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This article, titled "Editorial: Heterodienes in organic synthesis," discusses the chemistry and applications of heterodienes in organic synthesis. Heterodienes are vinylogous systems that have unique reactivity and structure. They are commonly used in reactions such as Michael addition, cycloadditions, annulations, and cascade reactions. Heterodienes are also involved in the biosynthesis of natural compounds and can be used in bioconjugation chemistry. The article includes research on specific types of heterodienes, such as azoalkenes and nitroso- and nitroalkenes, and their reactions with various nucleophiles. The authors conclude that the chemistry of heterodienes is an exciting and challenging research area with many more discoveries to be made. [Extracted from the article]

Piperazine is one of the most frequently found scaffolds in small-molecule FDA-approved drugs. In this study, a general approach to the synthesis of piperazines bearing substituents at carbon and nitrogen atoms utilizing primary amines and nitrosoalkenes as synthons was developed. The method relies on sequential double Michael addition of nitrosoalkenes to amines to give bis(oximinoalkyl)amines, followed by stereoselective catalytic reductive cyclization of the oxime groups. The method that we developed allows a straightforward structural modification of bioactive molecules (e.g., α-amino acids) by the conversion of a primary amino group into a piperazine ring. [ABSTRACT FROM AUTHOR]

The Nef reaction (nitro to carbonyl group conversion) and related Meyer reaction are among the key transformations of aliphatic nitro compounds. The interrupted versions of these reactions in which the normal pathway is redirected to a different end product by an external nucleophile are much less common, albeit these processes substantially increase the synthetic potential of nitro compounds. In this review, examples of interrupted Nef and Meyer reactions are summarized, and the prospects of this methodology in diversity-oriented organic synthesis are analyzed. The bibliography contains 90 references. [ABSTRACT FROM AUTHOR]

The review summarizes recent advances in the synthesis of C2‐halogenated nitrogen heterocycles via nucleophilic halogenation of corresponding N‐oxides as well as application of this methodology in the synthesis of pharmaceuticals. Both scientific and patent literature is reviewed mostly over the period of the last ten years. The review contains a practical guide (typical procedures and infographic based on extensive literature analysis), which can help practitioners in choosing optimal reagents/conditions for nucleophilic halogenation of N‐heterocycles of different types. The bibliography contains 199 references. [ABSTRACT FROM AUTHOR]

Suzuki-Miyaura cross-coupling reaction of 3-bromomethyl isoxazolines with arylboronic acids was suggested as final C􀀀 C bond forming step in convenient diastereoselective route to trisubstituted isoxazolines. The required bromides were readily available from nitroalkenes and sulfonium ylides through an efficient sequence of formal [4+1]-cycloaddition and C􀀀 H functionalization of intermediate isoxazoline N-oxides. The synthetic utility of the obtained isoxazolines was demonstrated by their conversion into valuable products such as hydroxy ketone, pyrrolidinone, etc. [ABSTRACT FROM AUTHOR]

Umpolung strategies are of considerable interest to organic chemists because they provide alternative synthetic routes to those imposed by the natural polarity of classical synthons. Reverse-polarity reactions of aldehydes, α,β-unsaturated carbonyl compounds, and imines are deeply embedded in the methodology of organic synthesis. In recent years, umpolung of enols and enamines has received much attention as a novel strategy to access α-substituted ketones. Here, state-of-the-art approaches to umpolung of enamine reactivity are discussed, with a particular focus on recent developments in this field from the author's research group. 1 Introduction 2 Approaches toward Umpolung of Enamines 3 Umpolung of Enamines through Single-Electron Oxidation 4 Azadienes as Synthetic Equivalents of Enamine Umpolung Synthons 5 Enamines Possessing a Leaving Group at the Nitrogen Atom 6 Enamines Possessing a Directing Group at the Nitrogen Atom 7 Summary and Outlook [ABSTRACT FROM AUTHOR]

The review summarizes the chemistry of nitrones and nitronates in the context of the C−H reactivity of their α‐carbon atoms. Electrophilic, nucleophilic and radical reactions leading to functionalization of the α‐position are described. Examples of the application of these processes in total synthesis are outlined. [ABSTRACT FROM AUTHOR]

