Nitrogen Heterocycles Research Articles

Optimization of Fermentation Conditions for 2,3,5-Trimethylpyrazine Produced by Bacillus amyloliquefaciens from Daqu

2,3,5-trimethylpyrazine (TMP), as a volatile heterocyclic nitrogen compound, has a wide range of applications. To explore an efficient and environmentally friendly way to produce TMP, Bacillus strains were isolated from Daqu using traditional separation and purification methods. The fermentation products were detected by gas chromatography–mass spectrometry (GC-MS), and the species relationship of strains was analyzed by morphological and phylogenetic tree construction. Single factors were selected to optimize the fermentation process of TMP production, and a Box–Behnken design was used for response surface testing. The LC-6 strain isolated from Daqu was Bacillus amyloliquefaciens, and its fermentation products contained TMP, with a relatively high value of 0.071 ± 0.011 mg/g, indicating that the LC-6 strain was a potentially valuable TMP-producing bacterium. The results of single-factor testing showed that temperature, bottle capacity, and water addition significantly affected TMP production. Box–Behnken design and response surface analysis revealed that the order of influence on TMP yield was as follows: water addition > temperature > bottle capacity. Response surface optimization results showed that the optimal parameters for wheat medium fermentation were temperature 37 °C, bottle capacity 100 g/250 mL, and water addition 39 mL. Under these fermentation conditions, the average production of TMP was 0.446 ± 0.052 mg/g, which was 0.375 mg/g higher than that obtained before optimization. Compared with the previous period, the production of TMP indeed increased, providing a basis for further research on the solid-state fermentation process of TMP synthesis.

Benzo‐fused Nitrogen Heterocycles by Asymmetric Ring Expansion and Stereochemically Retentive Re‐contraction of Cyclic Ureas

AbstractBenzo‐fused nitrogen heterocycles are common features of bioactive molecules, and the enantioselective synthesis of their substituted analogues is an important goal. In this paper we demonstrate a practical and mechanistically intriguing approach to the enantioselective synthesis of 1‐arylbenzazepines and their analogues. The reaction sequence starts with an asymmetric migratory ring expansion of indoline, tetrahydroquinoline, or tetrahydrobenzazepine ureas on treatment with a chiral lithium amide base. Treatment of the ring‐expanded ureas with acid triggers a two‐atom ring contraction—an ‘azatropic shift’ in which one urea nitrogen displaces the other—with almost complete retention of stereochemistry. Aminolysis of the urea products provides enantioenriched 1‐aryl‐tetrahydrobenzazepine derivatives and their congeners, including an analogue of an intermediate in the synthesis of the drug solifenacin. Deuteration, in situ IR, and DFT studies provide evidence for the mechanisms of the reaction steps.

Benzo-fused Nitrogen Heterocycles by Asymmetric Ring Expansion and Stereochemically Retentive Re-contraction of Cyclic Ureas.

Benzo-fused nitrogen heterocycles are common features of bioactive molecules, and the enantioselective synthesis of their substituted analogues is an important goal. In this paper we demonstrate a practical and mechanistically intriguing approach to the enantioselective synthesis of 1-arylbenzazepines and their analogues. The reaction sequence starts with an asymmetric migratory ring expansion of indoline, tetrahydroquinoline, or tetrahydrobenzazepine ureas on treatment with a chiral lithium amide base. Treatment of the ring-expanded ureas with acid triggers a two-atom ring contraction-an 'azatropic shift' in which one urea nitrogen displaces the other-with almost complete retention of stereochemistry. Aminolysis of the urea products provides enantioenriched 1-aryl-tetrahydrobenzazepine derivatives and their congeners, including an analogue of an intermediate in the synthesis of the drug solifenacin. Deuteration, in situ IR, and DFT studies provide evidence for the mechanisms of the reaction steps.

Mechanistic Investigation, Wavelength-Dependent Reactivity, and Expanded Reactivity of N-Aryl Azacycle Photomediated Ring Contractions.

