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The absence of catalytic asymmetric methods for synthesizing chiral (hetero)bicyclo[n.1.1]alkanes has hindered their application in new drug discovery. Here we demonstrate the achievability of an asymmetric polar cycloaddition of bicyclo[1.1.0]butane using a chiral Lewis acid catalyst and a bidentate chelating bicyclo[1.1.0]butane substrate, as exemplified by the current enantioselective formal (3 + 3) cycloaddition of bicyclo[1.1.0]butanes with nitrones. In addition to the diverse bicyclo[1.1.0]butanes incorporating an acyl imidazole group or an acyl pyrazole moiety, a wide array of nitrones are compatible with this Lewis acid catalysis, successfully assembling two congested quaternary carbon centers and a chiral aza-trisubstituted carbon center in the pharmaceutically important hetero-bicyclo[3.1.1]heptane product with up to 99% yield and >99% ee. The absence of catalytic asymmetric methods for synthesizing chiral (hetero)bicyclo[n.1.1]alkanes has hindered their application in new drug discovery. Herein the authors report an enantioselective formal (3 + 3) cycloaddition of bicyclobutanes with nitrones using a chiral Lewis acid catalyst for the synthesis of hetero-bicyclo[3.1.1]heptane. [ABSTRACT FROM AUTHOR]

An experimental and computational study (including DFT calculations and distortion/interaction analysis) was conducted to assess the effect of the nitrone structure in the outcome of dipolar 1,3‐cycloadditions with levoglucosenone, a biomass derived chiral enone. While B3LYP/6‐31G* (the most popular method for modeling these reactions according to our literature search) provides qualitatively good results, large outliers were found for some systems versus experimental data. An exhaustive exploration of other levels allowed us to determine the most appropriate ones to predict simultaneously reactivity and selectivity. The systematically predicted high exo selectivity by the majority of the levels led us to reconsider our initial assignment for the reaction with the nitrone derived from piperidine, which resulted in the discovery of an interesting case of conformational dynamics. [ABSTRACT FROM AUTHOR]

Stroke is a leading cause of death worldwide, yet current therapeutic strategies remain limited. Among the neuropathological events underlying this disease are multiple cell death signaling cascades, including autophagy. Recent interest has focused on developing agents that target molecules involved in autophagy to modulate this process under pathological conditions. This study aimed to analyze the role of autophagy in cell death induced by an in vitro ischemia–reperfusion (IR) model and to determine whether nitrones, known for their neuroprotective and antioxidant effects, could modulate this process. We focused on key proteins involved in different phases of autophagy: HIF-1α, BNIP3, and BECN1 for induction and nucleation, LC3 for elongation, and p62 for degradation. Our findings confirmed that the IR model promotes autophagy, initially via HIF-1α activation. Additionally, the neuroprotective effect of three of the selected synthetic nitrones (quinolylnitrones QN6 and QN23, and homo-bis-nitrone HBN6) partially derives from their antiautophagic properties, demonstrated by a downregulation of the expression of molecular markers involved in various phases of autophagy. In contrast, the neuroprotective power of cholesteronitrone ChN2 seems to derive from its promoting effects on the initial phases of autophagy, which could potentially help inhibit other forms of cell death. These results underscore the importance of autophagy modulation in neuroprotection, highlighting the potential of inhibiting prodeath autophagy and promoting prosurvival autophagy as promising therapeutic approaches in treating ischemic stroke clinically. [ABSTRACT FROM AUTHOR]

A class of novel chiral‐bridged biphenyl monophosphine ligands with a benzofuran moiety (He‐phos) has been successfully synthesized and reported. These ligands exhibited good performance in the gold‐catalyzed enantioselective cycloaddition reaction of 2‐(1‐alkynyl)‐2‐en‐1‐ones with nitrones, resulting in the successful preparation of a series of polyaryl‐substituted heterocyclic compounds with high enantioselectivities (up to 99% yield, 98% ee). The wide substrate adaptability (53 examples) and mild reaction conditions demonstrate the practicability of He‐phos in this reaction. [ABSTRACT FROM AUTHOR]

Diastereoselectivity of the 1,3-dipolar cycloaddition of nitrone with some N-substituted maleimides was studied theoretically in gas phase and in solvents, using DFT methods at the B3LYP/6-31G(d) theoretical level. The reactivity indices indicate that nitrone is a moderate nucleophile whereas the maleimides are moderate electrophiles. Analysis of different energy profiles shows that these competitive reactions favour the formation of the exo cycloadducts, in all reactions. Solvent effect showed that water was the best solvent for this reaction, which is in agreement with the experiment. [ABSTRACT FROM AUTHOR]

