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The absence of effective active pockets makes traditional molecularly targeted drug strategies ineffective against 80 % of human disease-related proteins. The PROTAC technology effectively makes up for the deficiency of traditional molecular targeted drugs, which produces drug activity by degrading rather than inhibiting the target protein. The degradation of PROTAC is not only affected by POI ligand and E3 ligand, but by the selection of suitable linker which can play an important role in the efficiency and selectivity of the degradation. In the early exploring stage of the PROTAC, flexible chains were priorly applied as the linker of PROTAC. Although PROTAC with flexible chains as linkers sometimes perform well in vitro bioactivity evaluations, the introduction of lipophilic flexible chains reduces the hydrophilicity of these molecules, resulting in generally poor pharmacokinetic characteristics and pharmacological activities in vivo. In addition, recent reports have also shown that some PROTAC with flexible chains have some risks to causing hemolysis in vivo. Therefore, PROTAC with flexible chains show less druggability and large difficulty to entering the clinical trial stage. On the other hand, the application of nitrogen heterocycles in the design of PROTAC linkers has been widely reported in recent years. More and more reports have shown that the introduction of nitrogen heterocycles in the linker not only can effectively improves the metabolism of PROTAC in vivo, but also can enhance the degradation efficiency and selectivity of PROTAC. These PROTAC with nitrogen heterocycle linkers have attracted much attention of pharmaceutical chemists. The introduction of nitrogen heterocycles in the linker deserves priority consideration in the primary design of the PROTAC based on various druggabilities including pharmacokinetic characteristics and pharmacological activity. In this work, we summarized the optimization process and progress of nitrogen heterocyclic rings as the PROTAC linker in recent years. However, there were still limited understanding of how to discover, design and optimize PROTAC. For example, the selection of the types of nitrogen heterocycles and the optimization sites of this linker are challenges for researchers, choosing between four to six-membered nitrogen heterocycles, selecting from saturated to unsaturated ones, and even optimizing the length and extension angle of the linker. There is a truly need for theoretical explanation and elucidation of the PROTAC to guide the developing of more effective and valuable PROTAC., Competing Interests: Declaration of competing interest The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Betulinic acid (BA) was used as starting building block to create a library of novel BA-derived compounds containing O - and N -heterocycles. Firstly, BA was converted into methyl betulonate (BoOMe), which was used as intermediate in the developed methodologies. 1,2-Oxazine-fused BoOMe compounds were obtained in 12-25% global yields through a Michael addition of nitromethane to methyl ( E )-2-benzylidenebetulonate derivatives, followed by nitro group reduction and intramolecular cyclization. Remarkably, the triterpene acts as a diastereoselective inducer in the conjugate addition of nitromethane, originating only one diastereomer out of four possible ones. Furthermore, other oxygen and nitrogen-containing heterocycles were installed at the A-ring of BoOMe, affording 2-amino-3-cyano-4 H -pyran-fused BoOMe, diarylpyridine-fused BoOMe and 1,2,3-triazole-BoOMe compounds, using simple and straightforward synthetic methodologies. Finally, BA was revealed to be a versatile starting material, allowing the creation of a molecular diversification of compounds containing a triterpenic scaffold and O - and N -heterocycles.

The ability of amino acid "customizable units" to generate structural diversity is illustrated by the conversion of 4-hydroxyproline (Hyp) units into a variety of nitrogen heterocycles. After a first common step, where the unit underwent a one-pot decarboxylation-alkylation reaction to afford 2-alkylpyrrolidines with high stereoselectivity, a divergent step was carried out. Thus, the deprotected 4-hydroxy group was used either to initiate a radical scission that afforded aliphatic β-amino aldehydes, or to carry out an elimination reaction, to give 2-alkyl-2,5-dihydro-1H-pyrroles. In the first case, the amines underwent a tandem reductive amination-cyclization to afford β-amino-δ-lactams, an efficient rigidifying unit in peptides. Different lactam N-substituents, such as alkylamines, peptides, and alkenyl chains suitable for olefin metathesis were introduced this way. In the second case, the pyrrole derivatives were efficiently converted into alkaloid and iminosugar derivatives in good global yields and with excellent stereoselectivity., (© 2022. The Author(s).)

