Nitrogen-containing Aromatic Heterocycles Research Articles

Green Synthesis of Aromatic Nitrogen-Containing Heterocycles by Catalytic and Non-Traditional Activation Methods.

Recent advances in the environmentally benign synthesis of aromatic N-heterocycles are reviewed, focusing primarily on the application of catalytic methods and non-traditional activation. This account features two main parts: the preparation of single ring N-heterocycles, and their condensed analogs. Both groups include compounds with one, two and more N-atoms. Due to the large number of protocols, this account focuses on providing representative examples to feature the available methods.

Iridium-Catalyzed Asymmetric Cascade Allylation/Lactonization of Indole Esters: Access to Chiral Tricyclic Oxazinoindolones.

Ir-catalyzed asymmetric cascade allylation/lactonization of indole 2-carboxylates with vinyl cyclic carbonate was successfully developed, which provided efficient access to chiral tricyclic oxazinoindolones with excellent results (up to 85% yield, 99% ee). This protocol could be well extended to pyrroles and other nitrogen-containing aromatic heterocycles. A reasonable reaction pathway was provided on the basis of preliminary mechanistic investigation. Importantly, the key intermediate toward marine alkaloid (+)-agelastatin A could be readily accessible through this methodology.

Analysis of Complex Mixtures by Chemosensing NMR Using para-Hydrogen-Induced Hyperpolarization.

ConspectusNuclear magnetic resonance (NMR) is a powerful technique for chemical analysis. The use of NMR to investigate dilute analytes in complex systems is, however, hampered by its relatively low sensitivity. An additional obstacle is represented by the NMR signal overlap. Because solutes in a complex mixture are usually not isotopically labeled, NMR studies are often limited to 1H measurements, which, because of the modest dispersion of the 1H resonances (typically ∼10 ppm), can result in challenging signal crowding. The low NMR sensitivity issue can be alleviated by nuclear spin hyperpolarization (i.e., transiently increasing the differences in nuclear spin populations), which determines large NMR signal enhancements. This has been demonstrated for hyperpolarization methods such as dynamic nuclear polarization, spin-exchange optical pumping and para-hydrogen-induced polarization (PHIP). In particular, PHIP has grown into a fast, efficient, and versatile technique since the recent discovery of non-hydrogenative routes to achieve nuclear spin hyperpolarization.For instance, signal amplification by reversible exchange (SABRE) can generate proton as well as heteronuclear spin hyperpolarization in a few seconds in compounds that are able to transiently bind to an iridium catalyst in the presence of para-hydrogen in solution. The hyperpolarization transfer catalyst acts as a chemosensor in the sense that it is selective for analytes that can coordinate to the metal center, such as nitrogen-containing aromatic heterocycles, sulfur heteroaromatic compounds, nitriles, Schiff bases, diaziridines, carboxylic acids, and amines. We have demonstrated that the signal enhancement achieved by SABRE allows rapid NMR detection and quantification of a mixture of substrates down to low-micromolar concentration. Furthermore, in the transient complex, the spin configuration of p-H2 can be easily converted to spin hyperpolarization to produce up to 1000-fold enhanced NMR hydride signals. Because the hydrides’ chemical shifts are highly sensitive to the structure of the analyte associating with the iridium complex, they can be employed as hyperpolarized “probes” to signal the presence of specific compounds in the mixture. This indirect detection of the analytes in solution provides important benefits in the case of complex systems, as hydrides resonate in a region of the 1H spectrum (at ca. −20 ppm) that is generally signal-free. The enhanced sensitivity provided by non-hydrogenative PHIP (nhPHIP), together with the absence of interference from the complex matrix (usually resonating between 0 and 10 ppm), set the detection limit for this NMR chemosensor down to sub-μM concentrations, approximately 3 orders of magnitude lower than for conventional NMR. This nhPHIP approach represents, therefore, a powerful tool for NMR analysis of dilute substrates in complex mixtures as it addresses at once the issues of signal crowding and NMR sensitivity. Importantly, being performed at high field inside the NMR spectrometer, the method allows for rapid acquisition of multiple scans, multidimensional hyperpolarized NMR spectra, in a fashion comparable to that of standard NMR measurements.In this Account, we focus on our chemosensing NMR technology, detailing its principles, advantages, and limitations and presenting a number of applications to real systems such as biofluids, beverages, and natural extracts.

Synthesis of Dihydroisoquinoline and Dihydropyridine Derivatives via Asymmetric Dearomative Three-Component Reaction

Synthesis of Dihydroisoquinoline and Dihydropyridine Derivatives via Asymmetric Dearomative Three-Component Reaction

A radical approach for the selective C-H borylation of azines.