The synthesis, antioxidant capacity, and anti-inflammatory activity of four novel N-benzyl-2-[4-(aryl)-1H-1,2,3-triazol-1-yl]ethan-1-imine oxides 10a–d are reported herein. The nitrones 10a–d were tested for their antioxidant properties and their ability to inhibit soybean lipoxygenase (LOX). Four diverse antioxidant tests were used for in vitro antioxidant assays, namely, interaction with the stable free radical DPPH (1,1-diphenyl-2-picrylhydrazyl radical) as well as with the water-soluble azo compound AAPH (2,2′-azobis(2-amidinopropane) dihydrochloride), competition with DMSO for hydroxyl radicals, and the scavenging of cationic radical ABTS•+ (2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonate) radical cation). Nitrones 10b, 10c, and 10d, having the 4-fluorophenyl, 2,4-difluorophenyl, and 4-fluoro-3-methylphenyl motif, respectively, exhibited high interaction with DPPH (64.5–81% after 20 min; 79–96% after 60 min), whereas nitrone 10a with unfunctionalized phenyl group showed the lowest inhibitory potency (57% after 20 min, 78% after 60 min). Nitrones 10a and 10d, decorated with phenyl and 4-fluoro-3-methylphenyl motif, respectively, appeared the most potent inhibitors of lipid peroxidation. The results obtained from radical cation ABTS•+ were not significant, since all tested compounds 10a–d showed negligible activity (8–46%), much lower than Trolox (91%). Nitrone 10c, bearing the 2,4-difluorophenyl motif, was found to be the most potent LOX inhibitor (IC50 = 10 μM). [ABSTRACT FROM AUTHOR]

A new procedure for the synthesis of novel ketonitrones has been developed. The procedure involves the coupling of Grignard reagents with the easily accessible and stable N-substituted α-(1H-benzotriazol-1-yl) nitrones in the presence of catalytic amounts of zinc bromide. [ABSTRACT FROM AUTHOR]

An asymmetric 1,3‐dipolar cycloaddition of β‐fluoroalkylated α,β‐unsaturated 2‐acyl imidazole with nitrones or N,N'‐cyclic azomethine imines to construct chiral α‐fluoroalkylated γ‐amino alcohols or chiral α‐fluoroalkylated 1,3‐diamino compounds has catalyzed by chiral‐at‐metal rhodium complexes is reported. The corresponding products with three contiguous tertiary stereocenters were obtained in 62%–98% yields with stereoselectivities up to >20:1 dr and 99% ee. Remarkably, as low as 0.06 mol% of chiral‐at‐metal rhodium complex can promote a gram‐scale reaction with nitrones or N,N'‐cyclic azomethine imines. [ABSTRACT FROM AUTHOR]

Owing to their distinctive 1,3‐dipolar structure, the catalytic asymmetric hydrogenation of nitrones to hydroxylamines has been a formidable and longstanding challenge, characterized by intricate enantiocontrol and susceptibility to N−O bond cleavage. In this study, the asymmetric hydrogenation and transfer hydrogenation of nitrones were accomplished with a tethered TsDPEN‐derived cyclopentadienyl rhodium(III) catalyst (TsDPEN: p‐toluenesulfonyl‐1,2‐diphenylethylene‐1,2‐diamine), the reaction proceeds via a novel 7‐membered cyclic transition state, producing chiral hydroxylamines with up to 99 % yield and >99 % ee. The practical viability of this methodology was underscored by gram‐scale catalytic reactions and subsequent transformations. Furthermore, mechanistic investigations and DFT calculations were also conducted to elucidate the origin of enantioselectivity. [ABSTRACT FROM AUTHOR]

The manuscript presents an efficient method for the synthesis of various cis-azetidin-2-ones with high regio- and diastereoselectivity. This approach utilizes Kinugasa reaction involving diverse functionalized nitrones, including diaryl nitrones and α,β-unsaturated nitrones, in conjunction with acetylenic alcohols. Copper (I) serves as a catalyst to facilitate the transformation. [ABSTRACT FROM AUTHOR]

The recent advances in research on the use of the antioxidant and neuroprotective agent α-phenyl-N-tert-butylnitrone (PBN) for the therapy of stroke have been reviewed. The protective effect of PBN in the transient occlusion of the middle cerebral artery (MCAO) has been demonstrated, although there have been significant differences in the neuronal salvaging effect between PBN-treated and untreated animals, each set of data having quite large inter-experimental variation. In the transient forebrain ischemia model of gerbil, PBN reduces the mortality after ischemia and the neuronal damage in the hippocampal cornu ammonis 1 (CA1) area of the hippocumpus caused by ischemia. However, PBN fails to prevent postischemic CA1 damage in the rat. As for focal cerebral ischemia, PBN significantly reduces cerebral infarction and decreases neurological deficit after ischemia using a rat model of persistent MCAO in rats. Similarly, the antioxidant and neuroprotective capacity of a number of PBN-derived nitrones prepared in the author's laboratory have also been summarized here, showing their high potential therapeutic power to treat stroke. [ABSTRACT FROM AUTHOR]