Glycals (carbohydrate enol-ethers) have enjoyed profound applications in organic synthesis for more than a century. They not only serve as versatile glycosyl donors or as substrates for Ferrier rearrangement, but also find extensive synthetic applications especially as a "chiral pool" for accomplishing the synthesis of a variety of natural and biologically important compounds. As cyclic enol ethers, they demonstrate high reactivity and are among the most and variously transformable monosaccharide derivatives. The uniqueness of the reactivity of glycals is that they can be synthetically tuned to get a library of derivatives through stereo- and regioselective introduction of a variety of functional groups at C1, C2, C3 as well as C4 carbons of the sugar. We have developed a practical approach for stereoselective mono- and diamination of glycals and over the years utilized these scaffolds for the synthesis of a variety of biologically important nitrogen heterocycles and carbocycles through a "Diversity Oriented Approach". Our synthetic strategy in this direction mainly relied on the cleavage of ring O-C bond of the sugar followed by an "intramolecular recombination" reaction. Utilizing this strategy, we have accomplished the synthesis of several biologically important natural products, their analogues and related unnatural derivatives. Examples of such compounds reported from our group include polyhydroxypyrrolidines, DMDP, anisomycin, steviamine, pochonicine, conduramines, bulgecinine, aminocyclitols, azepanes, 4-hydroxy-D-proline, azanucleosides and their analogues. A personal account highlighting these syntheses is presented here., (© 2021 The Chemical Society of Japan & Wiley-VCH GmbH.)

Understanding the stabilization of nitrogen heterocycles is critical in the field of energetic materials and calls for innovative knowledge of nitrogen aromatics. Herewith, we report for the first time that nitrogen lone pair electron (NLPE) delocalization in five-membered nitrogen heterocycles creates a second σ-aromaticity in addition to the prototypical π-aromaticity. The NLPE delocalization and the attendant dual-aromaticity are enhanced as more carbon atoms in the ring are substituted by unsaturated nitrogen atoms. The presence of adjacent nitrogen atoms in the ring can enhance the aromaticity of the nitrogen heterocycles and improve in-crystal intermolecular binding strength but will decrease the firmness of the individual molecular architecture. Notably, such σ-aromaticity is not present in six-membered nitrogen heterocycles, probably due to the longer bonds and broader regions of their rings; therefore, six-membered heterocycles present overall lower aromaticity than five-membered heterocycles. This work brings new knowledge to nitrogen aromatics and is expected to inspire broad interest in the chemistry community.

The development of a concise total synthesis of (±)-phyllantidine (1), a member of the securinega family of alkaloids containing an unusual oxazabicyclo[3.3.1]nonane core, is described. The synthesis employs a unique synthetic strategy featuring the ring expansion of a substituted cyclopentanone to a cyclic hydroxamic acid as a key step that allows facile installation of the embedded nitrogen-oxygen (N-O) bond. The optimization of this sequence to effect the desired regiochemical outcome and its mechanistic underpinnings were assessed both computationally and experimentally. This synthetic approach also features an early-stage diastereoselective aldol reaction to assemble the substituted cyclopentanone, a mild reduction of an amide intermediate without N-O bond cleavage, and the rapid assembly of the butenolide found in (1) via use of the Bestmann ylide., (© 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

An aerobic radical approach for the synthesis of unsymmetrical heteroaryl ketones is described herein. The reaction involves cross-dehydrogenative coupling between aldehydes and heteroaromatic bases with molecular oxygen (O 2 ). The key aspect of the method is the generation of reactive acyl radical via homolytic activation of aldehyde C-H bond using O 2 as the sole oxidant. The reaction has a good substrate scope with respect to aldehydes and functionalized nitrogen heterocycles. Based on our mechanistic studies, a radical chain pathway is suggested for the reaction. A synthetic application of the method is demonstrated in the formal synthesis of natural alkaloid (±) angustureine., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Anaerobic bottle experiments were conducted in parallel for 120 consecutive days to perform the bioaugmentation hydrolysis of selected nitrogen heterocyclic compounds (NHCs) in coal gasification wastewater. Due to enhancement with PAC and Fe(OH) 3 @PAC, quinoline, pyridine, and indole were hydrolyzed more effectively. The addition of PAC and Fe(OH) 3 @PAC improved the coagulation capacity of microorganisms, which laid a solid foundation for the removal of selected NHCs and the adverse environmental conditions. Anaerobic degradation of the NHCs occurred first through hydrogenation, then through the opening of the nitrogen heterocycles, followed by the release of ammonia nitrogen and finally the opening of the benzene rings. Enriched Acinetobacter, Levilinea, Comamonas, and Longilinea were the main functional groups responsible for the anaerobic biodegradation of the selected NHCs., (Copyright © 2018. Published by Elsevier Ltd.)