Under mild blue-light irradiation, α-acylated saturated heterocycles undergo a photomediated one-atom ring contraction that extrudes a heteroatom from the cyclic core. However, for nitrogenous heterocycles, this powerful skeletal edit has been limited to substrates bearing electron-withdrawing substituents on nitrogen. Moreover, the mechanism and wavelength-dependent efficiency of this transformation have remained unclear. In this work, we increased the electron richness of nitrogen in saturated azacycles to improve light absorption and strengthen critical intramolecular hydrogen bonding while enabling the direct installation of the photoreactive handle. As a result, a broadly expanded substrate scope, including underexplored electron-rich substrates and previously unsuccessful heterocycles, has now been achieved. The significantly improved yields and diastereoselectivities have facilitated reaction rate, kinetic isotope effect (KIE), and quenching studies, in addition to the determination of quantum yields. Guided by these studies, we propose a revised ET/PT mechanism for the ring contraction, which is additionally corroborated by computational characterization of the lowest-energy excited states of α-acylated substrates through time-dependent DFT. The efficiency of the ring contraction at wavelengths longer than those strongly absorbed by the substrates was investigated through wavelength-dependent rate measurements, which revealed a red shift of the photochemical action plot relative to substrate absorbance. The elucidated mechanistic and photophysical details effectively rationalize empirical observations, including additive effects, that were previously poorly understood. Our findings not only demonstrate enhanced synthetic utility of the photomediated ring contraction and shed light on mechanistic details but may also offer valuable guidance for understanding wavelength-dependent reactivity for related photochemical systems.

A novel co-metabolic mode with Spirulina powder in enhancing the anaerobic degradation of typical nitrogen heterocyclic compounds

ABSTRACT Spirulina powder emerged as a novel and suitable co-metabolism substance significantly enhancing the anaerobic degradation of specific nitrogen heterocyclic compounds. On the addition of 1.0 mg/L of Spirulina powder, the reactor demonstrated optimal degradation efficiency for quinoline and indole, achieving ratios of 99.77 ± 1.83% and 99.57 ± 1.98%, respectively. Moreover, the incorporation of Spirulina powder resulted in increased concentrations of mixed liquor suspended solids, mixed liquor volatile suspended solids, proteins, and polysaccharides in anaerobic sludge. In addition, Spirulina powder led to reduced levels of Acinetobacter and enriched Aminicenantes genera incertae sedis, Levilinea, and Longilinea. The analysis of the archaeal community structure confirmed that the addition of Spirulina powder increased archaeal sequences, fostering greater richness and diversity in the archaeal community.

A density functional theory investigation of the substituent effect on acyclovir and guanine derivatives for applications on energetic materials

The main challenge in designing new energetic materials is to find a good balance between four seemingly incompatible requirements, namely, high-energy content, low sensitivity, low production costs and less-polluting content. Fused nitrogen heterocycles of imidazole and pyrimidine, such as acyclovir and guanine, may offer interesting features due to the combination of a coplanar framework and a large conjugate system, which contribute to a reduced sensitivity, and a number of energetic bonds that can be increased by the introduction of explosophore substituents. In this work, to evaluate the potential of acyclovir and guanine derivatives as energetic materials, density functional theory (DFT) calculations were carried out to investigate the influence of the type and position of the explosophore substituent groups –NO2, –NHNO2, –N3, –ONO2, –CN, −N=N−, and −N=N(O)− on the energetic properties and chemical reactivity of 91 acyclovir- and guanine-based molecules, including thirty one nitramines, three nitroheterocycles, seventeen azides, seventeen nitrate esters, seventeen nitriles, three azo and three azoxy compounds. Several molecular properties were computed, including the chemical reactivity, the heat of formation and the detonation velocities and pressures using semiempirical equations. Among the molecules with no bridge groups, we found that, except for cyano group, position 4 were the most stable for acyclovir derivatives, whereas, except for the azido group, position 2 and 5 provided the most stable compounds for guanine derivatives. Among the bridged derivatives, depending on the molecule and positions, the nitrate esters and the nitro derivatives were more stable. In comparison with the parent compounds, calculations showed that the heat of formation (HOF) increased the most with azido and cyano groups, the density increased substantially with nitrate esters, nitro and nitramino groups, and the detonation velocities and pressures increased the most with nitrate ester, nitro and nitramino groups. Although azo groups resulted in higher HOFs than azoxy groups, azoxy derivatives showed superior values in terms of density, heat of maximum detonation, detonation velocity and pressure. Four nitrate esters (GD134, GD245, AZOXYGD13 and AZOXYGD25) displayed higher values of detonation velocity and pressure than RDX. The designed nitramines are less sensitive to impact than RDX. Except for GD134 and GD245, all guanine-based nitrate esters, with no bridge linkages, are expected to be less sensitive to impact than TNT. Due to the combination of good performance and stability, the compounds GD25, GD13, GD45, GD34, and GD14 have considerable potential as energetic materials. Therefore, their synthesis and further investigation are recommended.