Herein, we have synthesized multifunctionalized 2‐oxa‐3‐azabicyclo[3.1.1]heptanes, which are considered potential bioisosteres for meta‐substituted arenes, through Eu(OTf)3‐catalyzed formal dipolar [4π+2σ] cycloaddition of bicyclo[1.1.0]butanes with nitrones. This methodology represents the initial instance of fabricating bicyclo[3.1.1]heptanes adorned with multiple heteroatoms. The protocol exhibits both mild reaction conditions and a good tolerance for various functional groups. Computational density functional theory calculations support that the reaction mechanism likely involves a nucleophilic addition of nitrones to bicyclo[1.1.0]butanes, succeeded by an intramolecular cyclization. The synthetic utility of this novel protocol has been demonstrated in the concise synthesis of the analogue of Rupatadine. [ABSTRACT FROM AUTHOR]

A Sc(OTf)3‐catalyzed tandem (3 + 3)‐annulation/lactonization of donor‐acceptor cyclopropane 1,1‐dieters with salicylaldehyde nitrones has been reported, affording a wide range of tetrahydrochromeno[4,3‐c][1,2]oxazin‐5(1H)‐ones in moderate yields with excellent diastereoselectivities. Besides, the gram‐scale reaction has also been explored to demonstrate the utility of this protocol. Moreover, the mechanism was investigated through control experiments, which show the reaction proceeds via a tandem (3 + 3)‐annulation/lactonization reaction. [ABSTRACT FROM AUTHOR]

Herein, we report a new synthetic route to 1,4-epoxy-2-aryltetrahydro-1-benzazepine derivatives with high efficiency, namely the Rh(III)-catalyzed C–H allylation of nitrones with allyl precursors, followed by subsequent intramolecular 1,3-dipolar cycloaddition, to deliver the title compounds. This reaction is regio- and stereo-selective, generating the cis-isomer with a broad substrate scope and good functional group tolerance. [ABSTRACT FROM AUTHOR]

N‐Selective carbamoylation reaction of oximes with isocyanates generates nitrones, which undergo 1,3‐dipolar cycloaddition with various dipolarophiles to afford diverse isoxazolidines. Notably, combinations of highly electron‐rich oxime and highly electron‐deficient dipolarophile exhibited high reactivity, with product yields of up to 94 %. The substituent on the isoxazolidine‐nitrogen atom could be successfully removed without loss of the cyclic structure. Computational studies have also elucidated the mechanism of the reaction and origin of stereoselectivity. [ABSTRACT FROM AUTHOR]

This article explores the synthesis of vinyloxaziridines from conjugated nitrones using visible-light-promoted cycloisomerization. Previous attempts to synthesize oxaziridines under photochemical conditions have been unsuccessful, but the authors of this study discovered a successful method using benzaldehyde and benzylhydroxylamine hydrochloride. Further optimization of the reaction led to high yields of vinyloxaziridines. The study also found that substituted cinnamaldehydes and enals were ideal for the reaction, and changing the electronic nature of the cinnamyl ring did not affect the efficiency. The research provides valuable insights into the synthesis of complex nitrogen-containing heterocycles and suggests potential for further research in this area. [Extracted from the article]

The intramolecular [3 + 2] cycloaddition (32CA) reactions of allenic nitrones have been studied within the molecular electron density theory (MEDT) at the MPWB1K/6-311G(d,p) computational level. These zwitter-ionic type 32CA reactions show high activation free energies between 22.2 and 34.9 kcal mol−1 in ethanol consistent with their predicted non-polar character and follow one-step mechanism with highly asynchronous transition states. Interestingly, when the nitrone and the allene moieties are separated by two methylene units, the [3 + 2] addition is energetically feasible along the C5-C6 terminal double bond of the allene, while the presence of four methylene units change the cyclization selectivity towards the internal C4-C5 double bond of the allene. This is in complete agreement with the experimental outcomes. The molecular mechanism study in terms of bonding evolution theory (BET) shows varied electron density changes along these two reaction paths. Finally, the topological analysis of AIM (atoms-in-molecules) reveals the presence of non-covalent interactions at the interatomic bonding regions of the transition states, which agrees well with the electron localization function analysis and the forming C–C and C-O bond distances. [ABSTRACT FROM AUTHOR]

Stroke is a leading cause of death worldwide, yet current therapeutic strategies remain limited. Among the neuropathological events underlying this disease are multiple cell death signaling cascades, including autophagy. Recent interest has focused on developing agents that target molecules involved in autophagy to modulate this process under pathological conditions. This study aimed to analyze the role of autophagy in cell death induced by an in vitro ischemia–reperfusion (IR) model and to determine whether nitrones, known for their neuroprotective and antioxidant effects, could modulate this process. We focused on key proteins involved in different phases of autophagy: HIF-1α, BNIP3, and BECN1 for induction and nucleation, LC3 for elongation, and p62 for degradation. Our findings confirmed that the IR model promotes autophagy, initially via HIF-1α activation. Additionally, the neuroprotective effect of three of the selected synthetic nitrones (quinolylnitrones QN6 and QN23, and homo-bis-nitrone HBN6) partially derives from their antiautophagic properties, demonstrated by a downregulation of the expression of molecular markers involved in various phases of autophagy. In contrast, the neuroprotective power of cholesteronitrone ChN2 seems to derive from its promoting effects on the initial phases of autophagy, which could potentially help inhibit other forms of cell death. These results underscore the importance of autophagy modulation in neuroprotection, highlighting the potential of inhibiting prodeath autophagy and promoting prosurvival autophagy as promising therapeutic approaches in treating ischemic stroke clinically.

