Nitrogen-containing Heterocycles Research Articles

Editorial: Recent advances in synthesizing and utilizing nitrogen-containing heterocycles

Editorial: Recent advances in synthesizing and utilizing nitrogen-containing heterocycles

Nickel-Photoredox-Catalyzed Stereoconvergent Coupling of Alkenyl Halides and Nitrogen-Containing Heterocycles.

Nitrogen-containing heterocycles possessing N-alkenyl substituents are an important structural motif. However, the synthetic methods reported thus far cannot selectively synthesize the Z stereoisomer on the basis of the stereochemistry of the substituted alkenes. Herein, we report the stereoconvergent coupling of heterocycles and alkenyl halides consisting of a mixture of E/Z stereoisomers, which selectively afforded the thermodynamically less stable Z-coupling product. Mechanistic studies suggest that a nickel photoredox catalyst facilitates the formation of N-centered heteroarene radicals.

Novel ultra-low NOx coal combustion technologies based on local microenvironment targeted regulation. Part 1. Selective oxygenation

Developing a novel high-efficiency coal combustion technology with ultra-low NOx emission is urgently needed to sustain the good ecological environment. Here, the targeted regulation of local microenvironment around fuel-N, such as functional groups, radicals, molecular configurations, and reaction atmosphere, is realized by the selective oxidation. The molecular configurations, including pore networks and microcrystalline structure in coal, are well characterized through synchrotron radiation-induced SAXS (small angle X-ray scattering) and WAXS (wide angle X-ray scattering) simultaneously. Furthermore, by combining density functional theory (DFT) and experiments, the effects of the local microenvironment on the nitrogen transformation and NO evolution during the thermal conversion are focused on. The results indicate that for the PPA oxidation, the H radicals attack the adjacent carbon to pyrrole/pyridine nitrogen, promoting the conversion of fuel-N to HCN. On the other hand, for the H2O2 oxidation, disrupting the π bond electron cloud by the CO and C = O on the ortho carbon of pyrrole/pyridine dominates the NH3 generation. Additionally, the increased La (average graphene layer extent), a3 (average interlayer spacing), σ3 (standard deviation of interlayer spacing) and σ1 (standard deviation of the first-neighbor distribution) induce massive smaller pores, promoting the generation of abundant reaction defects inside the particles. Importantly, the intensified adsorption on abundant active sites lead to the decreased HCN and increased NH3 evolution, which is adverse for the interaction between homogeneous and heterogeneous NO reduction. Interestingly, the PAA selective oxidation can reduce NO emission by 31.72 % - 34.30 % during the air combustion, which is far better than the H2O2 oxidation. Overall, the attack of free radicals on nitrogen-containing heterocycles promotes the conversion of fuel-N to HCN, the adsorption of which on char surfaces can further enhance the heterogeneous reduction in a lean oxygen atmosphere. The work here provides a novel route for developing high-efficiency and low-NOx combustion technologies.

Tributyl(hexyl)phosphonium chloride as a new leveler for microvia copper superconformal electronic plating

A phosphorus-containing new compound of tributyl(hexyl)phosphonium chloride (TBHP), but not the commonly used nitrogen-containing heterocycles and quaternary ammonium salts, is successfully applied for the superconformal copper filling of microvia in acid sulfate electroplating bath for the application of electronic industry. The molecular interaction mechanisms of TBHP combined with suppressor (polyethylene glycol, PEG) and accelerator (bis-(sodium sulfopropyl)-disulfide, SPS) are investigated in detail. Galvanostatic measurements at platinum rotation disk electrode indicate that the leveler of TBHP among with the suppressor and accelerator behaves the key characters of inhibition and convection-dependent adsorption during copper ions electroreduction for the bottom-up filling of microvia. Cyclic voltammetry measurements and in-situ FTIR spectroscopy further reveal that TBHP synergistically interacts with the suppressor to inhibit copper ions electroreduction at the mouth of microvia; while TBHP competes for adsorption with the accelerator, behaving as TBHP gradually replaced by the accelerator at the bottom. Based on the sufficient theoretical supports, the practical copper electroplating is conducted for the verification of microvia void free filling. In the developed novel copper plating formula containing TBHP, PEG and SPS, the void free filling is successfully achieved and the filling percentage (FP) is high in 95.5%.