Due to their availability and versatile reactivity, nitronates have become important building blocks in the stereoselective synthesis of bioactive molecules. This short review provides a summary of recent developments on the synthesis, chemistry and applications of O-alkyl and O-silyl nitronates. 1 Introduction 2 Approaches to the Synthesis of Nitronates 2.1 Synthesis of Six-Membered Cyclic Nitronates 2.1.1 Formal [4+2] Approaches 2.1.2 Formal [3+3] Approaches 2.1.3 Other Approaches 2.2 Synthesis of Five-Membered Cyclic Nitronates 2.2.1 Formal [3+2] Approaches 2.2.2 Formal [4+1] Approaches 2.2.3 Oxidation Approaches 3 Chemistry of Nitronates 3.1 Nitronates as a-C-Nucleophiles 3.2 Nitronates as a-C-Electrophiles 3.3 Nitronates in [3+n]-Annulation Reactions 3.4 Reactions Involving the ß-Carbon Atom of Nitronates 3.5 Miscellaneous Transformations 4 Conclusion. [ABSTRACT FROM AUTHOR]

Condensation of oximes with boronic acids RB(OH)2 or B(OH)3 affords remarkably stable 2,4,10-trioxa-1,5,7-triaza-3-boroadamantanes via an unprecedented multicomponent process. The mechanism involves the reversible generation of unstable oxime cyclotrimers, which are readily intercepted by boronic acids. [ABSTRACT FROM AUTHOR]

An approach to the synthesis of α-halo oxime ethers from readily accessible nitronates and nitro compounds via bis(oxy)enamines is reported. A key step of the strategy involves the unprecedented reaction of bis(oxy)enamines with a metal (Co, Zn, Mg, Mn) halide that acts as both a promoter and halide (Br, I, Cl) source. A variety of cyclic and acyclic ethers of α-halo oximes, including previously unavailable trimethylsilyl ethers of α-iodo oximes, have been synthesized in good-to-high yields. [ABSTRACT FROM AUTHOR]

Thirteen 2-oxazine-based small molecules were synthesized targeting 5-lipoxygenase (LOX), and acetylcholinesterase (AChE). The test revealed that the newly synthesized compounds had potent inhibition towards both 5-LOX and AChE in lower micro molar concentration. Among the tested compounds, the most active compound, 2-[(2-acetyl-6,6-dimethyl-4-phenyl-5,6-dihydro-2 H -1,2-oxazin-3-yl)methyl]-1 H -isoindole-1,3(2 H )-dione ( 2a ) showed inhibitory activity towards 5-LOX and AChE with an IC 50 values of 1.88, and 2.5 μM, respectively. Further, the in silico molecular docking studies revealed that the compound 2a bound to the catalytic domain of AChE strongly with a highest CDOCKER score of −1.18 kcal/mol when compared to other compounds of the same series. Additionally, 2a showed a good lipophilicity (log P = 2.66), suggesting a potential ability to penetrate the blood–brain-barrier. These initial pharmacological data revealed that the compound 2a could serve as a drug-seed in developing anti-Alzheimer’s agents. [ABSTRACT FROM AUTHOR]

The first synthesis of 1,4,6,10-tetraazaadamantane, the C3v-symmetrical structural isomer of urotropine (1,3,5,7-tetraazaadamantane), and a series of its derivatives is reported. X-ray and quantum-chemical studies revealed remarkable distinctions in structures of urotropine and "isourotropine" cations, probably arising from different types of hyperconjugation between lone electron pairs of nitrogen atoms and σ*C-N orbitals in these heterocage systems. Since substitution at bridge and bridgehead nitrogen atoms can be easily introduced, 1,4,6,10-tetraazaadamantane may be considered as a new rigid multivalent (3 + 1) scaffold for the design of functional molecules and materials. [ABSTRACT FROM AUTHOR]