Tribological properties of matrine in soybean oil as additive

To enhance the oxidation stability and tribological properties of soybean oil, we synthesized a novel environmentally benign, modified soybean oil (MSO) by incorporating matrine into soybean oil under solvent-free conditions. Furthermore, we experimentally investigated the molecular structure and tribological performance of MSO. Results reveal that the long-chain links of the N–H bonds is formed between matrine and soybean oil molecules through electrostatic interaction, rendering MSO with excellent thermal oxidation stability similar to matrine. The average friction coefficient and wear volume of MSO decreased by 40.5% and 76.4%, respectively, compared to soybean oil. Further, MSO exhibits excellent friction-reducing and antiwear properties compared to PAO. Raman and X-ray photoelectron spectroscopy analyses reveal that MSO containing nitrogen heterocycles is more inclined to penetrate the friction contact zone and form a physical adsorption film. Simultaneously, a chemical adsorption film comprising nitrogen-containing metal complexes and iron complexes was formed during the friction reaction.

Why pyrrolidines did not work in the alkylation–cyclization–isomerization–3-aza-Cope cascade?

Alkylation–cyclization–isomerization–3-aza-Cope cascade is a powerful method for constructing fused nitrogen heterocycles bearing tetrasubstituted carbons. Despite this, the use of pyrrolidines as starting substrates in these reactions remains limited. In our study, we conducted a detailed analysis of the cascade product using OTBS-substituted pyrrolidine. Our findings revealed that the main product was a nine-five-membered bicyclic enamine, which formed through a 3-aza-Cope rearrangement from syn-vinylammonium. Further, our comprehensive DFT calculations of the transition states of the 3-aza-Cope rearrangement from both anti- and syn-dienolates and vinylammoniums demonstrated that the rearrangement from syn-vinylammonium was more favorable. This preference stems from its progression through a late transition state that minimizes distortion of the pyrrolidine ring. These findings enhance our understanding of the mechanism and facilitate the prediction of outcomes of future cascade reactions.

14N to 15N Isotopic Exchange of Nitrogen Heteroaromatics through Skeletal Editing.

The selective modification of nitrogen heteroaromatics enables the development of new chemical tools and accelerates drug discovery. While methods that focus on expanding or contracting the skeletal structures of heteroaromatics are emerging, methods for the direct exchange of single core atoms remain limited. Here, we present a method for 14N → 15N isotopic exchange for several aromatic nitrogen heterocycles. This nitrogen isotope transmutation occurs through activation of the heteroaromatic substrate by triflylation of a nitrogen atom, followed by a ring-opening/ring-closure sequence mediated by 15N-aspartate to effect the isotopic exchange of the nitrogen atom. Key to the success of this transformation is the formation of an isolable 15N-succinyl intermediate, which undergoes elimination to give the isotopically labeled heterocycle. These transformations occur under mild conditions in high chemical and isotopic yields.

