N-containing Heterocycles Research Articles

Tuning the electrochemical behavior of organodisulfides in rechargeable lithium batteries using N-containing heterocycles

N-containing heterocycles can tune the electrochemical properties of organodisulfides in lithium batteries. 2,2′-Dipyridyl disulfide exhibits outstanding cycling stability.

Fast Methods for Prediction of Aldehyde Oxidase-Mediated Site-of-Metabolism

Aldehyde Oxidase (AO) is an enzyme involved in the metabolism of aldehydes and N-containing heterocyclic compounds. Many drug compounds contain heterocyclic moieties, and AO metabolism has lead to failure of several late-stage drug candidates. Therefore, it is important to take AO-mediated metabolism into account early in the drug discovery process, and thus, to have fast and reliable models to predict the site of metabolism (SOM). We have collected a dataset of 78 substrates of human AO with a total of 89 SOMs and 347 non-SOMs and determined atomic descriptors for each compound. The descriptors comprise NMR shielding and ESP charges from density functional theory (DFT), NMR chemical shift from ChemBioDraw, and Gasteiger charges from RDKit. Additionally, atomic accessibility was considered using 2D-SASA and relative span descriptors from SMARTCyp. Finally, stability of the product, the metabolite, was determined with DFT and also used as a descriptor. All descriptors have AUC larger than 0.75. In particular, descriptors related to the chemical shielding and chemical shift (AUC = 0.96) and ESP charges (AUC = 0.96) proved to be good descriptors. We recommend two simple methods to identify the SOM for a given molecule: 1) use ChemBioDraw to calculate the chemical shift or 2) calculate ESP charges or chemical shift using DFT. The first approach is fast but somewhat difficult to automate, while the second is more time-consuming, but can easily be automated. The two methods predict correctly 93% and 91%, respectively, of the 89 experimentally observed SOMs.

Dioxygen-triggered oxidative cleavage of the C–S bond towards C–N bond formation

Research on the cleavage of C-C bonds has been well developed. By comparison with this, the activation of C-S bonds remains challenging. Herein, dioxygen-triggered oxidative cleavage of C-S bonds has been achieved, delivering a series of N-containing heterocyclic compounds that are frequently found in pesticides and pharmaceuticals. Additionally, the potential utility of this protocol was further demonstrated by a gram-scale experiment. Mechanistically, dioxygen plays a key role in the cleavage of C-S bonds towards C-N bond formation.

S8-Catalyzed triple cleavage of bromodifluoro compounds for the assembly of N-containing heterocycles.

An unprecedented S8-catalyzed selective triple-cleavage of bromodifluoroacetamides is disclosed for the first time. Valuable 2-amido substituted benzimidazoles, benzoxazoles and benzothiazoles were obtained in good to excellent yields in a cascade protocol in this strategy. Mechanistic studies suggested that a C2 source was generated in situ by selective cleavage of three C-X bonds, including two inert C(sp3)-F bonds on bromodifluoroacetamides, while leaving C-C bonds intact. This strategy will undoubtedly further consummate the role of halo difluoro compounds and enrich both fluorine chemistry and pharmaceutical sciences.

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.

Synthesis of tetrazoles, triazoles, and imidazolines catalyzed by magnetic silica spheres grafted acid

The magnetically separable catalysts are used in the synthesis of N-containing heterocycles, including tetrazoles, triazoles, and imidazolines. The magnetic silica sphere grafted sulfonic acid (MSS-SO3H) is suitable for the synthesis of 1,2,3-triazole via the cycloaddition of nitroalkene with NaN3, whereas the zinc-modified silica sphere catalyst (MSS-SO3Zn) is more suitable for the synthesis of tetrazoles. The MSS-SO3Zn catalyst also works well for the synthesis of 2-substituted imidazoline via the condensation of nitriles with ethylenediamine. Both of the MSS-SO3H and MSS-SO3Zn catalysts can be recovered easily by a magnet, and they can be reused without further tedious activation.