Development in the Inhibition of Dengue Proteases as Drug Targets.

Viral infections continue to increase morbidity and mortality severely. The flavivirus genus has fifty different species, including the dengue, Zika, and West Nile viruses that can infect 40% of individuals globally, who reside in at least a hundred different countries. Dengue, one of the oldest and most dangerous human infections, was initially documented by the Chinese Medical Encyclopedia in the Jin period. It was referred to as "water poison," connected to flying insects, i.e., Aedes aegypti and Aedes albopictus. DENV causes some medical expressions like dengue hemorrhagic fever, acute febrile illness, and dengue shock syndrome. According to the World Health Organization report of 2012, 2500 million people are in danger of contracting dengue fever worldwide. According to a recent study, 96 million of the 390 million dengue infections yearly show some clinical or subclinical severity. There is no antiviral drug or vaccine to treat this severe infection. It can be controlled by getting enough rest, drinking plenty of water, and using painkillers. The first dengue vaccine created by Sanofi, called Dengvaxia, was previously approved by the US-FDA in 2019. All four serotypes of the DENV1-4 have shown re-infection in vaccine recipients. However, the usage of Dengvaxia has been constrained by its adverse effects. Different classes of compounds have been reported against DENV, such as nitrogen-containing heterocycles (i.e., imidazole, pyridine, triazoles quinazolines, quinoline, and indole), oxygen-containing heterocycles (i.e., coumarins), and some are mixed heterocyclic compounds of S, N (thiazole, benzothiazine, and thiazolidinediones), and N, O (i.e., oxadiazole). There have been reports of computationally designed compounds to impede the molecular functions of specific structural and non-structural proteins as potential therapeutic targets. This review summarized the current progress in developing dengue protease inhibitors.

Carbonylative synthesis and functionalization of indoles.

Carbonylation processes have become widely recognized as a versatile, convenient, and low-cost method for the synthesis of high-value compounds. Given the great importance of heterocyclic compounds, the carbonylative approach has become increasingly important for their synthesis. In this mini-review, as a class of benzo-fused nitrogen-containing heterocyclic compounds, we summarized and discussed the recent achievements on the synthesis and functionalization of indole derivatives via carbonylative approaches.

Electrochemical Oxidative (4 + 2) Cyclization of Anilines and o-Phenylenediamines for the Synthesis of Phenazines.

Phenazines, crucial constituents of nitrogen-containing heterocycles, widely exist in functional compounds. Herein, we report an anodic oxidative (4 + 2) cyclization between anilines and o-phenylenediamines for the uniform construction of phenazines in a simple undivided cell. Dual C-H amination followed by oxidation represents an outstanding step and atom efficiency. A sequence of phenazines is produced with excellent functional group tolerance at room temperature.

Research Progress and Prospect of Nitrogen-containing Heterocycle in Anti-gastric Cancer Drugs: A Review.

Gastric cancer was the fifth most common cancer, and its drug treatment mainly included chemotherapy, targeted therapy, and immunotherapy. With the rise of immunotherapy in gastric cancer, small-molecule anti-gastric cancer drugs still have irreplaceable places because of many advantages, such as high stability and mass-productivity, high efficiency, and low cost. At present, the small-molecule anti-gastric cancer drugs in the clinic are constrained by their side effects. So, developing more novel anti-gastric cancer drugs with better efficacy and fewer side effects is urgently needed. Nitrogen-containing heterocycle molecules have attracted much attention from researchers due to their high biocompatibility, activity, and bioavailability, and they even could act with a unique mechanism. This review summarized various types of nitrogen-containing heterocycle antigastric cancer lead compounds from 2017 to 2022 in the last five years. Compared with monocyclic nitrogen-containing heterocycle and bicyclic nitrogen-containing heterocycle, the thick nitrogen-containing heterocycle applied as the skeleton not only showed high efficiency and low toxicity but also, interestingly, may have had some unique mechanism such as inhibition of aurora A and B kinases, etc. We propose two prospective and valuable strategies to develop more efficient candidates for anti-gastric cancer. One strategy was further optimized for some lead compounds mentioned in this review. The other strategy involved utilizing the "pseudo-natural products" concept proposed by Professor Wilhelm Waldmann, combining different nitrogen-containing heterocycle fragments in two and three-dimensional spaces to obtain new thick nitrogen-containing heterocycle skeletons. The strategy will contribute to the expansion of the thick nitrogenous heterocycle's framework, and it was expected that more novel mechanisms and more effective antigastric drugs could be found. These two strategies are expected to help researchers develop more anti-gastric cancer drugs with better potency and lower side effects.