Boron functional groups are often introduced in place of aromatic carbon-hydrogen bonds to expedite small-molecule diversification through coupling of molecular fragments1-3. Current approaches based on transition-metal-catalysed activation of carbon-hydrogen bonds are effective for the borylation of many (hetero)aromatic derivatives4,5 but show narrow applicability to azines (nitrogen-containing aromatic heterocycles), which are key components of many pharmaceutical and agrochemical products6. Here we report an azine borylation strategy using stable and inexpensive amine-borane7 reagents. Photocatalysis converts these low-molecular-weight materials into highly reactive boryl radicals8 that undergo efficient addition to azine building blocks. This reactivity provides a mechanistically alternative tactic for sp2 carbon-boron bond assembly, where the elementary steps of transition-metal-mediated carbon-hydrogen bond activation and reductive elimination from azine-organometallic intermediates are replaced by a direct, Minisci9-style, radical addition. The strongly nucleophilic character of the amine-boryl radicals enables predictable and site-selective carbon-boron bond formation by targeting the azine's most activated position, including the challenging sites adjacent to the basic nitrogen atom. This approach enables access to aromatic sites that elude current strategies based on carbon-hydrogen bond activation, and has led to borylated materials that would otherwise be difficult to prepare. We have applied this process to the introduction of amine-borane functionalities to complex and industrially relevant products. The diversification of the borylated azine products by mainstream cross-coupling technologies establishes aromatic amino-boranes as a powerful class of building blocks for chemical synthesis.

Evaluation Preparation of Apatinib-Loaded Polymer Nanoparticles and Its Effect in the Treatment of Advanced Ovarian Cancer.

Ovarian cancer is a common gynecological malignant tumor, second only to cervical cancer and uterine body cancer. In China, ovarian cancer has the highest mortality rate in gynecological tumors. Due to the rapid spread of cancer cells, the prognosis is relatively poor. Because the ovarian epithelial cancer is relatively insidious, there are no obvious clinical manifestations in the early stage. At present, apatinib chemotherapy is widely used, which can reduce the disease of patients by inhibiting the migration and proliferation of vascular endothelial cells. Fluorescence imaging is widely used in biomedical imaging. Organic fluorescent dyes are stable in nature and can be linked to a variety of molecules. They are often used in targeted imaging and therapeutic research. A cyanine dye is an organic molecule formed by two nitrogen-containing aromatic heterocycles connected by a polymethine bridge. Because neither MR contrast agents nor fluorescent dyes are targeted, specific biomolecules and contrast agents are often used in the research to diagnose and treat tumors. In this paper, a polymer nanoparticle loaded with apatinib was prepared and its therapeutic effect in advanced ovarian cancer was explored. The results show that nanoparticles loaded with apatinib are more effective than ordinary therapeutic drugs.

Zinc(II) complexes with aromatic nitrogen-containing heterocycles as antifungal agents: Synergistic activity with clinically used drug nystatin

Three novel Zn(II) complexes, [ZnCl2(qz)2] (1), [ZnCl2(1,5-naph)]n (2) and [ZnCl2(4,7-phen)2] (3), where qz is quinazoline, 1,5-naph is 1,5-naphthyridine and 4,7-phen is 4,7-phenanthroline, were synthesized by the reactions of ZnCl2 and the corresponding N-heterocyclic ligand in 1:2 molar ratio in ethanol at ambient temperature. The characterization of these complexes was done by NMR, IR and UV–Vis spectroscopy, and their crystal structures were determined by single-crystal X-ray diffraction analysis. Complexes 1 and 3 are mononuclear species, in which Zn(II) ion is tetrahedrally coordinated by two nitrogen atoms belonging to two qz or 4,7-phen ligands, respectively, and by two chloride anions, while complex 2 is a 1D coordination polymer that contains 1,5-naph as bridging ligand between two metal ions. In agar disc-diffusion assay, complexes 1–3 manifested good inhibitory activity against two investigated Candida strains (C. albicans and C. parapsilosis), while not inducing toxic effects on the healthy human fibroblast cell line (MRC-5). This activity was not fungicidal, as revealed by the broth microdilution assay, however complex 3 showed the ability to modulate Candida hyphae formation, which is an important process during infection and showed significant synergistic effect with clinically used antifungal polyene nystatin.