The present review contains a representative sampling of mechanistic studies, which have appeared in the literature in the last 5 years, on 1,3-dipolar cycloaddition reactions, using DFT calculations. Attention is focused on the mechanistic insights into 1,3-dipoles of propargyl/allenyl type and allyl type such as aza-ylides, nitrile oxides and azomethyne ylides and nitrones, respectively. The important role played by various metal–chiral–ligand complexes and the use of chiral eductors in promoting the site-, regio-, diastereo- and enatioselectivity of the reaction are also outlined. [ABSTRACT FROM AUTHOR]

The reaction of 1-vinyl-4,5-dihydro-1H-benzo[g]indole with C-aryl-N-methylnitrones in the presence of nickel (II) perchlorate proceeds regioselectively to form a mixture of diastereomeric adducts of formal (3+3) cycloaddition, whereas the main products of the reaction with C,N-diarylnitrones are dipyrromethanes. [ABSTRACT FROM AUTHOR]

One of the promising directions in 1,3-dipolar cycloaddition is the implementation of these reactions under organocatalysis conditions, which makes it possible to achieve not only high products yields, but also complete stereocontrol of the process. The presented review analyzes data published over the past 5 years according to the types of 1,3-dipoles involved into reactions. In a number of cases, the mechanisms of 1,3-dipolar cycloaddition reactions occurring in the presence of organocatalysts are discussed in detail. [ABSTRACT FROM AUTHOR]

The influence of ethylene substitution and the tether length between the two reacting counterparts on the selectivity and reactivity of the intramolecular [3 + 2] cycloaddition (IM32CA) reactions of cyclic nitrones leading to tricyclic isoxazolidines have been studied within the Molecular Electron Density theory at the MPWB1K/6‐311G(d,p) computational level. These zw‐type IM32CA reactions follow one‐step mechanism, and the activation barrier decreases with the introduction of electron withdrawing (EW) substituent at the alkene moiety in both the intramolecular and intermolecular versions. The IM32CA reactions involving unsubstituted alkene have non‐polar character with minimal electron density flux classified as null electron density flux type, while that involving the EW nitro substituted ethylene is more facile with a strong electron density flux from the nitrone to the ethylene moiety, classified as forward electron density flux type. The increase in the polar character of the IM32CA reaction decreases the activation Gibbs free energies associated with these intramolecular processes, while the highly polar IM32CA reactions are disfavored with respect to the intermolecular ones. Interestingly, the preferred regioselectivity observed in low polar IM32CA reactions having three methylene units between the nitrone and ethylene frameworks is reversed to that in nitrones separated with four methylene units, in conformity with the experimental outcome. Finally, electron localization function and quantum theory of atoms‐in‐molecules studies reveal that, in general, these IM32CA reactions involve early transition state structures in which the formation of new C‐C and C‐O single bonds have not yet started. [ABSTRACT FROM AUTHOR]

Isoxazolidine, isoxazole, and isoquinolinone rings are present in the structure of several natural products and/or pharmaceutically interesting compounds. In this work, facile and efficient pathways have been developed for the preparation of fused frameworks bearing those heterocycles. The successful approaches for both isoxazolidine/isoquinolinone and isoxazole/isoquinolinone hybrid syntheses relied initially on 1,3-dipolar cycloadditions of nitrones and nitrile oxides to indenone and 2-propargylbenzamide, respectively. The construction of the isoquinolinone lactam system followed by performing a selective Schmidt reaction for isoxazolidine derivatives (two steps overall), whereas the isoxazole lactams were reached via an Ullmann-type cyclisation (three steps overall). Key observations were made regarding the stereo- and regioselectivities of the reactions employed, and small libraries of the targeted hybrids were prepared, demonstrating the general applicability of these strategies. [ABSTRACT FROM AUTHOR]

Complex spirocyclic isoindolines and pyrrolidines are formed in a tandem process involving Co(III)‐catalyzed dienylation of cyclic C‐aryl nitrones with 2,3‐butadien‐1‐ol carbonates, followed by intramolecular 1,3‐dipolar cycloaddition. The nitrone moiety serves both as a directing group for the C(aryl)−H activation and the dipole in the cycloaddition step. High regioselectivity of the fused vs. bridged product can be obtained by adjusting the reaction temperature. Reactions with substituted allenic substrates provide heterocycles with additional stereocenters usually with complete diastereoselectivity. The reaction products were readily transformed further into other complex nitrogen‐containing spirocyclic systems. [ABSTRACT FROM AUTHOR]