Functionalized N-containing heterocyclic scaffolds derived from N-substituted pyrroles via inter- and intramolecular annulations

Two series of N-containing heterocycles were synthesized by one-step intramolecular or intermolecular annulations of N-substituted pyrrole-2-carbaldehydes and pyrrole-2-carbonitriles. These facile and atom-economic synthetic routes involved the inherent three potential electrophilic and nucleophilic reactive sites of the synthons and the reaction solvent plays a crucial role leading to these different types of products. Additionally, plausible mechanisms are proposed.

Gold-Catalyzed Formal Dehydro-Diels-Alder Reactions of Ene-Ynamide Derivatives Bearing Terminal Alkyne Chains: Scope and Mechanistic Studies.

A new protocol for the synthesis of a variety of N-containing aromatic heterocycles by a formal gold-catalyzed dehydro-Diels-Alder reaction of ynamide derivatives has been developed. Deuterium-labeling experiments and kinetic studies support the involvement of a dual gold catalysis mechanism in which a gold acetylide moiety adds onto an aurated keteneiminium.

Discovery of a New Class of Inhibitors of Vaccinia Virus Based on (-)-Borneol from Abies sibirica and (+)-Camphor.

A series of the bornyl ester/amide derivatives with N-containing heterocycles were designed and synthesized as vaccinia virus (VV) inhibitors. Bioassay results showed that among the designed compounds, derivatives 6, 13, 14, 34, 36 and 37 showed the best inhibitory activity against VV with the IC50 values of 12.9, 17.9, 3.4, 2.5, 12.5 and 7.5 μm, respectively, and good cytotoxicity. The primary structure-activity relationship (SAR) study suggested that the combination of a saturated N-heterocycle, such as morpholine or 4-methylpiperidine, and a 1,7,7-trimethylbicyclo[2.2.1]heptane scaffold was favorable for antiviral activity.

Corrosion inhibition of perimidine derivatives for mild steel in acidic media: Electrochemical and computational studies

1H‑perimidine (PER) and 1H‑perimidin‑2‑amine (NPER) are investigated as corrosion inhibitors of mild steel in acidic media. Electrochemical impedance spectroscopy, potentiodynamic polarization and theoretical calculations are used to study the inhibition performance and adsorption mechanism. At a concentration < 0.15 mM, the inhibition efficiencies of these compounds are >90% for mild steel in 1.0 M HCl. Moreover, the inhibitive capability of NPER is slightly higher than that of PER due to the presence of 2-position amino-group. The fusion of large π-bond system with N-containing heterocycles makes the compounds strongly adsorb on iron surfaces in a nearly parallel mode.

Recent Synthetic Strategies for Monocyclic Azole Nucleus and Its Role in Drug Discovery and Development

Background: In recent years, the development and diversification of heterocyclic compounds has become central to the discovery of bioactive compounds with novel or improved pharmacological properties. In particular, N-containing heterocycles are proved to be promising leads and drug candidates, and received huge attention of the medicinal chemists. Objective: Many drugs especially antibiotics are becoming obsolete due to the development of multidrug resistance. Moreover, toxicity and other side effects of some drugs necessitated the quest for safer and more potent drug candidates. The current review article described biological potential of various monocyclic azoles. Recent developments in the synthesis of azole derivatives have been also reviewed. Conclusion: The presence of N-heterocyclic rings can influence the pharmacokinetics, pharmacodynamics, pKa and bioavailability profile of the drug molecules. Compounds containing monocyclic azole rings showed various biological activities and number of molecules are in clinical practice. A number of important leads and potential drug candidates containing azole nucleus are in advance stages of drug developments. Thus, simple, atom economic and more efficient synthetic strategies are desired for the synthesis of new libraries of the compounds.

Luminescence Mechanism of Carbon Dots by Tailoring Functional Groups for Sensing Fe3+ Ions.