Copper-catalyzed direct α-peroxidation of nitrogen heterocycles

Copper-catalyzed direct α-peroxidation of nitrogen heterocycles

Synthesis of polysubstituted azepanes by dearomative ring expansion of nitroarenes.

The synthesis of functionalized nitrogen heterocycles is integral to discovering, manufacturing and evolving high-value materials. The availability of effective strategies for heterocycle synthesis often biases the frequency of specific ring systems over others in the core structures of bioactive leads. For example, while the six- and five-membered piperidine and pyrrolidine are widespread in medicinal chemistry libraries, the seven-membered azepane is essentially absent and this leaves open a substantial area of three-dimensional chemical space. Here we report a strategy to prepare complex azepanes from simple nitroarenes by photochemical dearomative ring expansion centred on the conversion of the nitro group into a singlet nitrene. This process is mediated by blue light, occurs at room temperature and transforms the six-membered benzenoid framework into a seven-membered ring system. A following hydrogenolysis provides the azepanes in just two steps. We have demonstrated the utility of the strategy with the synthesis of several azepane analogues of piperidine drugs.

QSAR and docking based lead optimization of nitrogen heterocycles for enhanced prostaglandin EP2 receptor agonistic potency

In the existing effort, a dataset of 309 experimentally screened molecules for in vitro (Ki) agonist potential for Prostaglandin E2 (PGE2) receptor 2 subtype (EP2), which is a metabolite of arachidonic acid that binds with and regulates cellular responses to PGE2, was investigated in the QSAR (Quantitative structure–activity relationship) study. A six-parameter QSAR model was developed that meets the specified values ​​for internal and external validation as well as random parameters such as R2tr = 0.808, Q2LMO = 0.794, R2ex = 0.781. Insightful and quantitative opinion reveals several underappreciated and distinct structural features that are responsible for the agonist potency of these molecules on Prostaglandin EP2 receptor such as; the hydrogen atom is correct 2 bonds from the donor atom, the sp2 hybridized carbon atom is correct 2 bonds from the cyclic nitrogen atom, and so on. The developed QSAR model captures the narrative as well as the novel pharmacophoric features. The QSAR effect was further demonstrated using the reported crystalline buildings of CP533536 with the Prostaglandin EP2 receptor activity. The evaluation led to the identification of valuable new pharmacophoric properties that will be used to optimize lead compounds in the future.

Modulating effect of urea/melamine on Co2+/Co3+ ratio of Co3O4 microplates for rapid hydrogen generation via NaBH4 hydrolysis

The oxidation state of an active metal is vital in the hydrolysis of NaBH4 for rapid hydrogen generation since the electron-rich and electron-deficient sites facilitate BH4− and H2O adsorption. Herein, we systematically design a tunable oxidation state of Co in Co3O4 by in situ N-doing using the combination of melamine (M) and urea (U) as nitrogen precursors during thermal treatment. The oxidation state of Co was tuned via electronic interaction between N and Co. This interaction was optimized by varying the amount of N doping and calcination temperature. The types of heterocyclic nitrogen, mainly pyridinic- and graphitic-N, and their carbon matrix content are critical in controlling the Co oxidation state. Various Co2+/Co3+ ratios showed a different catalytic performance, and the catalytic activity reached its peak at the highest ratio of 2.74 due to the synergetic effect of the maximum adsorption of BH4− and H2O by Co2+ and Co3+, respectively. Consequently, an excellent hydrogen generation rate (2042 mL g−1 min−1) was achieved with a low activation energy of 46.9 kJ mol−1 of M2.5U10Co3O4-400. Hence, N doping from a dual N source significantly enhanced the hydrogen performance compared to the reported cobalt-based catalyst. Furthermore, M2.5U10Co3O4-400 is highly recyclable, implying its stability and practical application.