δ,ϵ‐Unsaturated oximes, on heating with O‐alkyl S‐(pyridin‐2‐yl)carbonothioates (PySCO2R) in refluxing toluene, undergo intramolecular cycloaddition to give N‐alkoxycarbonylated multi‐cyclic compounds. Mechanistic studies indicate that the reaction involves direct generation of N‐alkoxycarbonyl nitrones followed by cycloaddition, instead of intramolecular oxime‐olefin cycloaddition (IOOC) followed by alkoxycarbonylation. DFT calculation indicates that N‐alkoxycarbonylation of oxime with PySCO2R is a concerted reaction. The reaction of oxime with a chiral alkoxycarbonylation reagent exhibits a reasonably high diastereo‐face selectivity. [ABSTRACT FROM AUTHOR]

Readily available hydroxamic acids were leveraged to access challenging nitrones in the presence of H3PO4 as a Brønsted acid catalyst and engaged in an intramolecular (3+2) annulation reaction to make valuable cyclopentane-fused isoxazolidines with high yields and excellent diastereoselectivity. The products were further utilized in a unique base-promoted benzilic amide rearrangement to provide cyclopentane-fused γ-lactams bearing three contiguous stereocenters as a single diastereomer. [ABSTRACT FROM AUTHOR]

We herein disclose a simple and general method for the synthesis of chromendiones through Rh(III)‐catalyzed C−H functionalization/annulation reactions of nitrones with cyclic 2‐diazo‐1,3‐diones by using nitrone group as a traceless directing group. This method exhibits high efficiency and broad functional group compatibility. The derivatization of these chromendiones has been also demonstrated to further strengthen the synthetic utility of the transformation. [ABSTRACT FROM AUTHOR]

A convenient approach towards previously unknown phosphonium salts containing a non-aromatic 2H-imidazole moiety is reported. The approach is based on a direct nucleophilic C(sp2)-H functionalization of 2H-imidazole 1-oxides with triphenylphosphine acting as a nucleophile. Herewith, the heterocyclic N-oxide moiety is utilized as an auxiliary group contributing to an abstraction of C-H proton during the elimination process. Newly obtained compounds can be a subject of further modification, e.g. used for the synthesis of monodeuterated 2H-imidazoles. [ABSTRACT FROM AUTHOR]

The synthesis, antioxidant capacity, and anti-inflammatory activity of four novel N-benzyl-2-[4-(aryl)-1H-1,2,3-triazol-1-yl]ethan-1-imine oxides 10a–d are reported herein. The nitrones 10a–d were tested for their antioxidant properties and their ability to inhibit soybean lipoxygenase (LOX). Four diverse antioxidant tests were used for in vitro antioxidant assays, namely, interaction with the stable free radical DPPH (1,1-diphenyl-2-picrylhydrazyl radical) as well as with the water-soluble azo compound AAPH (2,2′-azobis(2-amidinopropane) dihydrochloride), competition with DMSO for hydroxyl radicals, and the scavenging of cationic radical ABTS•+ (2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonate) radical cation). Nitrones 10b, 10c, and 10d, having the 4-fluorophenyl, 2,4-difluorophenyl, and 4-fluoro-3-methylphenyl motif, respectively, exhibited high interaction with DPPH (64.5–81% after 20 min; 79–96% after 60 min), whereas nitrone 10a with unfunctionalized phenyl group showed the lowest inhibitory potency (57% after 20 min, 78% after 60 min). Nitrones 10a and 10d, decorated with phenyl and 4-fluoro-3-methylphenyl motif, respectively, appeared the most potent inhibitors of lipid peroxidation. The results obtained from radical cation ABTS•+ were not significant, since all tested compounds 10a–d showed negligible activity (8–46%), much lower than Trolox (91%). Nitrone 10c, bearing the 2,4-difluorophenyl motif, was found to be the most potent LOX inhibitor (IC50 = 10 μM).

By resorting to the principle of remote activation, we herein demonstrate the first photoredox catalyzed (3+3) dipolar cycloaddition of nitrones with aryl cyclopropanes. Key to the fidelity of the reaction resides in a facile manner of substrate activation by single‐electron transfer (SET) oxidation with photoredox catalysis, and the reaction takes place through a stepwise cascade encompassing a three‐electron‐type nucleophilic substitution triggered cyclopropane ring‐opening and a diastereoselective 6‐endo‐trig radical cyclization manifold. The reaction proceeds under mild conditions with excellent regio‐ and stereoselectivity, nicely complementing the well‐developed Lewis acid catalyzed cycloaddition of donor‐acceptor cyclopropanes. Other merits of the protocol include wide scope of aryl cyclopropanes with diversified substitution patterns and good functional‐group compatibility. A mechanism involving an aryl radical cation promoted remote activation mode was also proposed and supported by mechanistic experiments. [ABSTRACT FROM AUTHOR]

The first asymmetric (3+3)-cycloaddition of ortho-substituted phenyl nitrones with aryl cyclopropane carbaldehydes has been demonstrated by secondary amine catalysts. While the other ortho-substituents gave 1,2-oxazinanes, ortho-hydroxy ones provided a novel class of tetrahydrochromeno-1,2-oxazine cores via rare 1,3-aryl migration, followed by cyclization. An unusual type of asymmetric approach was also recognized. [ABSTRACT FROM AUTHOR]