We present a simple method for the fabrication of a magnetic amino-functionalized zinc metal-organic framework based on a magnetic graphene oxide composite. The resultant framework exhibited a porous 3D structure, high surface area and good adsorption properties for nitrogen-containing heterocyclic fungicides. The adsorption process and capacity indicated that the primary adsorption mechanism might be hydrogen bonding and π-π conjugation. In addition, an optimized protocol for magnetic solid phase extraction was developed (such as adsorbent content, pH, and desorption solvent), and utilized for the extraction of nitrogen-containing heterocyclic fungicides from vegetable samples. Quantitation by high performance liquid chromatography coupled with tandem mass spectrometry offered a detection limit of 0.21-1.0 μg/L (S/N = 3) with correlation coefficients larger than 0.9975. These results demonstrate that magnetic amino-functionalized zinc metal-organic framewor is a promising adsorbent for the extraction and quantitation of nitrogen-containing heterocyclic fungicides., (© 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Nitrogen heterocycles represent vital structural motifs in biologically-active natural products and pharmaceuticals. As a result, the development of new, convenient and more efficient processes to N -heterocycles is of great interest to synthetic chemists. Samarium(II) iodide (SmI₂, Kagan's reagent) has been widely used to forge challenging C-C bonds through reductive coupling reactions. Historically, the use of SmI₂ in organic synthesis has been focused on the construction of carbocycles and oxygen-containing motifs. Recently, significant advances have taken place in the use of SmI₂ for the synthesis of nitrogen heterocycles, enabled in large part by the unique combination of high reducing power of this reagent (E 1/2 of up to -2.8 V) with excellent chemoselectivity of the reductive umpolung cyclizations mediated by SmI₂. In particular, radical cross-coupling reactions exploiting SmI₂-induced selective generation of aminoketyl radicals have emerged as concise and efficient methods for constructing 2-azabicycles, pyrrolidines and complex polycyclic barbiturates. Moreover, a broad range of novel processes involving SmI₂-promoted formation of aminyl radicals have been leveraged for the synthesis of complex nitrogen-containing molecular architectures by direct and tethered pathways. Applications to the synthesis of natural products have highlighted the generality of processes and the intermediates accessible with SmI₂. In this review, recent advances involving the synthesis of nitrogen heterocycles using SmI₂ are summarized, with a major focus on reductive coupling reactions that enable one-step construction of nitrogen-containing motifs in a highly efficient manner, while taking advantage of the spectacular selectivity of the venerable Kagan's reagent., Competing Interests: The authors declare no conflict of interest.

The first syntheses of privileged [5,6]-bicyclic heterocycles, with ring-junction nitrogen atoms, by transition metal catalyzed C-H functionalization of C-alkenyl azoles is disclosed. Several reactions are applied to alkenyl imidazoles, pyrazoles, and triazoles to provide products with nitrogen incorporated at different sites. Alkyne and diazoketone coupling partners give azolopyridines with various substitution patterns. In addition, 1,4,2-dioxazolone coupling partners yield azolopyrimidines. Furthermore, the mechanisms for the reactions are discussed and the utility of the developed approach is demonstrated by iterative application of C-H functionalization for the rapid synthesis of a patented drug candidate., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Samarium(II) iodide enables a wide range of highly chemoselective umpolung radical transformations proceeding by electron transfer to carbonyl groups; however, cyclizations of important nitrogen-containing precursors have proven limited due to their prohibitive redox potential. Herein, we report the first reductive cyclizations of unactivated cyclic imides onto N-tethered olefins using SmI2 /H2 O. This new umpolung protocol leads to the rapid synthesis of nitrogen-containing heterocycles that are of particular significance as precursors to pharmaceutical pharmacophores and numerous classes of alkaloids. The reaction conditions tolerate a wide range of functional groups. Excellent chemoselectivity is observed in the cyclization over amide and ester functional groups. Such unconventional reactivity has important implications for the design and optimization of new bond-forming reactions by umpolung radical processes. The reaction advances the SmI2 cyclization platform to the challenging unactivated N-tethered acyl-type radical precursors to access nitrogen-containing architectures., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

In this report, the activity of N-heterocyclic olefins (NHOs) as a newly emerging class of organocatalyst is investigated for the chemical fixation of carbon dioxide through reactions with aziridines to form oxazolidinones and the N-formylation of amines with polymethylhydrosiloxane (PMHS) or 9-borabicyclo[3.3.1]nonane (9-BBN) as the reducing agent under mild conditions. The exocyclic carbon atoms of NHOs are highly nucleophilic owing to the electron-donating ability of the two nitrogen atoms. This high nucleophilicity of the NHOs activates CO2 molecules to form zwitterionic NHO-carboxylate (NHO-CO2 ) adducts, which are active in formylation reactions as well as the carboxylation of aziridines to oxazolidinones., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The BN analogue of ortho-benzyne, 1,2-azaborine, is generated by flash vacuum pyrolysis, trapped under cryogenic conditions, and studied by direct spectroscopic techniques. The parent BN aryne spontaneously binds N2 and CO2, thus demonstrating its highly reactive nature. The interaction with N2 is photochemically reversible. The CO2 adduct of 1,2-azaborine is a cyclic carbamate which undergoes photocleavage, thus resulting in overall CO2 splitting., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Azocine derivatives were successfully synthesized from O-propargylic oximes by means of a Rh-catalyzed 2,3-rearrangement/heterocyclization cascade reaction. Moreover, the chirality of the substrate was maintained throughout the cascade process to afford the corresponding optically active azocines., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