Oxidative Transformation of 2-Furylanilines into Indolin-3-ones.

Oxidation of 2-furylaninlies with m-CPBA followed by treatment with a base provides access to functionalized indolin-3-ones. The designed oxidative transformation utilizes an underassessed chemical behavior of furyl-containing amines to form a C-N bond via engaging a β-carbon atom of the furan core upon a ring-forming step, thereby providing an alternative disconnection toward nitrogen-containing heterocycles.

Design and Screening of Fluorescent Probes Based upon Hemicyanine Dyes for Monitoring Mitochondrial Viscosity in Living Cells.

Viscosity, at the subcellular level, plays a crucial role as a physicochemical factor affecting microenvironment homeostasis. Abnormal changes in mitochondrial viscosity often lead to various diseases in the organism. Based on the twisted intramolecular charge transfer mechanism, four hemicyanine dye fluorescent probes (HT-SA, HT-SA-S, HT-Bzh, and HT-NA) were designed and synthesized for viscosity response. The single bond between the nitrogen-containing heterocycle and the carbon-carbon double in the structure of the probe bond served as the viscosity response site. Finally, the probe HT-Bzh was screened as the optimal mitochondrial viscosity probe according to its responsiveness, targeting, and interference resistance. The fluorescence intensity of the probe HT-Bzh increased 22-fold when the viscosity was increased from 13.75 to 811.2 cP. In summary, all four viscosity probes we have developed can be used in different applications depending on the external environment, providing a valuable reference for the design of potential tools to address viscosity monitoring in biological systems.

Exploring theophylline-1,2,4-triazole tethered N-phenylacetamide derivatives as antimicrobial agents: unraveling mechanisms via structure-activity relationship, in vitro validation, and in silico insights.

Theophylline, a nitrogen-containing heterocycle, serves as a promising focal point for medicinal researchers aiming to create derivatives with diverse pharmacological applications. In this work, we present an improved synthetic method for a range of theophylline-1,2,4-triazole-S-linked N-phenyl acetamides (4a‒g) utilizing ultrasound-assisted synthetic approach. The objective was to assess the effectiveness of synthesized theophylline-1,2,4-triazoles (4a‒g) as inhibitors of HCV serine protease and as antibacterial agents against B. subtilis QB-928 and E. coli AB-274. Theophylline-1,2,4-triazoles were obtained in good to excellent yields (69%-95%) in a shorter time than conventional approach. 4-Chlorophenyl moiety containing theophylline-1,2,4-triazole 4c displayed significantly higher inhibitory activity against HCV serine protease enzyme (IC50 = 0.015 ± 0.25mg) in comparison to ribavirin (IC50 = 0.165 ± 0.053mg), but showed excellent binding affinity (-7.55kcal/mol) with the active site of serine protease, better than compound 4c (-6.90kcal/mol) as well as indole-based control compound 5 (-7.42kcal/mol). In terms of percentage inhibition of serine protease, 2-chlorophenyl compound 4b showed the maximum percentage inhibition (86%), more than that of the 3,4-dichlorophenyl compound 4c (76%) and ribavirin (81%). 3,4-Dimethylphenyl-based theophylline-1,2,4-triazole 4g showed the lowest minimum inhibitory concentration (MIC = 0.28 ± 0.50μg/mL) against the B. subtilis bacterial strain as compared to the standard drug penicillin (MIC = 1 ± 1.50μg/mL). The other 4-methylphenyl theophylline-1,2,4-triazole 4e (MIC = 0.20 ± 0.08μg/mL) displayed the most potent antibacterial potential against E. coli in comparison to the standard drug penicillin (MIC = 2.4 ± 1.00μg/mL). Molecular docking studies further helped in an extensive understanding of all of the interactions between compounds and the enzyme active site, and DFT studies were also employed to gain insights into the molecular structure of the synthesized compounds. The results indicated that theophylline-linked triazole derivatives 4b and 4c showed promise as leading contenders in the fight against the HCV virus. Moreover, compounds 4e and 4g demonstrated potential as effective chemotherapeutic agents against E. coli and B. subtilis, respectively. To substantiate these findings, additional in vivo studies and clinical trials are imperative, laying the groundwork for their integration into future drug design and development.