In this paper, spherical carbon dots (CDs) with distinct compositions and surface states have been successfully synthesized by a facile microwave method. From the fluorescence spectra, several characteristic luminescence features have been observed: surface amino groups are dominant in the whole emission spectra centering at 445 nm, and the fingerprint emissions relevant to the impurity levels formed by some groups related to C and N elements, including C-C/C=C (intrinsic C), C-N (graphitic N), N-containing heterocycles (pyridine N) and C=O groups, are located around 305 nm, 355 nm, 410 nm, and 500 nm, respectively. Those fine luminescence features could be ascribed to the electron transition among various trapping states within the band structure caused by different chemical bonds in carbon cores, or functional groups attached to the CDs’ surfaces. According to the theoretical calculations and experimental results, a scheme of the band structure has been proposed to describe the positions of those trapping states within the band gap. Additionally, it has also been observed that the emission of CDs is sensitive to the concentration of Fe3+ ions with a linear relation in the range of Fe3+ concentration from 12.5 to 250 μM.

Formation of aromatics and removal of nitrogen in catalytic fast pyrolysis of sewage sludge: A study of sewage sludge and model amino acids

To elucidate the catalytic mechanism and nitrogen transfer behavior of sewage sludge (SS) during catalytic fast pyrolysis (CFP), product distributions and nitrogen transformation from SS and amino acids during CFP were investigated on a drop tube quartz reactor at various temperatures and HZSM-5 catalysts. Phenylalanine (Phe), proline (Pro), leucine (Leu) and aspartic acid (Asp) were employed as model compounds with different chemical structures for protein-rich SS to help analyze catalytic cracking behavior of SS. During CFP of SS, the maximum aromatics yield of 16.4% was obtained over HZSM-5 with Si/Al ratio of 25 at 500 °C, and increasing temperature promoted the conversion of nitrogen to NH3. Amino acids with aromatic ring or saturated hydrocarbon side chain such as Phe and Leu in SS favored the formation of aromatics and NH3. Amino acids of N-ring structure in SS promoted the formation of N-containing heterocyclic compounds, which were prone to coke on catalyst and inhibited the catalytic cracking of SS to produce more aromatics and NH3. In addition, excessive Asp of short chain dibasic acid structure in SS was not conducive to the complete thermal decomposition of SS under the optimum pyrolysis condition. A general catalytic mechanism of SS was proposed to provide support for the resource reuse of SS.

Aminocarbonylation of N-Containing Heterocycles with Aromatic Amines Using Mo(CO)6

We describe herein the palladium-catalyzed aminocarbonylation of nitrogen-containing heterocycles with aniline derivatives using molybdenum hexacarbonyl as a CO solid source, expanding the scope of the limited examples. This method is compatible with a variety of substitutions on the aniline moiety. The simple reaction conditions include easily available Pd(dppf)Cl2 catalyst, DBU as base in DMF at 120 °C for 3 hours in sealed tube thereby leading to the isolation of 21 compounds with yields ranging from 18 to 82%. We also show that double aminocarbonylation reactions are possible in satisfactory yields regarding both coupling partners.

Diastereoselective Synthesis of Morphan Derivatives by Michael and Hetero-Michael Addition of 1,1-Enediamines to Quinone Monoketals

A general and concise method was developed for the synthesis of highly functionalized morphans 3–4 by the Michael and hetero-Michael addition reaction of different types of quinone monoketals 1 and 1,1-enediamines 2 in ethanol or 1,4-dioxane at reflux. This method is suitable for the efficient parallel syntheses of N-containing heterocycles. A library of highly functional morphan derivatives was easily constructed using the Michael/hetero-Michael reaction.

Metal-Free Synthesis of N-Containing Heterocycles from o-Substituted Aniline Derivatives via 2,4,6-Trihydroxybenzoic Acid-Catalyzed Oxidative Dehydrogenation of Benzylamines under Oxygen Atmosphere

Metal-Free Synthesis of N-Containing Heterocycles from o-Substituted Aniline Derivatives via 2,4,6-Trihydroxybenzoic Acid-Catalyzed Oxidative Dehydrogenation of Benzylamines under Oxygen Atmosphere

Discovery of 2-[(E)-2-(7-Fluoro-3-methylquinoxalin-2-yl)vinyl]-6-pyrrolidin-1-yl-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-amine Hydrochloride as a Highly Selective PDE10A Inhibitor.