A mild, convenient, and step-economical intramolecular aminotrifluoromethylation of unactivated alkenes with a variety of electronically distinct, nitrogen-based nucleophiles in the presence of a simple copper salt catalyst, in the absence of extra ligands, is described. Many different nitrogen-based nucleophiles (e.g., basic primary aliphatic and aromatic amines, sulfonamides, carbamates, and ureas) can be employed in this new aminotrifluoromethylation reaction. The aminotrifluoromethylation process allows straightforward access to diversely substituted CF3-containing pyrrolidines or indolines, in good to excellent yields, through a direct difunctionalization strategy from the respective acyclic starting materials. Mechanistic studies were conducted and a plausible mechanism was proposed., (Copyright © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Metal‐nitrenes are valuable reactive intermediates for synthesis and are widely used to construct biologically relevant scaffolds, complexes and functionalized molecules. The ring expansion of cyclic molecules via single‐nitrogen‐atom insertion via nitrene or metal‐nitrenoid intermediates has emerged as a promising modern strategy for driving advantageous nitrogen‐rich compound synthesis. In recent years, the catalytic insertion of a single nitrogen atom into carbocycles, leading to N‐heterocycles, has become an important focus of modern synthetic approaches with applications in medicinal chemistry, materials science, and industry. Catalytic single‐nitrogen‐atom insertions have been increasing in prominence in modern organic synthesis due to their capability to construct high‐value added nitrogen‐containing heterocycles from simple feedstocks. In this review, we will discuss the rapidly growing field of skeletal editing via single‐nitrogen‐atom insertion using transition metal catalysis to access nitrogen‐containing heterocycles, with a focus on nitrogen insertion across a wide spectrum of carbocycles. [ABSTRACT FROM AUTHOR]

An efficient access to novel families of 7‐membered dibenzodiazepines and 6‐membered benzo[c]cinnoline derivatives has been elaborated. The synthetic strategy is based on a copper‐catalyzed double N‐arylation of cyclic diaryliodoniums with imidamides and 4‐substituted 1, 2, 4‐triazoline‐3, 5‐diones (TADs) respectively under ambient reaction conditions. A mechanistic rationale for the double N‐arylation is discussed. [ABSTRACT FROM AUTHOR]

Comprehensive Summary: We herein describe a Cp*RhIII‐catalyzed C(sp3)–H mono‐arylation of 8‐methylquinolines with benign arylsilanes. The use of 1‐adamantane carboxylic acid can benefit the efficiency in this transformation, and AgF was both activator and reoxidant. Control experiments indicated inability of C—H cleavage in determining the rate of the reaction. [ABSTRACT FROM AUTHOR]

Introduction of non‐hexagons and/or heteroatoms allows for finely tuning the physicochemical properties of nanographenes. Heteroatoms doping have dominated the modulation of nanographenes with tunable band gap, rich electrochemical activities and so on. The pair of non‐hexagons, for instance, pentagon‐heptagon pairs, have furnished nanographenes with aromatic and/or antiaromatic characteristics, open‐shell properties and so on. In order to meet the growing demand for versatile nanographenes in materials science, research on novel nanographenes with heteroatom doped non‐hexagonal pairs has been aroused in recent years. In this review, we focus on nanographenes with nitrogen‐doped non‐hexagonal paris including the synthesis, structure analysis, photophysical properties, and potential applications in organic devices. [ABSTRACT FROM AUTHOR]

Hypervalent iodine reagents are versatile and readily accessible reagents that have been extensively applied in contemporary synthesis in modern organic chemistry. Among them, iodonitrene (ArI=NR), is a powerful reactive species, widely used for a single‐nitrogen‐atom insertion reaction, and skeletal editing to construct N‐heterocycles. Skeletal editing with reactive iodonitrene components has recently emerged as an exciting approach in modern chemical transformation. These reagents have been extensively used to produce biologically relevant heterocycles and functionalized molecular architectures. Recently, the insertion of a nitrogen‐atom into hydrocarbons to generate N‐heterocyclic compounds using hypervalent iodine reagents has been a significant focus in the field of molecular editing reactions. In this review, we discuss the rapidly emerging field of nitrene insertion, including skeletal editing and nitrogen insertion, using hypervalent iodine reagents to access nitrogen‐containing heterocycles, and the current mechanistic understanding of these processes. [ABSTRACT FROM AUTHOR]

Minireview describes recent (2014–2024) advances in the synthesis of five- to seven-membered azaheterocycles using heteroannulation of monosubstituted ferrocenes. Most of the methods described here are based on asymmetric transition metal catalysis. [ABSTRACT FROM AUTHOR]