Gold‐catalyzed cascade reactions between 1,5‐diyn‐3‐ols and nitrones to deliver carbazole derivatives are described. Such cascade reactions are applicable to facile synthesis of polyaromatic compounds containing carbazole subunits. Notably, the reaction mechanism involves unexpected oxoarylations, rather than oxidative Mannich reactions as known for but‐1‐yn‐4‐ols. Our control experiments indicate that the presence of a second alkyne as in 1,5‐diyn‐3‐ols enables such oxoarylations due to a weak bonding between gold and this alkyne, rending the tethered alcohol less conformationally flexible. [ABSTRACT FROM AUTHOR]

A variety of functionalized 2‐pyrrolidinones bearing N‐trifluoromethylphenyl moieties were prepared in moderate to good yields with high diastereoselectivity through copper(II)‐catalyst and base co‐catalyzed formal [4+1] cycloaddition of cinnamaldehyde nitrones with 1‐ethynylnaphthalen‐2‐ols in the presence of m‐CPBA as the oxidant. The triple bond of 1‐ethynylnaphthalen‐2‐ol served as one‐carbon synthon for the pyrrolidinone ring formation. Mechanistic studies revealed that m‐CPBA played an important role to interrupt the intramolecular O‐cyclization to afford the 2‐pyrrolidinones. Moreover, the reaction could be easily performed at gram scales and the obtained products were selectively converted into diverse pyrroline scaffolds. [ABSTRACT FROM AUTHOR]

This paper describes the synthesis of two complexes from the ligand α-(2-Salsayl)-N-phenyl nitrone with CoCl2 and CrCl2. The ligand was characterized by several spectroscopic techniques (ultraviolet/visible (UV/Vis), nuclear magnetic resonance (1H-NMR and 13C-NMR), Fourier-transform infrared spectroscopy (FTIR), and mass spectrometry (MS). While infrared, ultraviolet-visible (UV-Vis), thermal analysis, and job method studies were used to reveal the structure of the complexes. The synthesized complexes were then synthesized by the sonochemical method, and the copper and chromium oxide nanoparticles were produced using the thermal decomposition method. Scanning electron microscopy (SEM), Energy dispersive X-ray spectroscopy (EDX), and X-ray diffraction (XRD) characterization confirmed the formation of Co3O4 and Cr2O3 nanoparticles. Antimicrobial studies of the complexes against some microorganisms, such as Staphylococcus epidermis and Escherichia coli, utilizing the disk diffusion method, revealed the antibacterial activity of the complexes.

The recent advances in research on the use of the antioxidant and neuroprotective agent α-phenyl-N-tert-butylnitrone (PBN) for the therapy of stroke have been reviewed. The protective effect of PBN in the transient occlusion of the middle cerebral artery (MCAO) has been demonstrated, although there have been significant differences in the neuronal salvaging effect between PBN-treated and untreated animals, each set of data having quite large inter-experimental variation. In the transient forebrain ischemia model of gerbil, PBN reduces the mortality after ischemia and the neuronal damage in the hippocampal cornu ammonis 1 (CA1) area of the hippocumpus caused by ischemia. However, PBN fails to prevent postischemic CA1 damage in the rat. As for focal cerebral ischemia, PBN significantly reduces cerebral infarction and decreases neurological deficit after ischemia using a rat model of persistent MCAO in rats. Similarly, the antioxidant and neuroprotective capacity of a number of PBN-derived nitrones prepared in the author’s laboratory have also been summarized here, showing their high potential therapeutic power to treat stroke.

The electro‐reductive coupling of nitro and carbonyl compounds enables a facile, environmentally friendly and energy benign transformation toward value‐added nitrones or imines, but the selectivity is still challenging. Here, the surface roughness of Cu electrodes is introduced for the first time as the determinant to switch products from nitrones to imines owing to the controllable reduction of nitroarenes to hydroxylamines or amines on tailored CuI/Cu0 interfaces. The roughness‐dependent selectivity, that is the decrease of nitrones and the increase of imines with enhanced roughness, is visible in the electro‐reductive coupling of nitrobenzene and furfural. Thus, the high selectivity of nitrone (98 %) and imine (80 %) can be achieved on a surface smooth Cu foil and the one electrochemically roughened in the presence of I−, respectively. Such roughness‐dependence of nitrone/imine selectivity on Cu electrodes is further verified in a wide substrate scope, highlighting the promise of surface/interfacial engineering for electrochemical synthesis. [ABSTRACT FROM AUTHOR]