Abstract: Four nickel complexes with β-(oximinoalkyl)amine ligands Ox n H n containing one (Ox1H1), two (Ox2H2), four (Ox4H4) and six (Ox6H6) oxime groups were synthesized and characterized by elemental analysis, FTIR, HRMS and single crystal X-ray diffraction. β-Oximinoalkylamines Ox n H n act as polydentate ligands forming five-membered chelate rings, in which nickel is coordinated with both amine and oxime nitrogen atoms. In all structurally characterized complexes, OH-groups of oximes arms are involved in hydrogen bonding with counterions (Cl−), which are located in the inner or outer coordination sphere of the nickel atom. Two new structural types of pseudo-octahedral Ni(II) β-oximinoalkylamine complexes containing two ligands per one nickel ion (Ni(Ox1H1)2Cl2 and Ni(Ox2H2)2Cl2) were identified. Dioxygen reactivity of the obtained complexes in aerobic oxidation of triphenylphosphine was studied. Bis-oxime complex Ni(Ox2H2)2Cl2 was found to be the most active promoter of triphenylphosphine oxidation among the synthesized nickel complexes. [Copyright &y& Elsevier]

Asymmetric synthesis of GlaxoSmithKline's highly potent phosphodiesterase inhibitor 1 has been accomplished in nine steps and 16% overall yield. The original strategy suggested involves as a key step the silylation of enantiopure six-membered cyclic nitronates 4 obtained by a highly stereoselective [4 + 2]-cycloaddition of an appropriate nitroalkene 5 to trans-1-phenyl-2-(vinyloxy)cyclohexane. Functionalization of the resulting 5,6-dihydro-4H-1,2-oxazine and subsequent stereoselective reduction of 1,2-oxazine ring in intermediate 2 furnished the pyrrolizidinone framework with the recovery of chiral auxiliary alcohol. [ABSTRACT FROM AUTHOR]

first general approach to the synthesis of unsymmetrically substituted tris(ß-oximinoalkyl)amines containing two or three different ß-oximinoalkyl fragments has been developed. This procedure employs available aliphatic nitro compounds as starting building blocks and their silylation as the key step. This approach provides an efficient strategy for the diversity-oriented synthesis of 1,4,6,10-tetraazaadamantane derivatives. [ABSTRACT FROM AUTHOR]

The article discusses the findings of the study about the synthetic potential of six-membered cyclic oxime ethers (SCOE) for organic synthesis. It states that SCOE are a promising intermediates for total synthesis and they are synthetic equivalents of pyrrolidines, pyrroles and functionalized carbonyl compounds and it exhibits high stereoselectivity. It mentions that it has ester or carboxyl groups which are considered as convenient precursors of natural and unnatural amino acids.

Piperazine (Pipz) is widely used as a building block for the self-assembly of supramolecular hydrogen-bonded crystalline networks. Here, piperazine-1,4-diol (PipzDiol) has been suggested as an analog of piperazine with an extended H-bond donor geometry. A convenient synthesis of PipzDiol has been developed and the compound has been fully characterized. Structural and stereodynamic studies showed that PipzDiol exists in solution as a dynamic mixture of conformers/invertomers. The formation of co-crystals with acids is accompanied by preferable selection of one stereoisomeric form depending on the nature of the co-former. Piperazine and PipzDiol were found to form distinct supramolecular H-bonded networks with topologically different H-bonded motifs. In crystalline adducts with sulfuric, oxalic, and para-aminobenzoic acids, piperazine forms 3D H-bonded networks, while 2D layers are assembled with PipzDiol. [ABSTRACT FROM AUTHOR]

A novel two‐step access to polysubstituted pyrroles from nitroalkenes was developed. It involves [4+2]‐cycloaddition with enol ethers to give six‐membered cyclic nitronates followed by reductive ring contraction with Ra−Ni/AcOH or Ra−Ni/EtOH systems. The process is applicable to a variety of nitroalkenes and enol ethers bearing electron‐rich and electron‐poor substituents and functional groups. The anti‐inflammatory drug Bimetopyrol and its structural modifications were successfully synthesized by the strategy developed. The key side products were identified that provided an insight into the mechanism of the developed reductive ring contraction to pyrroles. [ABSTRACT FROM AUTHOR]

Simple three-step asymmetric and racemic syntheses of GlaxoSmithKline's highly potent PDE IVb inhibitor 1 were developed. The suggested approach is based on reductive domino transformations of 3-β-carbomethox-yethyl-substituted six-membered cyclic nitronates, which are easily accessed by a stereoselective [4 + 2] cydoaddition of an appropriate nitroalkene to vinyl ethers. In vitro studies of PDE IVb inhibition by enantiomeric pyrrolizidinones (+)-1 and (-)-1 were performed. [ABSTRACT FROM AUTHOR]