Acyliminium ions and related species are potent electrophiles that can be quite valuable in the synthesis of nitrogen‐containing molecules. This manuscript describes a protocol to form these intermediates through hydride abstractions of easily accessible allylic carbamates, amides, and sulfonamides that avoids the reversibility that is possible in classical condensation‐based routes. These intermediates are used in the preparation of a range of nitrogen‐containing heterocycles, and in many cases high levels of stereocontrol are observed. Specifically areas of investigation include the impact of chemical structure on oxidation efficiency, the geometry of the intermediate iminium ions, the impact of a substrate stereocenter on stereocontrol, and an examination of transition state geometry. [ABSTRACT FROM AUTHOR]

Synthetic methodology is considered a holy grail in both organic chemistry and materials science. Over the past few decades, researchers have explored graphene‐type molecules (or nanographenes) through classic Scholl oxidative cyclodehydrogenation. Despite the successes achieved with various nanographenes, the development of new methods to synthesize these highly desired molecules lags behind. Herein, we developed a facile and effective method to produce a series of nanographenes bearing nitrogen (N)‐doped pentagon‐heptagon pairs in acceptable yields. Modification of the heptagonal ring endowed the resultant nanographenes with tunable physicochemical properties; for instance, M9 exhibited both aggregation‐caused quenching and aggregation‐induced emission behavior. Most strikingly, novel nanographenes containing N‐doped pentagon‐octagon pairs were also obtained using the same synthetic strategy, demonstrating the superior versatility and efficiency of the proposed ring expansion method. [ABSTRACT FROM AUTHOR]

Several nitrogen heterocyclic analogues have been applied to clinical practice, and about 75% of drugs approved by the FDA contain at least a heterocyclic moiety. Thus, nitrogen heterocycles are beneficial scaffolds that occupy a central position in the development of new drugs. The fact that certain nitrogen heterocyclic compounds significantly activate the NRF2/ARE signaling pathway and upregulate the expression of NRF2-dependent genes, especially HO-1 and NQO1, underscores the need to study the roles and pharmacological effects of N-based heterocyclic moieties in NRF2 activation. Furthermore, nitrogen heterocycles exhibit significant antioxidant and anti-inflammatory activities. NRF2-activating molecules have been of tremendous research interest in recent times due to their therapeutic roles in neuroinflammation and oxidative stress-mediated diseases. A comprehensive review of the NRF2-inducing activities of N-based heterocycles and their derivatives will broaden their therapeutic prospects in a wide range of diseases. Thus, the present review, as the first of its kind, provides an overview of the roles and effects of nitrogen heterocyclic moieties in the activation of the NRF2 signaling pathway underpinning their antioxidant and anti-inflammatory actions in several diseases, their pharmacological properties and structural–activity relationship are also discussed with the aim of making new discoveries that will stimulate innovative research in this area. [ABSTRACT FROM AUTHOR]

This review aims to collect and analyze recent results with respect to the use of varied palladium preparations in the synthesis of five‐membered nitrogen heterocycles including condensed derivatives. Results have been selected with focus on studies of the last three years. Furthermore, a common feature of all methods treated here is that the nitrogen‐containing five‐membered ring is formed via ring closing of appropriate starting materials. Selected examples discussed will reveal that a plethora of products from small monocycles to condensed multi‐ring systems can be successfully accessed. Major features are wide product ranges, high product yields and stereoselectivities often achieved under mild reaction conditions. [ABSTRACT FROM AUTHOR]

A stereoselective synthesis of isoindolo[2,1‐a]quinolin‐11(5H)‐ones containing three contiguous stereogenic centers is described. This Lewis‐acid mediated reaction of enamides with N‐aryl‐acylimines affords the desired fused heterocyclic isoindolinones in high yields and diastereoselectivities. Scope and limitations of this method are discussed. The stereochemical outcome of this transformation indicates a stepwise reaction pathway. [ABSTRACT FROM AUTHOR]

This review is devoted to the analysis of works published over the past 20 years on the chemistry of saturated annulated nitrogen-containing polycyclic compounds, the molecules of which consist of four, five, six, and seven cycles, and contain from one to eight endocyclic nitrogen atoms. [ABSTRACT FROM AUTHOR]

A series of pleuromutilin derivatives containing alkylamine and nitrogen heterocycle groups were designed and synthesised under mild conditions. The in vitro antibacterial activity of these semisynthetic derivatives against four strains of Staphylococcus aureus (MRSA ATCC 43300, S.aureus ATCC 29213, S.aureus AD3, and S.aureus 144) were evaluated by the broth dilution method. Compound 13 was found to have excellent antibacterial activity against MRSA (MIC = 0.0625 µg/mL). Furthermore, compound 13 was further studied by the time-killing kinetics and the post-antibiotic effect approach. In the mouse thigh infection model, compound 13 exhibited superior antibacterial efficacy than that of tiamulin. Meanwhile, compound 13 showed a lower inhibitory effect than that of tiamulin on RAW264.7 and 16HBE cells at the concentration of 10 µg/mL. Molecular docking study revealed that compound 13 can effectively bind to the active site of the 50S ribosome (the binding free energy = - 9.66 kcal/mol). [ABSTRACT FROM AUTHOR]