Site-directed spin labeling followed by investigation using Electron Paramagnetic Resonance spectroscopy is a rapidly expanding powerful biophysical technique to study structure, local dynamics and functions of biomolecules using pulsed EPR techniques and nitroxides are the most widely used spin labels. Modern trends of this method include measurements directly inside a living cell, as well as measurements without deep freezing (below 70 K), which provide information that is more consistent with the behavior of the molecules under study in natural conditions. Such studies require nitroxides, which are resistant to the action of biogenic reductants and have high spin relaxation (dephasing) times, Tm. (1R(S),5R(S),7R(S),8R(S))-1,8-bis(hydroxymethyl)-6-azadispiro[4.1.4.2]tridecane-6-oxyl is a unique nitroxide that combines these features. We have developed a convenient method for the synthesis of this radical and studied the ways of its functionalization. Promising spin labels have been obtained, the parameters of their spin relaxation T1 and Tm have been measured, and the kinetics of reduction with ascorbate have been studied. [ABSTRACT FROM AUTHOR]

4-Isoxazolines are important motifs in various biologically interesting molecules and versatile synthons for the preparation of various cyclic and acyclic compounds. Herein, two green and facile protocols were reported for the synthesis of a wide range of polyfluoroalkanesulfinyl or alkylsulfinyl 4-isoxazolines. A variety of aldehyde and ketone derived nitrones reacted with α-alkynyl sulfoxides under catalyst- and solvent-free conditions at room temperature to provide a series of polyfluoroalkanesulfinyl or alkylsulfinyl 4-isoxazolines with high efficiency. The synthesis of these sulfinyl 4-isoxazolines was further improved to a one-pot process in aqueous medium starting from aldehydes and hydroxylamine hydrochlorides without the need for isolating the nitrones. The reactions developed in this work are easy to perform and demonstrate significant ecological advantages. [ABSTRACT FROM AUTHOR]

Water-soluble spin probes were obtained from reduction-resistant sterically shielded pyrrolidine nitroxides by forming a 4,5-dicarboxy-1H-1,2,3-triazole fragment in the side chain by the Huisgen reaction of the azido group with acetylenedicarboxylic acid ester followed by hydrolysis. For the synthesized radicals, the reduction rate constants by ascorbate and the partition coefficient in an octanol—water system were determined. [ABSTRACT FROM AUTHOR]

Ischemic stroke is the leading cause of disability and the second leading cause of death worldwide. However, current therapeutic strategies are scarce and of limited efficacy. The abundance of information available on the molecular pathophysiology of ischemic stroke has sparked considerable interest in developing new neuroprotective agents that can target different events of the ischemic cascade and may be used in combination with existing treatments. In this regard, nitrones represent a very promising alternative due to their renowned antioxidant and anti-inflammatory effects. In this study, we aimed to further investigate the neuroprotective effects of two nitrones, cholesteronitrone 2 (ChN2) and quinolylnitrone 23 (QN23), which have previously shown great potential for the treatment of stroke. Using an experimental in vitro model of cerebral ischemia, we compared their anti-necrotic, anti-apoptotic, and antioxidant properties with those of three reference compounds. Both ChN2 and QN23 demonstrated significant neuroprotective effects (EC50 = 0.66 ± 0.23 μM and EC50 = 2.13 ± 0.47 μM, respectively) comparable to those of homo-bis-nitrone 6 (HBN6) and N-acetylcysteine (NAC) and superior to those of α-phenyl-N-tert-butylnitrone (PBN). While primarily derived from the nitrones' anti-necrotic capacities, their anti-apoptotic effects at high concentrations and antioxidant powers—especially in the case of QN23—also contribute to their neuroprotective effects. [ABSTRACT FROM AUTHOR]

In the present article, a theoretical and computational study was carried out on the reactivity and antioxidant capacity of a series of nitrone derivatives (hBNn) in the presence of the OH· radical. For the antioxidant characterization of these compounds, tools such as global and local reactivity indices were used, as well as thermodynamic aspects to obtain the most energetically stable product. In addition, the NBO analysis, which described the SOMO generated by the electron radical of the spin adduct hBNn-OH. The results obtained show that the nitrone derivatives studied present the antioxidant capacity of radical trapping, forming energetically stable spin adducts. In turn, the reactivity of the systems (nitrone and radical) shows their nucleophilic and electrophilic tendencies, allowing us to propose a reaction mechanism for these radical traps. [ABSTRACT FROM AUTHOR]

The roles of substituent and solvent effects in promoting the 4π electrocyclization of N‐alkenylnitrones to give azetidine nitrones have been investigated by experimental examination of relative rates, activation energies, and linear free energy relationships. These transformations are synthetically important because they favor the formation of a strained heterocyclic ring with imbedded functionality and stereochemical information for versatile derivatization. Mechanistic investigations, including Hammett studies, solvent‐dependent Eyring studies, and solvent isotope effects, provide insight into the steric and electronic factors that control these electrocyclizations and identify trends that can be used to advance this approach towards the rapid synthesis of complex azetidines. [ABSTRACT FROM AUTHOR]