Phosphodiesterase (PDE) 10A is a dual hydrolase of cAMP and cGMP and highly expressed in striatal medium spiny neurons. Inhibition of PDE10A modulates the activity of medium spiny neurons (MSN) via the regulation of cAMP and cGMP. Signal control of MSN is considered associated with psychotic symptoms. Therefore PDE10A inhibitor is expected as a therapeutic method for psychosis disease such as schizophrenia. Avanafil (1) is a PDE5 inhibitor (treatment for erectile dysfunction) discovered by our company. We paid attention to the homology of PDE10A and PDE5 and took advantage of PDE5 inhibitor library to discover PDE10A inhibitors, and found a series of compounds that exhibit higher potency for PDE10A than PDE5. We transformed the afforded derivatives, which had weak inhibitory activity against PDE10A, and discovered stilbene as a PDE10A inhibitor. Brain penetration of this compound was improved by further conversion of N-containing heterocycles and their substituents. The afforded dimethylaminopyrimidine was effective for rat conditioned avoidance response (CAR) test; however, it did not exhibit good brain penetration. We performed in-depth optimization focusing on substituents of the quinoxaline ring, and produced 3-methyl-7-fluoro quinoxaline. This compound was the most effective in rat CAR test due to its strong PDE10A inhibitory activity and good pharmacokinetics.

Physical Adsorption of N-containing Heterocycles on Hexagonal Boron Nitride: DFT-D3 Study

Physical Adsorption of N-containing Heterocycles on Hexagonal Boron Nitride: DFT-D3 Study

Photodegradation of Moxifloxacin Hydrochloride Solutions under Visible Light Irradiation: Identification of Products and the Effect of pH on their Formation.

The photodegradation study is essential for the phototoxicity assessment of fluoroquinolones. Various LC-MS techniques and ultraviolet (UV) lamp irradiation conditions have been used for the identification of their photodegradation products. In this study, visible light (400-760nm) lamp irradiation was selected for the photodegradation of moxifloxacin (MOXI) hydrochloride solutions. Two photodegradation products were identified by LC-MS/MS at first, but one product could not be speculated from the mass spectrum and any known degradation mechanisms. To obtain an adequate amount for the structure elucidation, this unknown product was isolated by recrystallization and semi-preparative HPLC. Then, its structure was further identified by 1H-NMR, 13C-NMR, and 2D-NMR. Based on spectral data, this new photodegradation product was unambiguously named as 7-[3-(3-aminopropyl)-1H-pyrrol-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, which was formed through the open of hexahydroxy N-containing heterocycle and the formation of two alkene bonds in pyrrole ring. The effects of solution pH value on the formation of photodegradation products were compared. Their production was minimum at pH5.0 and maximum at pH7.0. Because MOXI hydrochloride has been used extensively in clinical practice and visible light is the most possible light source that pharmaceutical products are exposed to, our study is important for the quality control of MOXI liquid preparations.

Syntheses and crystal structure of copper (II) and cobalt (II) complexes containing N-heterocyclic compounds

Four Cu(II) and Co(II) complexes with N-containing heterocycles as ligands were reported firstly. In a simple method, the reaction of 2-benzenediacetonitrile and pyridine-2-carboxaldehyde 2-quinolylhydrazone with Cu(OAc)2·H2O afforded the copper(II) complexes I–II, and addition of 2-(2-pyridyl)-1-(2-thiazolylazo)-2-naphthol with CoCl2·6H2O and 2-(2-pyridyl)benzimidazole with Co(OAc)2·4H2O furnished two mononuclear cobalt complexes III–IV. The structures of complexes I–IV were determined by elemental analysis, X-ray diffraction, NMR spectroscopy and IR spectroscopy.