Catalysis by first-row transition metals is of increasing interest in the context of the scarcity of chemical resources. For instance, iron is promising due to its abundance, low toxicity and unique electronic features. Here we synthesized quinazoline alkaloids from alkynoic acids and functionalized amines in the presence of iron dibromide and pyridine in toluene or, alternatively, in a solventless reaction system. We studied iron sources, reaction media and the effect of additives. Results show 39–99% yields and regioselective preparation of nitrogen- and oxygen-containing scaffolds. This is the first example of a cascade process involving alkynoic acids catalyzed by iron. Fe is more abundant, cheaper and less toxic than other Au, Cu and Ru catalysts previously reported for similar transformations. [ABSTRACT FROM AUTHOR]

This study reports the invention of di‐ or trifunctionalization of readily available pyridines (including all the pyridine substrates utilized in this paper, such as 3‐cyanopyridine and 3‐chloropyridine) through dearomative functionalization‐oxidative rearomatization under transition‐metal‐ and reductant‐free conditions. Although a two‐step operation is required, the crude product of the first step could be used in the next step directly. Typically, 3‐π‐EWG pyridines undergo difunctionalization, whereas 3‐σ‐EWG pyridines participate in trifunctionalization, affording multisubstituted piperidines. Computational studies provide detailed insights for their distinct reactivity in the title reaction. [ABSTRACT FROM AUTHOR]

A new simple one-pot two-step protocol for the synthesis of 2-oxo-1,2,3,4-tetrahydroquinoline-3-carboxylate from 2-(2-(benzylamino)benzylidene)malonate under the action of BF3·Et2O was developed. It was shown that the reaction proceeds through the formation of a stable iminium intermediate containing a difluoroboryl bridge in the dicarbonyl fragment of the molecule. [ABSTRACT FROM AUTHOR]

The marriage of heterocyclic compounds with ferrocene has proven to be an extremely fruitful field of research. In fact, in the last years, several ferrocene‐embedded heterocyclic compounds have been reported. In some cases, the synergistic combination of the properties of the heterocyclic and metallacyclic motifs provides to the fused systems interesting applications. This Review summarizes the major advances in the synthesis of ferrocene‐fused nitrogen heterocyclic compounds and their applications, particularly in asymmetric catalysis. [ABSTRACT FROM AUTHOR]

We report the method for synthesis of indole‐ and pyrrole‐fused seven‐membered nitrogen heterocycles by means of acid‐base switchable cyclization reactions. The reactions involved cleavage of amide C−N bonds, chemoselective N‐1 or C‐3 acylation, and 1,4‐Michael addition. This method could be used to construct two different kinds of seven‐membered rings in one step from the same starting material without the need for a transition‐metal catalyst. [ABSTRACT FROM AUTHOR]

A 3‐nm molecule comprising a cylindrical core and cross‐shaped rims was designed and synthesized by developing a modular synthetic route. By using a cyclic precursor from previous studies as a starting material, multiple carbazole units were installed at the rims of the defective cylinder. The defective cylinder was synthetically doped with two types of nitrogen atoms, that is, pyridinic and pyrrolic nitrogen atoms, which resulted in solvatochromic shifts in fluorescence by charge‐transfer interactions. The structure of the large, C552H496N24 molecule was fully disclosed by crystallographic analyses, and the unique helical arrangement of nitrogen‐doped cylinders in the crystal was revealed. [ABSTRACT FROM AUTHOR]

Pd‐catalyzed bromination of mesoionic 1,3‐diphenyltetrazolium‐5‐olate (1) was developed. In the presence of palladium acetate (5 mol%), N‐bromosuccinimide (110 mol%), and p‐toluenesulfonic acid (50 mol%) in 1,2‐dichloroethane under reflux, olate 1 underwent bromination to give 1‐(2‐bromophenyl)‐3‐phenyltetrazolium‐5‐olate in a moderate yield as the major product, indicating that the 4‐nitrogen atom acts as a directing group rather than the negatively charged oxygen atom. The X‐ray‐suitable crystals of the corresponding palladacycle were isolated from 1‐mesityl‐3‐phentytetrazolium‐5‐olate and fully characterized. When both the o‐positions of the 3‐phenyl group were occupied by bromine atoms, o‐bromination then occurred at the 1‐phenyl group with the aid of the olate oxygen. [ABSTRACT FROM AUTHOR]