Diastereoselective synthesis of 4-amino-7-hydroxyheptanoic acids 1, new GABA analogues, was performed involving reduction of C-3 functionalized 5,6-dihydro-4H-1,2-oxazines available from nitroethane. Molecular docking studies showed that amino acids of type 1 may bind to GABA transaminase, however, no inhibition was observed in the experiments with the enzyme. [Copyright &y& Elsevier]

A new type of phthalocyanine containing 3,5,7-trimethyl-1,4,6,10-tetraazatricyclo[3.3.1.13,7]decane-4,6,10-triol (1,4,6,10-tetraazaadamantane) within a peripheral substituent has been synthesised. Its spectral properties and interaction with human lymphoblastoma cells infected with the HIV-1BRU strain have been studied. [Copyright &y& Elsevier]

Sequential acylation‐silylation of nitroalkanes leads to O‐silylated α‐acyloxyoximes in high yields. The first step of the reaction involves deprotonation of nitro compound with sodium hydride promoted by DBU or alcohol/15‐crown‐5 system followed by treatment with acyl chloride. In situ generated acyl nitronate is further silylated by silyl triflate that triggers hetero‐Claisen [3,3]‐rearrangement within N‐acyloxyenamine moiety furnishing orthogonally protected oxime derivatives. The procedure has large substrate scope for both nitroalkanes and acylating agents (acyl chlorides, chloroformates) and allows tuning of reaction conditions depending on the particular type of substrate. Application of obtained oxime derivatives in organic synthesis is demonstrated. [ABSTRACT FROM AUTHOR]

Heterocyclic compounds can specifically regulate bacterial development by targeting specific bacterial enzymes and metabolic pathways. The ESKAPE pathogens are multidrug-resistant and cause nosocomial infections, which is one of the greatest challenges in clinical practice. The search for novel agents to combat resistant bacteria has become one of the most important areas of antibacterial research today. Heterocyclic compounds offer a valuable strategy in the fight against resistance as they can be designed to interact with bacterial targets that are less prone to developing resistance mechanisms. Bacterial histidine kinases (HKs), which are a component of two-component bacterial systems, are a promising target for new antibacterial compounds. We have designed and synthesized novel indole derivatives as antibacterial agents. Among the series, indole-coumarin (4b) and bisindole (4e) have shown the best inhibitory activity against S. aureus. Further, in silico docking studies show that compounds 4b and 4e could target histidine kinases in bacteria. [ABSTRACT FROM AUTHOR]

Review: [501 refs. [ABSTRACT FROM AUTHOR]

A protocol for the synthesis of 2,3‐dihydrofurans by reductive denitrogenation/ring contraction of 6‐membered cyclic nitronates was developed. The process utilizes cheap Raney® nickel both as catalyst and stoichiometric agent without the need for high‐pressure equipment. The products are formed in high purity and column chromatography is often not required. Studies on the substrate scope, functional group tolerance, and mechanism were performed. The developed approach provides a straightforward two‐step access to densely substituted 2,3‐dihydrofurans from nitrostyrenes and alkenes. [ABSTRACT FROM AUTHOR]

Abstract: Bis(oxy)enamines (I) and (XII) undergo an unprecedented reaction with cobalt(II) halides to produce a variety of cyclic and acyclic ethers of α‐halo oximes including previously unavailable trimethylsilyl ethers of α‐iodo oximes. [ABSTRACT FROM AUTHOR]

Nucleophilic addition of thiols to N,N-bis(oxy)enamines (nitrosoalkene acetals) produce valuable α-thiooximes in a highly efficient manner. The reaction was found to be solvent-dependent, likely because of distinct mechanisms operating in nonpolar and basic solvents (involving either Brønsted acid or Lewis base catalysis). By performing a series of competition experiments, the relative reactivity of S-, N-, and O-nucleophiles in reaction with N,N-bis(oxy)enamines was determined for the first time. Interestingly, the relative nucleophilicity was found to be highly dependent on the solvent, which allows regioselective control of these reactions by using an appropriate medium. [ABSTRACT FROM AUTHOR]