Different coordination abilities of 1,7- and 4,7-phenanthroline in the reactions with copper(II) salts: Structural characterization and biological evaluation of the reaction products

The reactions between equimolar amounts of CuX2 (X = NO3− and CF3SO3−) and two aromatic nitrogen-containing heterocycles differing in the position of nitrogen atoms, 1,7- and 4,7-phenanthroline (1,7- and 4,7-phen), were performed in ethanol/methanol at room temperature. When CuX2 salts were mixed with 4,7-phen, two copper(II) complexes, [Cu(NO3)2(4,7-Hphen)2](NO3)2 (1) and [Cu(CF3SO3)(4,7-phen)2(H2O)2]CF3SO3 (2), were formed. On the other hand, in the reaction of CuX2 salts with 1,7-phen, only 1,7-HphenNO3 (3a/b) and 1,7-HphenCF3SO3 (4) were obtained as the final products. The obtained products 1–4 were characterized by spectroscopic and X-ray diffraction techniques. In the copper(II) complexes 1 and 2, the coordination geometry around the Cu(II) ion is distorted octahedral and square pyramidal, respectively. The antimicrobial potential of the copper(II) complexes 1 and 2 and corresponding compounds used for their synthesis were assessed against four different bacterial species and Candida albicans, displaying moderate growth inhibiting activity. The cytotoxic properties of the investigated complexes were also evaluated against the normal human lung fibroblast cell line (MRC-5) indicating moderate, yet more pronounced cytotoxicity than antimicrobial properties.

Fate and distribution of nutrients and heavy metals during hydrothermal carbonization of sewage sludge with implication to land application

Hydrothermal carbonization has been considered effective to reduce sewage sludge volume and provide an opportunity to generate valuable byproducts for a wide range of potential applications. The fate and distribution of nutrients during hydrothermal carbonization of sewage sludge, along with that of heavy metals, is very important for realizing nutrient recovery and reuse by both hydrochar and liquid phase directly as soil amendments and/or organic fertilizer. In this study, we systematically investigated the migration and transformation of nutrients and heavy metals using chemical extractions and reaction severity (Ruyter model) methods at a temperature range of 120–300 °C for 30–180 min. With increasing reaction severity, carbon and nitrogen efficiency of hydrochar showed a liner and exponential decrease respectively, while phosphorus accumulated positively in hydrochar. Nitrogen species in hydrochar are mostly nitrogen-containing aromatic heterocycles whereas in liquid phase are predominantly ammonia-N and organic-N. The organic phosphorus in sewage sludge was transformed to inorganic species but non-apatite phosphorus showed an exponential reduction in hydrochar with increasing reaction severity, together with the decrease of orthophosphate in liquid phase. As for heavy metals, hydrothermal carbonization promoted decrease in direct bioavailable fractions (except arsenic) and increase in stable fraction (except cadmium and arsenic) in hydrochar as reaction severity elevated. Since hydrothermal effects led to redistribution of nutrients speciation and immobilization of heavy metals, non-farm land application of both hydrochar and liquid phase seems to be possible and unrestricted. This study provides fundamental knowledges for the construction of sludge management strategies to better nutrients recycling and reclamation.

Dual Gold-Catalyzed Formal Tetradehydro-Diels-Alder Reactions for the Synthesis of Carbazoles and Indolines.

This work reports a dual gold-catalyzed tetradehydro-Diels-Alder reaction for the synthesis of nitrogen-containing aromatic heterocycles. Under the catalytic system (IPrAuNTf2 /DIPEA), indolines and carbazoles as well as other N-containing aromatic heterocycles were prepared in high yields with good functional group tolerance. Unlike the traditional thermal tetradehydro-Diels-Alder reactions, diluted reaction concentration and radical prohibitors are not required for this protocol. Experimental data support a mechanism involving gold vinylidene species, which undergoes a 6 π electrocyclization, followed with 1,2-hydrogen shift.

Metal-catalyzed synthesis of five-membered ring N-heterocycles. A recent update

The review deals with the metal-catalyzed synthetic methods used for the construction of 5-membered nitrogen-containing aromatic and nonaromatic heterocycles with one to three nitrogen atoms, published in the years 2008–2017. The methodology is based on the metalcatalyzed activation of the alkyl C(sp3)–H, alkenyl C(sp2)–H, and terminal alkyne C(sp)–H bonds of appropriate precursors in order to perform intermolecular and intramolecular reactions. These bond forming reactions include C(sp3)–C(sp2), C(sp2)–C(sp2), and C(sp2)–C(sp) coupling, hydroamination at C(sp2)–H and C(sp)–H bonds, and oxidative amination of alkyl C(sp3)–H, alkenyl and arene C(sp2)–H, and terminal alkyne C(sp)–H bonds. Two further bond forming methods are intramolecular nitrenoid–arene C(sp2) coupling and cycloaddition reactions. Transition metals are systematically used in these synthetic methods, and only in a few cases Lewis acids are used as catalysts. In general, the metal-catalyzed cyclizations leading to five-membered heterocycles are very efficient and particularly useful in the synthesis of natural and unnatural biologically active products.