In this work, an universal synthetic approach for the synthesis of D2‐labeled nitrogen heterocycles based on cycloaddition reactions of in situ generated dideuteroacetylene is reported. A key feature of this method is the use of 1,4‐dioxane as a deuterium‐exchange‐proof solvent, which allowed the access to dideuterosubstituted heterocycles in up to 99 % deuteration degree. The method was demonstrated to be suitable for the synthesis of D2‐labeled triazoles, isoxazoles, pyrazoles and pyridazines. [ABSTRACT FROM AUTHOR]

Five-membered heterocyclic N -oxides attract special attention due to their significant potential applications in medicinal chemistry and advanced materials science. In this regard, novel methods for their synthesis and functionalization are in constant demand. In this short review, recent state-of-the-art achievements in the chemistry of isoxazoline N -oxides, 1,2,3-triazole 1-oxides and 1,2,5-oxadiazole 2-oxides are summarized. The main routes involving transition-metal-catalyzed and metal-free functionalization protocols along with mechanistic considerations are outlined. The transformations of these hetarene N -oxide rings as precursors to other nitrogen heterocyclic systems are also presented. 1 Introduction 2 Isoxazoline N -Oxides 3 1,2,3-Triazole 1-Oxides 4 1,2,5-Oxadiazole 2-Oxides 5 Conclusion [ABSTRACT FROM AUTHOR]

The need of understanding the interactions between small organic molecules and biological targets has stimulated the development of new methodologies for the synthesis of compounds with potential biological properties. In this scenario, multicomponent reactions have been considered as high atom‐efficient strategies which allow the generation of high levels of molecular diversity and complexity, using relatively simple and eco‐friendly experimental procedures. Among the plethora of catalysts used in multicomponent reactions, rare earth metal triflates, especially scandium(III) triflate [Sc(OTf)3], emerged as water‐resistant Lewis acids with remarkable catalytic activity in water‐containing environments. This review describes the recent progress on the use of scandium(III) triflate as Lewis acid catalyst for multicomponent reactions applied to the synthesis of nitrogen‐containing heterocycles, valuable privileged scaffolds in Organic and Medicinal Chemistry. [ABSTRACT FROM AUTHOR]

An efficient methodology for the copper‐catalyzed direct oxidative aroylations of quinoxalin‐2(1H)‐ones with methylarenes is reported. This methodology offers an efficient access to diverse and polyfunctionalized 3‐aroylated quinoxalin‐2(1H)‐ones starting from readily available quinoxalin‐2(1H)‐ones and various methylarenes using TBHP as an oxidant. This protocol is broadly compatible with diverse substrates and is highly functional‐group tolerant. [ABSTRACT FROM AUTHOR]

Nitrogen heterocycles are important structural subunits that occur widely in bioactive natural products, pharmaceuticals, agrochemicals, dyes, cosmetics, and functional materials. Considering the importance of these useful compounds in modern science, the synthesis of N‐heterocycles and their derivatives has always been a hot topic in organic synthesis. Recently, arenediazonium salts which can be easily prepared from inexpensive and abundantly available anilines, have been used as versatile nitrogen sources in the field of nitrogen heterocycle synthetic chemistry due to their ready availability, rich reactivity, and diverse transformations. The aim of the present review is to summarize the recent advances in the synthesis of nitrogen heterocycles using arenediazonium salts as nitrogen sources in the past ten years. Hopefully, it can provide practical guidance for the readers who are interested in utilizing arenediazonium salts as building blocks in organic synthesis. For simplicity and clarity, the organization of this review is based on the number of N atoms in the ring of nitrogen heterocycle. [ABSTRACT FROM AUTHOR]

Summary of main observation and conclusion: A highly efficient catalytic system for the N‐arylation reactions of (hetero)aryl chlorides and nitrogen heterocycles with a copper(I) complex containing a 1,10‐phenanthroline analogue N‐heterocyclic carbene (NHC) has been reported. The complex was characterized by 1H NMR and 13C NMR spectroscopy and elemental analysis, and its structure was determined by single‐crystal X‐ray diffraction. The NHC‐copper(I) complex was employed as pre‐catalyst for Ullmann type N‐arylation reactions of (hetero)aryl chlorides with various azoles. A variety of hindered and functionalized azoles and (hetero)aryl chlorides were transformed in good to excellent yields. [ABSTRACT FROM AUTHOR]