The regioselectivity of the addition of HO-acids to the activated π-bond in N,N-bis(oxy)enamines was found to be dramatically dependent on the solvent. Mechanism investigations and quantum-chemical calculations revealed that solvent affects the reaction pathway. In basic solvents (DMF, NMP, DMSO), N,Nbis( oxy)enamines are converted into nitrosoalkenes through a Lewis base promoted process followed by the oxy-Michael addition of HOacid. In non-polar solvents (toluene, CH2Cl2), reaction follows an acid-promoted SN' substitution of N-oxy-group via highly reactive Nvinyl- N-alkoxynitrenium species. Based on these studies, general and efficient protocols for oximinoalkylation of various HO-acids (carboxylic acids, phenols, hydroxamic, phosphoric and sulfonic acids) employing readily available N,N-bis(oxy)enamines were developed. These methods proved to be applicable for postmodification of natural molecules bearing acidic OH-groups (such as steroidal hormones, bile acids, protected amino acids and peptides) and ligands (BINOL). The resulting α-oxyoximes were demonstrated to be useful precursors of valuable 1,2-amino alcohol or 1,2- hydroxylamino alcohol derivatives, including the antiarrhythmic drug Mexiletine and a potent MMP inhibitor. [ABSTRACT FROM AUTHOR]

A concise seven‐step asymmetric synthesis of MSD's potent hNK1 antagonist containing a pyrrolizidinone core bearing two fluorine‐substituted aryl groups was developed. The pyrrolizidinone unit was constructed by reductive recyclization of a properly functionalized cyclic nitronate, which was assembled by stereoselective [4+2]‐cycloaddition of a nitroalkene with a vinyl ether bearing a Whitesell's chiral auxiliary group. The configuration of the hNK1 antagonist, which was previously suggested based on bioactivity data, was confirmed by X‐ray analysis. The crystal structure features multiple weak interactions involving fluorine atoms that are also found in a complex with the hNK1 receptor simulated by molecular docking. [ABSTRACT FROM AUTHOR]

The article titled "Accessing Polysubstituted NH Pyrroles from Nitroalkenes via [4+2]-Cycloaddition/Reductive Ring Contraction Strategy" in the European Journal of Organic Chemistry discusses a method for reducing N-O bonds using Raney nickel in acetic acid or ethanol. This process does not require flammable hydrogen gas or high-pressure equipment, as molecular hydrogen is formed in situ through the dissolution of metallic nickel in acid or borrowing hydrogen from ethanol. The researchers successfully achieved reductive ring contraction of 1,2-oxazine N-oxides to produce polysubstituted pyrroles. The full research article provides more detailed information on this topic. [Extracted from the article]

Hitherto unknown bis(β‐oximinoalkyl)malonates were demonstrated to be convenient platforms for the synthesis of saturated N‐heterocycles. Upon heterogeneous catalytic hydrogenation, these dioximes undergo reductive cyclization to give substituted piperidine‐4,4'‐dicarboxylates, which are valuable building blocks in medicinal chemistry. By using dioximes bearing an additional ester group in the side chain, tandem piperidine/pyrrolidinone ring closure leading to indolizidinone framework was showcased in this work. A modular synthesis of initial bis(β‐oximinoalkyl)malonates (both symmetrically and unsymmetrically substituted) was accomplished via a sequential Michael addition of two nitrosoalkene molecules to malonic ester. The mechanism of the reductive cyclization of dioximes to piperidines was investigated by isotope scrambling experiments and isolation of intermediates. [ABSTRACT FROM AUTHOR]

Acylation of nitroalkylmalonates was found to yield substituted isoxazoline derivatives. This redox‐neutral transformation has a wide substrate scope and produces target products with yields up to 92%. Various substituents (aryl, alkyl, and ester) at the C3 and C4 positions of the resulting isoxazolines were also tolerated. A quick assembly of the isoxazoline ring starting from nitroalkenes and malonates was successfully developed. Control experiments showed that the intramolecular ring closure is the most likely key mechanistic step. Subsequent transformations into pyrrolidine and furane derivatives demonstrated the synthetic utility of the obtained products. [ABSTRACT FROM AUTHOR]