Characterization of Nitrogen-Containing Polycyclic Aromatic Heterocycles in Crude Oils and Refined Petroleum Products.

A large amount of polycyclic aromatic hydrocarbons (PAHs) and their heterocyclic analogues (N, S, O) are released to the marine environment from natural oil seeps, oil spills, bilge discharges and input of land-based sources. Many of these compounds are toxic and have a deleterious effect on marine biota. Nitrogen-containing compounds in crude oils are typically present as cyclic compounds such as polycyclic aromatic nitrogen heterocycles (PANHs) and are generally classified into the two categories of nonbasic (N-PANHs) and basic compounds (B-PANHs). Chromatographic analyses of PANHs are easily to be interfered by other oil components without proper sample preparation prior to instrumental analysis. In this work, dual solid phase extraction columns of 3-(isocyanato)propyl-functionalized silica gel (Si-NCO) and silica gel were employed to efficiently separate both N-PANHs and B-PANHs from saturated and aromatic petroleum hydrocarbons, which enable simultaneous accurate analyses of these groups with single sample preparation. Crude oils studied contain various concentrations of N-PANHs including carbazole, benzocarbazole and B-PANHs including quinolone, acridine and benzoacridine as well as their alkylated homologues. These compounds in light fuel and lubricating oil are generally not detected or are only in trace concentration, but have considerable abundance in heavy fuel oils. Crude oils from different sources and various petroleum products have their unique absolute concentrations and relative distribution patterns of PANHs. Chemical fingerprints of PANHs can provide valuable information for forensic oil spill identification and improve the understanding of the fate, behaviour and chemical degradation of spilled crude oil.

Influence of temperature on nitrogen fate during hydrothermal carbonization of food waste

The influence of temperature (180–260°C) on the fate of nitrogen during hydrothermal carbonization (HTC) of food waste (FW) was assessed. The distribution and evolution of nitrogen in aqueous products and bio-oil, as well as hydrochar, were conducted. Results suggested that elevated temperature enhanced the deamination and the highest ammonium concentration (929.75mg/L) was acquired at 260°C. At temperatures above 220°C, the total N in the hydrochar became stable, whereas the mass percentage of N increased. Amines and heterocyclic-N compounds from protein cracking and Maillard reactions were identified as the main nitrogen-containing compounds in the bio-oil. As to the hydrochar, increasing temperature resulted in condensed nitrogen-containing aromatic heterocycles (e.g. pyridine-N and quaternary-N). In particular, remarkable Maillard reactions at 180°C and the highest temperature at 260°C enhanced nitrogen incorporation (i.e. quaternary-N) into hydrochar.

The nature of the Au–N bond in gold(iii) complexes with aromatic nitrogen-containing heterocycles: the influence of Au(iii) ions on the ligand aromaticity

Aromatic character of nitrogen-containing rings is decreased upon gold(iii) coordination.

Heterocyclic Naphthalimides as New Skeleton Structure of Compounds with Increasingly Expanding Relational Medicinal Applications.

Naphthalimide compounds are an important type of nitrogen-containing aromatic heterocycles with cyclic double imides and the naphthalene framework. This π-deficient large conjugated planar structure enables naphthalimide derivatives to readily interact with various biological cations, anions, small molecules and macromolecules such as DNAs, enzymes and recetors in living organism via noncovalent bonds, therefore exhibiting extensive potentiality in relatively medicinal applications. Currently, some naphthalimides as anticancer agents have entered into clinical trials and other naphthalimide-based medicinal developments as potential drugs for treatment of various diseases are actively and unprecedentedly expanding. Naphthalimide-derived artificial ion receptors, fluorescent probes and cell imaging agents are being overwhelmingly investigated and have a diversity of potential applications in real-time detecting ions and biomolecules, understanding biological processes and determining pharmacological and pharmacokinetic properties. All the above mentions have strongly implied that naphthalimide-based derivatives as new skeleton structure of compounds possess increasingly expanding relational medicinal applications, and the related research is becoming a quite attractive active topic and newly rising highlight. Combining with our research and referring other works from literature, this work systematically reviews the current research and development of heterocyclic naphthalimides as anticancer, antibacterial, antifungal, antiviral, anti-inflammatory, antidepressant agents as well as artificial cation and anion receptors, diagnostic agents and pathologic probes, and cell imaging agents for biologically important species. Some rational design strategies, structure-activity relationships and action mechanisms are discussed. The perspectives of the future development of naphthalimide-based medicinal chemistry are also presented.