2,2'-Bipyridine-Enabled Photocatalytic Radical [4+2] Cyclization of N-Aryl-α-amino Acids for Synthesizing Polysubstituted Tetrahydroquinolines.

A facile photocatalytic radical [4+2] cyclization of N-aryl-α-amino acids with various alkenes to access structurally polysubstituted tetrahydroquinolines has been developed. Using a simple bipyridine as a catalyst, different N-aryl-α-amino acids could be utilized as the radical precursors to react with diverse electrophilic alkenes, including exocyclic terminal alkenes, acyclic terminal alkenes, and cycloalkenes, producing 10 types of nitrogen-containing heterocyclic compounds fused in multiple frameworks in generally moderate yields with good diastereoselectivities. Scale-up synthesis and transformations of the products further demonstrated the synthetic application of this protocol. Moreover, a decarboxylative radial pathway via a proton-coupled electron transfer process for illustration of this [4+2] cyclization was proposed on the basis of the control experiments. This process is highlighted by a simple bipyridine photocatalysis, mild reaction conditions, various N-aryl-α-amino acids and alkene materials, and application for the modification of natural products.

Review on Pyrazole Hybrids as Anti-microbial Agents

Abstract: A five-membered heteroaromatic ring with two nitrogen atoms, pyrazole, is of immense significance. Pyrazole and its derivatives are well-known nitrogen-containing heterocyclic compounds that are significant in medicinal chemistry and have a variety of biological properties, according to a thorough analysis of this class of heterocyclic lead. This article summarises some biologically active, potent pyrazole hybrids and their structure-activity relationship for antimicrobial activity published by various researchers across the world. It is divided into two sections. The first part summarizes recent developments in pyrazole derivatives for various biological activities, such as anti-Alzheimer’s, antioxidant, anticancer, anti-inflammatory, and antiviral, while the second section focuses on a detailed substitution analysis of pyrazole with its hybrid, which is the structure-activity relationship needed for antimicrobial activity. The presence of pharmacological potential of pyrazole moiety has been demonstrated by the role of a nucleus in pharmacological agents from different therapeutic groups, such as the potent anti-inflammatory agent celecoxib, anti-obesity drug rimonabant, analgesic diphenamizole, H2-receptor agonist betazole, and antidepressant agent fezolamide. The design of new pyrazole derivatives has become an interesting research area due to their versatile nature and biological significance. Moreover, it has been observed that pyrazole in combination with another moiety has a strong potent antimicrobial effect.

Construction of S scheme ZnO/g-C3N4 heterojunction for the removal of pyridine from coal chemical wastewater

In order to achieve the removal of nitrogen-containing heterocyclic compound pyridine in coal chemical wastewater. The S scheme ZnO/g-C3N4 heterojunction was constructed by evaporation solvent-high temperature thermal polymerization. The construction of the S scheme heterojunction effectively improved the photocatalytic activity. The S scheme heterojunction well retained the h+ with high oxidation activity of ZnO-VB and the e− with high reduction activity of g–C3N4–CB, achieving efficient separation of e−-h+. The complex band structure and potential difference lead to the bending of the band and the formation of the internal electric field, which effectively realizes the charge separation. ZnO/g-C3N4 heterojunction shows good activity and stability, and has great potential in the field of organic pollutant wastewater treatment. The construction of S scheme heterojunction also provides a new way to improve the activity of photocatalyst.