4,6,10-Trihydroxy-1,4,6,10-tetraazaadamantane (TAAD) has been shown to form a stable Fe(IV) complex having a diamantane cage structure, in which the metal center is coordinated by three oxygen atoms of the deprotonated ligand. The complex was characterized by X-ray diffraction analysis, HRMS, NMR, FT-IR, Mössbauer spectroscopy and DFT calculations, which supported the d4 configuration of iron. The Fe(IV)-TAAD complex showed excellent performance in dioxygen activation under mild conditions serving as a mimetic of the thiol oxidase enzyme. The nucleophilicity of the bridgehead nitrogen atom in TAAD provides a straightforward way for the conjugation of Fe(IV)-TAAD complexes to various functional molecules. Using this approach, steroidal and peptide molecules having an iron(IV) label have been prepared for the first time. In addition, the Fe(IV)-TAAD complex was covalently bound to a polystyrene matrix and the resulting material was shown to serve as a heterogeneous catalyst for aerobic oxidation of thiols to disulfides. [ABSTRACT FROM AUTHOR]

[Display omitted] Michael addition of malonic esters to azoalkenes generated in situ from α-bromo- and α-chlorohydrazones was accomplished. Both aliphatic and aromatic substrates bearing different functional groups are tolerated. The use of a strong base (sodium hydride) for generation of azoalkenes and deprotonation of malonate was found to be essential for a successful coupling. Synthetic potential of the obtained β-hydrazonoalkylmalonates was demonstrated by their smooth conversion into five- and six-membered N -heterocycles, functionalized hydrazides, 2-(2-oxo-2-arylethyl)malonates and 2-arylethylmalonates. [ABSTRACT FROM AUTHOR]

2,4,9‐Triazaadamantanes (TRIADs) are promising yet scarcely available, conformationally rigid platforms for potential applications in the design of functional molecules and materials. Here, we report a facile synthesis of various N‐ and C7‐substituted 2,4,9‐triazaadamantanes, starting from amines and 4‐allylhepta‐1,6‐dienes. A focus was placed on the synthesis of 2,4,9‐triazaadamantanes bearing reactive groups (NH2, propargyl, OH) on the bridge nitrogen atoms, which were then used to decorate the 3D scaffold by hydrazone, triazole, and boronate linkages. A reversible opening of the adamantane cage to the acyclic tris‐oxime form was observed for 2,4,9‐triazaadamantanes possessing hydroxy‐groups on the nitrogen atoms (TRIAD‐triols). This process could be controlled by temperature or by complexation of TRIAD‐triol with a boronic acid. The structure of 2,4,9‐triazaadamantanes and the stereodynamics at the bridge nitrogen atoms were studied by X‐ray analysis and DFT calculations. [ABSTRACT FROM AUTHOR]

A novel access to isoxazolines was developed using the [4+1]‐annulation of α‐keto‐stabilized sulfur ylides with N,N‐bis(siloxy)enamines derived from aliphatic nitro compounds. The resulting 5‐keto‐substituted isoxazolines were shown to be convenient precursors of polysubstituted 3‐hydroxypyrrolidines via the one‐pot catalytic N−O hydrogenolysis/intramolecular reductive amination sequence. Application of this approach to the formal synthesis of Merck's potent NK1 receptor antagonist was demonstrated. [ABSTRACT FROM AUTHOR]

Acylation of cyclic nitronates with acyl bromides produces 3‐bromomethyl‐substituted 5,6‐dihydro‐2H‐1,2‐oxazines via an unusual multi‐stage process involving deoxygenation of N‐oxide and the formation of Br2. Low‐temperature in situ ATR FT‐IR monitoring and DFT calculations revealed α‐halo‐substituted N,N‐bis(oxy)amines as key intermediates of the process. The developed method was successfully exploited in the stereoselective synthesis of pharmaceutically relevant molecules. [ABSTRACT FROM AUTHOR]