A novel method for the synthesis of a diverse series of functionally substituted five-membered heterocyclic compounds via atom-economic, regio-, and diastereoselective one-pot reaction cascade was developed. This approach involves a ring opening in 4-arylfuroxans to α-oximinoarylacetonitrile oxides followed by [3+2] cycloaddition to various dipolarophiles to afford multisubstituted isoxazoles and isoxazolines. Subsequent azole–azole rearrangement of (oximino)isoxazolines/-isoxazoles, which can be conducted in a one-pot manner, results into functionally substituted furazans formation. The developed protocol is operationally simple, proceeds in mild conditions and with high yields of target heterocyclic systems. Overall, this study represents a new mode of isoxazole and 1,2,5-oxadiazole functionalization strategy, which is useful in medicinal and materials chemistry. [ABSTRACT FROM AUTHOR]

Examples of the use of α-diazocarbonyl compounds in the N–H insertion reactions with the formation of the products of selective N-alkylation of various five-membered nitrogen heterocycles and their derivatives are considered. The literature data is systematized according to the number of N atoms in the heterocycle. The review contains information published in the period from 2003 to 2020. [ABSTRACT FROM AUTHOR]

A series of representative diazines and pyridine N‐oxides were subjected to alkylation using several different alkylating agents. The 15N NMR chemical shifts (δN values) of the diazines, pyridine N‐oxides and derived alkylation products were determined using 1H‐15N HMBC NMR spectroscopy at natural 15N abundance. The changes in the 15N NMR chemical shifts (Δ(δN) values) that occurred on going from starting materials to products in these reactions were analyzed. N‐alkylation of diazines resulted in large upfield shifts of the δN values of the alkylated nitrogen (of the order of 100 ppm or greater). While O‐alkylation of pyridine N‐oxides resulted in upfield shifts of the δN values of the N‐(alkoxy)pyridinium nitrogen, the Δ(δN) values were of a much smaller magnitude (ca. –42 ppm) than those observed for N‐alkylations of diazines. Nitrogen NMR spectroscopic data from the literature of relevance to alkylation of azines, diazines, azine N‐oxides and diazine N‐oxides was gathered together, and using this in tandem with our 15N NMR spectroscopic data, we have been able to corroborate our observations on the trends observed in the Δ(δN) values associated with N‐ and O‐alkylation reactions of aromatic N‐heterocycles and N‐oxides. An analysis protocol that relies on synergistic evaluation of 1H‐15N HMBC and 1H‐13C HMBC NMR spectra has been developed that enables unambiguous diagnosis of the occurrence of N‐alkylation of aromatic N‐heterocycles and O‐alkylation of aromatic N‐oxides. [ABSTRACT FROM AUTHOR]

The importance of, and synthetic routes to, pyrrolidines and piperidines, along with their relevance to natural product synthesis and antibacterial drug discovery, are surveyed in the context of an extended programme of investigation from our own laboratories. 1 Introduction 2 Pyroglutamates 2.1 Synthesised by Modification of an Existing Ring 2.2 Synthesised by Construction of a New Ring 3 Tetramates 4 Metal Chelation 5 Biological Activity 6 Conclusion [ABSTRACT FROM AUTHOR]

Previously unknown bis-styryl derivatives in which two ortho-styryl-substituted nitrogen heterocycles are linked together through a polymethylene spacer have been designed and synthesized. Spectral and photochemical studies have confirmed high photochemical activity of the synthesized compounds. [ABSTRACT FROM AUTHOR]

Heterocycles are generally biologically active compounds and are the main basic scaffolds in many natural and non‐natural moieties. Recently, silver‐catalyzed syntheses have undergone remarkable progress in the field of synthetic heterocyclic chemistry. This review summarizes the recent trends in the silver‐catalyzed synthesis of nitrogen‐containing heterocyclic compounds. [ABSTRACT FROM AUTHOR]

An aerobic radical approach for the synthesis of unsymmetrical heteroaryl ketones is described herein. The reaction involves cross‐dehydrogenative coupling between aldehydes and heteroaromatic bases with molecular oxygen (O2). The key aspect of the method is the generation of reactive acyl radical via homolytic activation of aldehyde C−H bond using O2 as the sole oxidant. The reaction has a good substrate scope with respect to aldehydes and functionalized nitrogen heterocycles. Based on our mechanistic studies, a radical chain pathway is suggested for the reaction. A synthetic application of the method is demonstrated in the formal synthesis of natural alkaloid (±) angustureine. [ABSTRACT FROM AUTHOR]

Substituted pyrazolines were obtained by Ni(ClO4)2·6H2O‐catalyzed reaction of 1,5‐diazabicyclo[3.1.0]hexanes with donor‐acceptor cyclopropanes. The mechanism of this reaction includes alkylation of diaziridine nitrogen with Lewis acid‐activated donor‐acceptor cyclopropane followed by hydration of the formed 1,6‐zwitterionic intermediate and oxidation of pyrazolidine with air oxygen. This pathway is realized when starting bicyclic diaziridines have bulky alkyl substituent(s) at the C(6) atom preventing (3+3)‐annulation of two three‐membered rings. [ABSTRACT FROM AUTHOR]