A variety of 4‐phosphinylpyrrolidin‐3‐ones was prepared via a [3+2] cycloaddition between aryl aldonitrones and phosphinylallenes. The products were isolated as unique 4,5‐trans diastereomers, in yields between 47% and 80%, over 23 examples. In the case of chiral racemic allenes, a 2:1 to 4:1 moderate 2,5‐diastereoselectivity was observed. Under the reaction conditions, the cycloadducts directly undergo a rearrangement to afford selectively the corresponding pyrrolidin‐3‐ones. DFT calculations provide some insights into the mechanism, involving the homolytic cleavage of the N−O bond of the cycloadduct. [ABSTRACT FROM AUTHOR]

Cycloadditions of nitrones with alkynes usually occur best under heat activation. Due to the instability of the formed isoxazolines, alternative activation methods must be found. Here, hyperbaric conditions are used to transform nitrones generated from unprotected carbohydrates into the corresponding polyhydroxy-isoxazolines at room temperature. The reaction proved completely regioselective in favor of the 5-substituted 4-isoxazolines, and the products are obtained in good yields as mixtures of the two possible diastereoisomers. Further transformations into biologically valuable targets are described. The whole synthesis constitutes a very straightforward procedure for the transformation of aldoses, and is highly compatible with the principles of green chemistry. [ABSTRACT FROM AUTHOR]

[3 + 2] Cycloaddition reactions with the participation of Z-C-(3-pyridyl)-N-methylnitrone and series of E-2-R-nitroethenes were both experimentally and theoretically explored in the framework of Molecular Electron Density Theory. It was found that all considered processes are realized under mild conditions and in full regio- and stereocontrol. The ELF analysis additionally showed that the studied reaction proceeds by a two-stage, one-step mechanism. [ABSTRACT FROM AUTHOR]

Synthetic approached towards the synthesis of some novel nitrones derivatives have been started with reduction of nitrobenzene derivatives as starting material bearing electron withdrawing and electron donating groups to corresponding phenylhydroxylamine in presence of zinc dust as reducing agent in aqueous solution of ammonium chloride (NH4Cl). The prepared phenylhydroxylamine derivatives were reacted with different substituted benzaldehydes to give the target derivatives of nitrone. The structures of the synthesized nitrones were characterized by spectroscopic methods FT-IR, 1HNMR and 13C NMR. Finally, the newly synthesized compounds were screened for their microorganism activities at different concentration, and inhibited growth of Escherichia coli (E. coli) Gram negative, Staphylococcus aureus (S. aureus) Gram positive, and fungi (candida albicans). [ABSTRACT FROM AUTHOR]

We described a copper(II)‐catalyzed [3+2] cycloaddition of N‐aryl‐α,β‐unsaturated nitrones with disubstituted allenoates bifurcated to prepare various [1,3]oxazino[3,2‐a]indolines and dihydropyrido[1,2‐a]indolines in moderate to excellent yields. Mechanistic studies revealed that [1,3]oxazino[3,2‐a]indoline was a kinetically favored product and dihydropyrido[1,2‐a]indoline was thermodynamically favored product. Moreover, the reaction was easily performed at gram scales and chiral dihydropyrido[1,2‐a]indoline could be obtained by using chiral auxiliary. The present method highlights broad substrate scope, good functional group tolerance, and diversity of indoline scaffolds with high diastereoselectivity. [ABSTRACT FROM AUTHOR]

Inspired by the diverse bioactivities of α-amino phosphine oxides, an efficient strategy for the synthesis of less researched α-(hydroxyamino)diarylphosphine oxides has been developed and their antitumor activities are explored. Under water as a solvent and catalyst-free conditions, the addition of nitrones and diphenylphosphine oxide occurs smoothly to afford α-(hydroxyamino) diarylphosphine oxides in high yields. This reaction features a wide substrate scope, facile starting materials, atom economy, and easy purification. Moreover, the biological evaluation revealed that two synthesized derivatives 5e and 5f could serve as interesting anti-cancer agents for further development. [ABSTRACT FROM AUTHOR]

Herein we report the first redox‐neutral visible‐light photocatalytic intermolecular dipolar cycloaddition for the diastereoselective synthesis of isoxazolidines. We have found that vinyl nitrones with a diverse substitution pattern undergo visible‐light‐promoted cycloadditions with conjugated carbonyls in the presence of catalytic amounts of Ru(bpy)3Cl2, with the reaction proceeding with high yields and good selectivities. A redox‐neutral pathway is proposed as the primary photoredox mechanism for this transformation. [ABSTRACT FROM AUTHOR]

5,5,7,7-Tetrametyl-6,7-dihydro-5H-dibenzo[c,e]azepine has been synthesized as a possible pro-chiral (or tropos) unit for the construction of a chiral catalyst and as a molecular chirality sensor for the absolute configuration assignment by chiroptical spectroscopy. A straightforward synthetic strategy for the preparation of the title compound in high overall yield through sequential addition of the four methyl groups on benzylic positions has been described. A VT-NMR study was used to determine the rotational barrier of the aryl–aryl bond in this biphenylazepine, revealing its torsional flexibility at room temperature, which makes the biphenylazepine suitable as both a chirality probe and a tropos moiety in chiral ligands. [ABSTRACT FROM AUTHOR]