In situ generated magnesium cyanide [NaCN/Mg(ClO4)2] is suggested as a convenient, readily available, non‐volatile and organic‐soluble reagent for hydrocyanation reactions. It was successfully used for nucleophilic cyanation of nitrosoalkenes, nitronates, as well as other typical π‐electrophiles, such as imines, α,β‐unsaturated ketones, alkylidenemalonates and azoalkenes. In situ generated magnesium cyanide is a convenient, readily available, non‐volatile and organic‐soluble reagent for hydrocyanation reactions. Efficient nucleophilic cyanation of π‐electrophiles such as nitronates, conjugated nitrosoalkenes, imines, α,β‐unsaturated ketones, methylenemalonates and azoalkenes was demonstrated. [ABSTRACT FROM AUTHOR]

Extensive experimental and theoretical investigations on the isomerization and heterocyclizations of β‐chlorovinyl thiohydrazones derived from oxamic acid thiohydrazides and β‐chlorovinyl aldehydes were performed to elucidate the reaction mechanism of pyridazine formation. We showed that model β‐chlorovinyl thiohydrazone undergoes multiple isomerization reactions in solution induced by thione–thiol tautomerism and Z/E‐isomerization at the C=N bond. Mechanistic rationalization along with computational studies demonstrated that pyridazine is predominantly generated from the Z‐thiol isomers by 6π‐electrocyclization of the thiohydrazone‐derived 2,3‐diazatriene intermediate. The autocatalytic character of cyclization accelerated by the formation of acid was demonstrated by means of 1H NMR monitoring. β‐Chlorovinyl aldehydes undergo a condensation reaction with oxamic acid thiohydrazides to give pyridazines. Here, we report the results of extensive experimental and some theoretical mechanistic investigation. [ABSTRACT FROM AUTHOR]

A novel strategy for the synthesis of stereochemically defined 3,4,5-trisubstituted 2-pyrrolidones was developed. The suggested approach involves reductive domino-type recyclization of 3-aminomethyl-substituted isoxazolines as a key stage. The latter are prepared via a-C-H functionalization of readily available isoxazoline-N-oxides. [ABSTRACT FROM AUTHOR]

A general approach to the synthesis of borohydride complexes containing one or two dinitroamide fragments has been suggested. Based on a smooth substitution of halide in haloborane or dibromoborane complexes with N, N-dinitroamide salts, this method provides various N, N-dinitroamidoboranes complexes in good yields and in analytically pure form. By means of spectroscopic and computational methods, it was demonstrated that dinitroamidoborane complexes could form as both B,N- and B,O-isomers, which did not interconvert at ambient temperature. [ABSTRACT FROM AUTHOR]

Organic systems still dominate several traditional areas of chemical science and well-known applications, such as the synthesis of pharmaceutical compounds and drugs. However, a fascinating trend has appeared recently to combine pure organic systems into advanced molecular architectures and to create hybrid molecular systems. These interdisciplinary areas, where possible connections between organic and hybrid systems may be developed, are the focus of the present review to develop valuable practical applications. [ABSTRACT FROM AUTHOR]

Metal azides generated in situ by ion exchange exhibit divergent reactivity in reaction with cyclic N-alkoxy, N-siloxy-enamines. Depending on the nature of metal and the [M]/N3− ratio, addition of the azide ion to the C,C-double bond proceeds with regioselective cleavage of either exo- or endo-cyclic N−O bond leading to cyclic or open-chain α-azidooxime derivatives, respectively. Mechanistic studies in combination with solvent state FTIR spectroscopy and DFT calculations revealed that covalently bound metal azides (Co, Cu, Zn) transfer N3− anion to the C,C-double bond through a Lewis acid-assisted SN′ substitution of trialkylsilyloxy-group. More ionic metal azides (N1, Mg, Al, Sc, Ni, Yb) tend to react by initial nucleophilic attack of N3− anion on the silicon atom generating conjugated nitrosoalkenes. α-Azidooxime derivatives prepared by using the designed protocols were stereoselectively reduced to valuable 1,2-diaminoalcohols bearing up to four contiguous stereogenic centers. By reducing the α-azidooxime fragment in a stepwise manner site-selective protection and reductive amination of each of the emerging primary amino groups was achieved. [ABSTRACT FROM AUTHOR]