The yjdF riboswitch candidate regulates gene expression by binding diverse azaaromatic compounds.

The yjdF motif RNA is an orphan riboswitch candidate that almost exclusively associates with the yjdF protein-coding gene in many bacteria. The function of the YjdF protein is unknown, which has made speculation regarding the natural ligand for this putative riboswitch unusually challenging. By using a structure-probing assay for ligand binding, we found that a surprisingly broad diversity of nitrogen-containing aromatic heterocycles, or “azaaromatics,” trigger near-identical changes in the structures adopted by representative yjdF motif RNAs. Regions of the RNA that undergo ligand-induced structural modulation reside primarily in portions of the putative aptamer region that are highly conserved in nucleotide sequence, as is typical for riboswitches. Some azaaromatic molecules are bound by the RNA with nanomolar dissociation constants, and a subset of these ligands activate riboswitch-mediated gene expression in cells. Furthermore, genetic elements most commonly adjacent to the yjdF motif RNA or to the yjdF protein-coding region are homologous to protein regulators implicated in mitigating the toxic effects of diverse phenolic acids or polycyclic compounds. Although the precise type of natural ligand sensed by yjdF motif RNAs remains unknown, our findings suggest that this riboswitch class might serve as part of a genetic response system to toxic or signaling compounds with chemical structures similar to azaaromatics.

Copper(ii) complexes with aromatic nitrogen-containing heterocycles as effective inhibitors of quorum sensing activity in Pseudomonas aeruginosa

Copper(ii) complexes with aromatic nitrogen-containing heterocycles are a new class of quorum sensing inhibitors that attenuate virulence without a pronounced effect on the bacterial growth, thus offering a lower risk for resistance development.

A comparative antimicrobial and toxicological study of gold(iii) and silver(i) complexes with aromatic nitrogen-containing heterocycles: synergistic activity and improved selectivity index of Au(iii)/Ag(i) complexes mixture

Combination therapy may be applied in the case of gold(iii) and silver(i) complexes with aromatic nitrogen-containing heterocycles to improve their antimicrobial activity and reduce toxic-side effects.

Silver(I) complexes with phthalazine and quinazoline as effective agents against pathogenic Pseudomonas aeruginosa strains

Five silver(I) complexes with aromatic nitrogen-containing heterocycles, phthalazine (phtz) and quinazoline (qz), were synthesized, characterized and analyzed by single-crystal X-ray diffraction analysis. Although different AgX salts reacted with phtz, only dinuclear silver(I) complexes of the general formula {[Ag(X-O)(phtz-N)]2(μ-phtz-N,N′)2} were formed, X=NO3− (1), CF3SO3− (2) and ClO4− (3). However, reactions of qz with an equimolar amount of AgCF3SO3 and AgBF4 resulted in the formation of polynuclear complexes, {[Ag(CF3SO3-O)(qz-N)]2}n (4) and {[Ag(qz-N)][BF4]}n (5). Complexes 1–5 were evaluated by in vitro antimicrobial studies against a panel of microbial strains that lead to many skin and soft tissue, respiratory, wound and nosocomial infections. The obtained results indicate that all tested silver(I) complexes have good antibacterial activity with MIC (minimum inhibitory concentration) values in the range from 2.9 to 48.0μM against the investigated strains. Among the investigated strains, these complexes were particularly efficient against pathogenic Pseudomonas aeruginosa (MIC=2.9–29μM) and had a marked ability to disrupt clinically relevant biofilms of strains with high inherent resistance to antibiotics. On the other hand, their activity against the fungus Candida albicans was moderate. In order to determine the therapeutic potential of silver(I) complexes 1–5, their antiproliferative effect on the human lung fibroblastic cell line MRC5, has been also evaluated. The binding of complexes 1–5 to the genomic DNA of P. aeruginosa was demonstrated by gel electrophoresis techniques and well supported by molecular docking into the DNA minor groove. All investigated complexes showed an improved cytotoxicity profile in comparison to the clinically used AgNO3.

Enthalpy of formation of five-membered nitrogen-containing aromatic heterocycles

The correlation between experimental and computed (PM3) values of heat of formation of five-membered and fused nitrogen-containing aromatic heterocycles has been revealed. The corresponding linear regression equation has been applied to compute enthalpies of formation of 37 compounds.