Unveiling the innovation: Optimized biodiesel production from emerging Acer truncatum Bunge seed oil using novel and highly effective alkaline ionic liquid catalyst

Herein, three novel alkaline ionic liquids (ILs) with nitrogen-containing heterocycles were prepared via a two-step method, which were then utilized as excellent catalysts for biodiesel synthesis through transesterification of emerging Acer truncatum Bunge seed oil (ATBSO) and methanol. The alkaline ILs exhibited favorable catalytic performance, with 1-(2,3-dihydroxy)-propyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene) hydroxide ([DPTD][OH]) exhibiting the highest catalytic efficiency among them. Furthermore, the effect of the independent variables and their interactions on biodiesel yield were assessed and optimized using response surface methodology (RSM). Under the optimal parameters, which consisted of a reaction temperature of 71 °C, a reaction time of 137 min, a substrate molar ratio of methanol to ATBSO of 12:1, and a catalyst loading of 1.3 wt%, the biodiesel yield reached a maximum of 97.3 %. The catalytic transesterification of ATBSO for the preparation of biodiesel exhibited an activation energy (Ea), enthalpy (ΔH), entropy (ΔS) and the Gibbs free energy (ΔG) of 35.14 kJ·mol−1, 32.37 kJ·mol−1, −178.80 J·mol−1·K−1 and 93.70 kJ·mol−1 at 343 K, respectively. It is worth noting that, after the reaction, an automatic phase separation between biodiesel and the catalyst occurred, minimizing the processes of product isolation and purification. Additionally, [DPTD][OH] exhibited favorable reusability over the four reaction cycles, providing a sustainable and environmentally friendly approach for biodiesel production. The biodiesel obtained from ATBSO demonstrated excellent physicochemical properties, such as good cold flow property and flash point, which conform to the biodiesel standards outlined in ASTM D6751 and EN 14212.

One-Pot Multicomponent Synthesis of Pyrano[2,3-c]pyrazole and 2-Amino-4Hbenzo[ b]pyrans Catalyzed by Hercynite@SiO2@Tris as Novel and Efficient Nanocatalyst

Abstract: In this study, magnetic hercynite nanoparticles (FeAl2O4, MNPs) were functionalized by cheap and readily available tris(hydroxymethyl)aminomethane (Tris) as an organocatalyst. Various techniques, including Vibrating Sample Magnetometry (VSM), Energy Dispersive X-ray Spectroscopy (EDS), X-ray Diffraction (XRD), Scanning Electron Microscopy (SEM), and Thermogravimetric Analysis (TG) were employed to determine the morphology, particle size, physical properties, and magnetic properties of the nanoparticles. Additionally, Fourier transform infrared spectroscopy (FT-IR) techniques were used to investigate the presence of the functional group. The activity of this new catalyst as a magnetically recoverable nanocatalyst was investigated in the synthesis of oxygen and nitrogen-containing heterocyclic compounds. Pyranoprazole and 2-amino-4Hbenzo[ b]pyrans compounds were synthesized with high efficiency in a short time. FeAl2O4@SiO2@Tris can be separated using magnetic attraction and reused up to 5 consecutive times without a significant decrease in the yield of target products or catalytic activity.

Ruthenium-Induced Decomposition of Hexamethylenetetramine as a Tool for the Acid-Free Sommelet Reaction in Aqueous Medium.