Recent Studies of Nitrogen and Sulfur Containing Heterocyclic Analogues as Novel Antidiabetic Agents: A Review.

The prevalence of diabetes mellitus is on the rise, which demands the identification of novel antidiabetic drugs. There is a need for safer and more effective alternatives because the therapy methods now available to manage diabetes have limits. Due to their diverse pharmacological characteristics, heterocyclic molecules with nitrogen and Sulfur atoms have become intriguing candidates in medicinal chemistry. These substances have a wide variety of structures that can be customized to target different pathways associated with diabetes and can affect important biological targets involved in glucose homeostasis. This review provides a thorough summary of the most recent studies on heterocyclic analogues of nitrogen and Sulfur as prospective antidiabetic agents. This review examines the variety of their structural forms, their methods of action, and assesses the results of preclinical and clinical investigations on their effectiveness and safety. Additionally, further optimization and development of innovative antidiabetic medications are highlighted, as well as the difficulties and prospects for the future in utilizing the therapeutic potential of these analogues. This study seeks to stimulate additional investigation and cooperation between researchers and medicinal chemists, promoting improvements in the creation of efficient and secure antidiabetic medicines to fulfill the needs in the management of diabetes.

Bioinspired Pyrano[2,3-f]chromen-8-ones: Ring C-Opened Analogues of Calanolide A: Synthesis and Anti-HIV-1 Evaluation.

We have designed and synthesized a series of bioinspired pyrano[2,3-f]coumarin-based Calanolide A analogs with anti-HIV activity. The design of these new calanolide analogs involved incorporating nitrogen heterocycles or aromatic groups in lieu of ring C, effectively mimicking and preserving their bioactive properties. Three directions for the synthesis were explored: reaction of 5-hydroxy-2,2-dimethyl-10-propyl-2H,8H-pyrano[2,3-f]chromen-8-one with (i) 1,2,4-triazines, (ii) sulfonylation followed by Suzuki cross-coupling with (het)aryl boronic acids, and (iii) aminomethylation by Mannich reaction. Antiviral assay of the synthesized compounds showed that compound 4 has moderate activity against HIV-1 on enzymes and poor activity on the cell model. A molecular docking study demonstrates a good correlation between in silico and in vitro HIV-1 reverse transcriptase (RT) activity of the compounds when docked to the nonnucleoside RT inhibitor binding site, and alternative binding modes of the considered analogs of Calanolide A were established.

Ni‐Catalyzed Enantioselective Difunctionalization of Alkynes to Azepine Derivatives Bearing a Quaternary Center and an Unprotected Imine†

Comprehensive SummaryThe azepine ring is a prominent structural scaffold in biologically significant molecules. In this study, we present a Ni(II)‐catalyzed asymmetric difunctionalization of alkynes, involving intermolecular regioselective arylation and intramolecular nitrile addition, enabling the synthesis of enantioenriched azepine derivatives. This reaction simultaneously installs an all‐carbon quaternary stereocenter and introduces an unprotected imine functionality, showing great promise for subsequent transformations. The reaction exhibits good tolerance toward various functional groups, resulting in high yields and enantioselectivities. The synthetic utility of this methodology is further demonstrated through gram‐scale synthesis and product derivatization. This research offers an efficient approach to the synthesis of seven‐membered nitrogen heterocycles.

Recent Strategies in the Nucleophilic Dearomatization of Pyridines, Quinolines, and Isoquinolines.

