our research proposes a sustainable and environmentally friendly method for the oxidative dehydrogenation of N-heterocyclic compounds, which can drive crucial reactions with significant relevance to sustainability.

Multi-aspect and comprehensive atomic insight: the whole process of thermolysis of HMX/Poly-NIMMO-based plastic bonded explosive.

Based on the reactive molecular dynamics, the whole process of thermolysis of HMX/Poly-NIMMO-based PBX was studied in detail at the micro scale, which provided a novel atomic insight into the thermolysis mechanism of HMX/Poly-NIMMO. Further, it was compared with the HMX single substance system to explore the influence of binder on thermolysis of HMX. According to the findings, the activation energy required by pyrolysis of HMX in the mixed system is much less than that required by the pure HMX system at both phases. From the point of view of reaction energy, poly-NIMMO promoted the thermolysis of HMX. Especially, the mechanism analysis confirmed this point. The nitro and hydroxyl groups detached from Poly-NIMMO will react with HMX, and the generated HNO2 will further accelerate the decomposition process of nitrogen heterocycles. In addition, the number of the final products H2O and H2 in the two-component system increased greatly, but the number of CO2 and N2 molecules had not changed much, and C clusters were formed in the system. The evolution trend of bond number further verified the above analysis. While the maximum cluster number does drop with increasing temperature at first, after a particular temperature threshold is reached, it remains unchanged. In a nutshell, poly-NIMMO will hasten HMX's thermolysis and reduce the system's stability when subjected to heat.

Cover Picture: Six‐Membered Aromatic Nitrogen Heterocyclic Anti‐Tumor Agents: Synthesis and Applications (Chem. Rec. 12/2023)

Cover Picture: Six‐Membered Aromatic Nitrogen Heterocyclic Anti‐Tumor Agents: Synthesis and Applications (Chem. Rec. 12/2023)

Zinc-Phthalocyanine Loaded PLGA-PVA-Chitosan Nanosystem for the Enhancement of Antidiabetic Activity.

Zinc, one of the most common nutraceutical agents, proved to be effective for diabetes as it regulates the blood glucose level by inhibiting glucagon secretion. However, the hepatotoxicity of zinc creates necrosis, hepatic glycogen depletion, and apoptosis of hepatocytes at the concentration of 10 μg/kg. Phthalocyanine, a blue-colored compound, is an aromatic macrocyclic compound with good antioxidant ability owing to its heterocyclic nitrogen conjugation. The conjugation of zinc with phthalocyanine aimed to reduce the toxicity associated with zinc and enhance the antidiabetic activity at a lower dose. Hence, the present research work possessed the insights of the synthetic aspect of zinc with phthalocyanine along with its entrapment in the poly(lactic-co-glycolic acid) (PLGA)-chitosan nanosystem via oral administration in the treatment of diabetes. A nanoprecipitation technique was implemented for the synthesis of PLGA chitosan nanoparticles, and formulation was further optimized using a central composite design. Twenty trials provided by the software selected optimum concentrations of PLGA, poly(vinyl alcohol) (PVA), and chitosan in consideration with particle size up to 335.6 nm, zeta potential 27.87 mV, and entrapment efficiency of 75.67 ± 8.13%. Addition of chitosan to the nanocarrier system for controlling the release of the drug for 3 days was accompanied by the improvement in the glucose level within 28 days. The delivery of the nanoparticles showed enhancement in the cholesterol, triglyceride, alkaline phosphatase (ALP), urine parameters, and pro-inflammatory cytokines. The application of DoE (design of experiments) for the optimization of the nanoparticles established a controlled release formulation for diabetes, which displayed safety and effectiveness in streptozotocin (STZ)-induced diabetic rats.

Drug Discovery Based on Oxygen and Nitrogen (Non-)Heterocyclic Compounds Developed @LAQV-REQUIMTE/Aveiro.

Artur Silva's research group has a long history in the field of medicinal chemistry. The development of new synthetic methods for oxygen (mostly polyphenols, e.g., 2- and 3-styrylchromones, xanthones, flavones) and nitrogen (e.g., pyrazoles, triazoles, acridones, 4-quinolones) heterocyclic compounds in order to be assessed as antioxidant, anti-inflammatory, antidiabetic, and anticancer agents has been the main core work of our research interests. Additionally, the synthesis of steroid-type compounds as anti-Alzheimer drugs as well as of several chromophores as important dyes for cellular imaging broadened our research scope. In this review article, we intend to provide an enlightened appraisal of all the bioactive compounds and their biological properties that were synthesized and studied by our research group in the last two decades.

Synthesis of Deuterated Enaminones with High Isotopic Fidelity.

The unexpected oxidation of nitrogenous heterocycles by aldehyde oxidase (AO) may be addressed by the substitution of deuterium for hydrogen adjacent to the heterocycle nitrogen atom. Enaminones are versatile intermediates in the synthesis of nitrogenous heterocycles. We report that heretofore inaccessible monodeuterated enaminones of the general structure RC(=O)CH=CDNMe2 may be synthesized from methyl ketones and DCO2Me with high isotopic fidelity and efficient utilization of deuterium.

Base Metal-Controlled Chemodivergent Cyclization of Propargylamines for the Atom-Economic Synthesis of Nitrogen Heterocycles.

Herein, a base metal-enabled chemodivergent cyclization of propargylamines for the atom-economic construction of nitrogen heterocycles has been developed. Due to the different modes of activation of metal to propargylamine, copper-catalyzed 6-endo-dig cyclization generates functionalized 2-substitued quinoline-4-carboxylates, while iron-promoted cascade amino Claisen rearrangement, aromatization, and aza-Michael addition afford diverse 2-substituted indole-3-carboxylate derivatives. Excellent selectivity, broad functional group tolerance, mild conditions, and flexible late-stage functionalization illustrate the high efficiency and synthetic utility of this chemodivergent reaction.

Six-membered Aromatic Nitrogen Heterocyclic Anti-Tumor Agents: Synthesis and Applications.

Cancer stands as a serious malady, posing substantial risks to human well-being and survival. This underscores the paramount necessity to explore and investigate novel antitumor medications. Nitrogen-containing compounds, especially those derived from natural sources, form a highly significant category of antitumor agents. Among these, antitumor agents with six-membered aromatic nitrogen heterocycles have consistently attracted the attention of chemists and pharmacologists. Accordingly, we present a comprehensive summary of synthetic strategies and clinical implications of these compounds in this review. This entails an in-depth analysis of synthesis pathways for pyridine, quinoline, pyrimidine, and quinazoline. Additionally, we explore the historical progression, targets, mechanisms of action, and clinical effectiveness of small molecule inhibitors possessing these structural features.