Aberrant activation of nuclear factor kappa B (NF-κB) has been linked with the pathogenesis of several proinflammatory diseases including number of cancers and inflammatory bowel diseases. In the present work, we evaluated the anticancer activity of 1,2-oxazines derivatives against colorectal cancer cell lines and identified 2-((2-acetyl-6,6-dimethyl-4-phenyl-5,6-dihydro-2H-1,2-oxazin-3-yl)methyl)isoindoline-1,3-dione (API) as the lead anticancer agent among the tested compounds. The apoptosis inducing effect of API was demonstrated using flow cytometry analysis and measuring the caspase 3/7 activity in API treated cells. Based on the literature on inhibition of NF-κB by oxazines, we evaluated the effect of 1,2-oxazines against the ability of NF-κB binding to DNA, NF-κB-dependent luciferase expression and IκBα phosphorylation. We found that, API abrogate constitutive activation of NF-κB and inhibits IκBα phosphorylation in HCT116 cells. Our in silico analysis revealed the binding of oxazines to the hydrophobic cavity that present between the interface of p65 and IκBα. Given the relevance with aberrant activation of NF-κB in inflammation bowel disease (IBD), we evaluated the effect of API on dextran sulphate sodium-induced IBD mice model. The treatment of IBD induced mice with API decreased the myeloperoxidase activity in colonic extract, modulated the colon length and serum levels of pro- and anti-inflammatory cytokines such as TNF-α, IFN-γ, IL-6, IL-1β and IL-10. Furthermore, the histological analysis revealed the restoration of the distorted cryptic epithelial structure of colon in the API treated animals. In conclusion, we comprehensively validated the NF-κB inhibitory efficacy of API that targets NF-κB in in vitro colon cancer and an in vivo inflammatory bowel disease model. [ABSTRACT FROM AUTHOR]

Oximinoalkylamines were found to be efficient ligands for acceleration of the CuAAC reaction. ‘Mixed’ oxime–triazole ligands Tz β Ox 2 and Tz 2 β Ox demonstrate an approximately 10-fold enhanced acceleration effect compared to commonly employed ligand TBTA using 0.1 mol % of the [Cu]/ L catalytic system. The optimal catalytic system based on readily available Tz β Ox 2 provided 1,4-disubstituted triazoles in high yields with short reaction times. [ABSTRACT FROM AUTHOR]

Organic compounds bearing semi-polar nitrogen–oxygen bonds are considered as perspective platform for designing socially important medications and high energy materials. Herein, recently developed original syntheses of monocyclic and fused 1,2,3,4-tetrazine 1,3-dioxides, various (methylene)bis(1-oxy-1-triazene 2-oxide) derivatives, furoxan-containing polyheterocyclic scaffolds and diastereoor enantiomerically enriched functionalized aliphatic nitro compounds are summarized. Prospects for their practical applications are outlined. [ABSTRACT FROM AUTHOR]

In the present study, we used solution combustion synthesis-bismuth oxide (Bi 2 O 3 ) as catalyst for the simple and efficient synthesis of 1,2-oxazine based derivatives of 6-fluoro-3-(piperidin-4-yl)benzo[ d ]isoxazoles, 1-arylpiperazine and carbazoles. (4a R ,8a R )-4-(4-Methoxyphenyl)-3-((4-(4-methoxyphenyl)piperazin-1-yl)methyl)-4a,5,6,7,8,8a-hexahydro-4 H -benzo[ e ][1,2]oxazine was found to be the most potent compound with a high degree of selectivity in inhibition towards COX2 (1.7 μM) over COX1 (40.4 μM) demonstrating the significance of 1,2-oxazine derivatives in developing COX2 specific inhibitors. Molecular docking analyses demonstrated that an isoleucine residue in the active site of COX1 is responsible for lower affinity to COX1 and increased potency towards COX2. Overall, our study reveals that the new 1,2-oxazine-based small molecules qualify as lead structures in developing COX2-specific inhibitors for anti-inflammatory therapy. [ABSTRACT FROM AUTHOR]

An original approach to the synthesis of tris(γ-oximinoalkyl)amines was proposed. The suggested synthetic sequence is based on aza-Michael addition of ammonia to methyl vinyl ketone and oximation of obtained products with hydroxylamine orO-alkhylhydroxylamines. The tris(γ-oximinoalkyl)amines may be considered as prospective N4 tripodal ligands. [ABSTRACT FROM PUBLISHER]