Hexamethylenetetramine (HMTA) is one of the most versatile and most utilized nitrogen-containing heterocyclic compounds in academia and industry. Most of the reactions involving HMTA employ stoichiometric or excess amounts of acid, which hamper the sustainability of the reactions. Herein, we report the first example of the ruthenium-mediated decomposition of HMTA at room temperature, supported by a detailed mechanistic study using thermogravimetric analysis/differential thermal analysis, variable-temperature NMR, UV-vis spectroscopy, and density functional theory techniques. The mechanism study also involves a comparison of the decomposition of HMTA, protonated HMTA, [RuCl3(HMTA)], and [FeCl3(HMTA)], which revealed that [RuCl3(HMTA)] decomposes at the lowest temperature and has the lowest HOMO-LUMO band gap of 2.66 eV. The ruthenium-induced decomposition of HMTA is successfully used as a tool to increase the sustainability of the Sommelet reaction as it employs simple RuCl3·nH2O as a catalyst in as low as 0.5 mol % concentration in aqueous medium. The developed methodology is found to be very selective and efficient even for the very challenging substrates, namely, aliphatic aldehydes and substrates with electron-withdrawing substituents. The findings of this work are the first of its kind in which ruthenium is employed in the Sommelet reaction and also provide a possible platform to improve the sustainability of all reactions involving HMTA as a reactant/reagent.

Cu(I) Complexes Catalyzed the Dehydrogenation of N-Heterocycles.

A copper-catalyzed method for the dehydrogenation of various nitrogen-containing heterocycles to furnish quinolines and indoles has been developed. A range of 1,2,3,4-tetrahydroquinolines underwent dehydrogenation by employing 2 mol % of copper complex Cat 3 as a catalyst and using O2 as an oxidant at 120 °C in 1,2-dichlorobenzene to afford the desired quinolines. The method enables the dehydrogenation of a variety of indolines in the presence of 2 mol % of copper complex Cat 2, using 10 mol % of TEMPO as an additive and O2 as an oxidant under room temperature in tetrahydrofuran to furnish indoles in high yields. Mechanistic studies suggested that the dehydrogenative activity is ascribed to the formation of a copper(II) active species from copper(I) complexes oxidized by O2, which was proved by high-resolution mass spectrometry (HRMS). The copper-catalyzed dehydrogenation reaction proceeds via a superoxide radical anion (·O2-) as proved by electron paramagnetic resonance (EPR) spectrometry. In situ infrared spectroscopy revealed that the dihydroquinoline intermediate was formed in the dehydrogenation of 1,2,3,4-tetrahydroquinolines.

Synthesis and Energetic Characterization of Borane-Amines on High-Nitrogen Heterocycles.

Borane-amines have garnered attention over the last several decades in a variety of applications, ranging from hydrogen storage materials to hypergolic fuel systems. An investigation into the synthesis of borane-amines with high-nitrogen content heterocycles was undertaken in this work. Borane-amines were formed by the reaction of BH3·Me2S in tetrahydrofuran (THF) with the requisite nitrogen-containing heterocycle and isolated by placing the crude reaction mixture in hexanes to precipitate the product. X-ray crystallography, thermogravimetric analysis (TGA), high resolution mass spectroscopy (HRMS), 1H NMR, 13C NMR, and 11B NMR were utilized for product characterization, while impact and friction sensitivity testing were conducted to identify sensitivity in the synthesized compounds. Most isolated borane-amines, except one, were found to decompose in the atmosphere and were more sensitive to mechanical stimuli than their starting materials; however, all synthesized compounds were found to be hypergolic in the presence of white fuming nitric acid (WFNA).

The Effect of 1,3,4-Oxadiazol and 1,2,4-Triazole Compounds on Urease and Pepsin Enzymes

The helicobacter pylori affected urease and pepsin enzymes in the stomach, so the object of this study is to screen the effect of bis 1,3,4-oxadiazole and bis 1,2,4, triazole derivatives compounds on h-pylori urease enzyme in vitro. The results show that urease was inhibited by all produced compounds when the concentration increased. The most effective urease inhibitor is determined to be the compounds (A3e, A3c, A3d and B3c). The clinical study involved studying the pepsin enzyme activity level in H-pyloripatients and control, the results found that the activity of pepsin elevated in h-pylori patients as compared with control. The prepared compounds were screened on pepsin enzyme in vitro and showed that all the prepared compounds decreased the pepsin activity as the concentration increased. The nitrogen heterocyclic compounds. This study concludes that nitrogen-containing heterocyclic compounds have an important future in the treatment of Helicobacter pylori disease.