Dearomatization reactions have become fundamental chemical transformations in organic synthesis since they allow for the generation of three-dimensional complexity from two-dimensional precursors, bridging arene feedstocks with alicyclic structures. When those processes are applied to pyridines, quinolines, and isoquinolines, partially or fully saturated nitrogen heterocycles are formed, which are among the most significant structural components of pharmaceuticals and natural products. The inherent challenge of those transformations lies in the low reactivity of heteroaromatic substrates, which makes the dearomatization process thermodynamically unfavorable. Usually, connecting the dearomatization event to the irreversible formation of a strong C-C, C-H, or C-heteroatom bond compensates the energy required to disrupt the aromaticity. This aromaticity breakup normally results in a 1,2- or 1,4-functionalization of the heterocycle. Moreover, the combination of these dearomatization processes with subsequent transformations in tandem or stepwise protocols allows for multiple heterocycle functionalizations, giving access to complex molecular skeletons. The aim of this review, which covers the period from 2016 to 2022, is to update the state of the art of nucleophilic dearomatizations of pyridines, quinolines, and isoquinolines, showing the extraordinary ability of the dearomative methodology in organic synthesis and indicating their limitations and future trends.

Harnessing unprotected deactivated amines and arylglyoxals in the Ugi reaction for the synthesis of fused complex nitrogen heterocycles.

Piperazines and diazepines are examples of nitrogen heterocycles present in many marketed drugs highlighting their importance in the discovery of novel bioactive compounds. However, their synthesis often faces challenges, including complex functionalization and lengthy reaction sequences. Multicomponent reactions, notably the Ugi reaction, have emerged as powerful tools to address these hurdles. Here, we have demonstrated the possibility of using the combination of arylglyoxals and carboxylic acids tethered to nonprotected deactivated amines as a powerful strategy for the synthesis of complex fused heterocycles. The limited nucleophilic character of the amino group of the anthranilic acid, indole-2-carboxylic acid, pyrrole-2-carboxylic acid or N-phenylglycine has allowed the use of these compounds in the Ugi reaction without triggering competitive reactions. The additional functional group present in the resulting Ugi adduct can be leveraged in different post-condensation strategies to easily generate multiple fused nitrogen heterocycles including benzodiazepinone and piperazinone cores.

Recent advances in the radical cascade reaction for constructing nitrogen heterocycles using azides as radical acceptors.

Due to the high conversion properties, azide compounds are widely utilized in organic synthesis. For instance, azide compounds readily release nitrogen to form a new N-C bond when they function as radical acceptors for the active intermediates in the reaction. Over the past decade, strategies employing azides as radical acceptors to construct nitrogen heterocycles have been extensively developed. This approach has emerged as a crucial method for synthesizing nitrogen heterocycles. Therefore, this paper provides a review of the research advancements in tandem cyclization reactions using azides as radical acceptors, summarizing the process of reaction design, exploration, reasoning of the mechanism, and prospects for further research of these reactions.

Physical removal of PAXHs from highly contaminated soil by density differentiation: studying the effectiveness on the molecular level.

Contaminated soils from industrial sites, such as for coal mining or manufactured gas production, can contain polycyclic aromatic hydrocarbons (PAHs) with a concentration higher than 10 000 mg kg-1, which require an integrated approach for remediation. A physical treatment by separating organic contaminants from soil materials using the density difference could lower the cost for the upcoming chemical and/or biological treatment. In our study, a highly PAH contaminated soil was separated in a 39% (w/w) calcium chloride solution (ρ = 1.4 g cm-3) via stirring, aeration or ultrasonication. Both first and second methods could separate soil materials from organic particles efficiently. The light fraction comprised around 10% of the total soil weight but 80% of solvent extractable organics (SEO). Optical and transmission electron microscopic analysis showed the light fraction, which consisted of mainly black solid aggregates (BSA), differed strongly from soil materials. Additionally, the original contaminated soil, its light and heavy fractions and the corresponding water phase together with the manually separated BSA were analyzed on the molecular level using ultrahigh resolution mass spectrometry (HRMS) with different atmospheric pressure ionization (API) methods, such as electrospray (ESI) and atmospheric pressure photo ionization (APPI). Results showed that SEO, which were primarily associated with BSA and successfully separated through physical method, contained mainly condensed aromatic ring structures of pure hydrocarbons and nitrogen heterocycles with low oxygen content.