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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]

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]

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]

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]

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]

A novel strategy for the synthesis of 2-arylethenesulfonyl fluorides from nitrones and ethenesulfonyl fluoride (ESF) by the activation of the C–H bond using an inexpensive and readily available Ru-catalyst has been developed. In this process, the directing group can be concomitantly converted to an amide group. Interestingly, changing the substituent of the nitrogen of nitrones from a tert-butyl to a methyl group resulted in the formation of cyclic isoindolinones. Detailed mechanistic studies are also presented. [ABSTRACT FROM AUTHOR]

A chiral N,N′-dioxide/cobalt(II) complex catalytic system is developed to promote the multistep cascade reaction of α,β-unsaturated-N-aryl nitrones with allenes, giving a variety of chiral dihydropyridoindoles in moderate to good yields with excellent dr and ee values. Mechanistic studies support a [3+2] cycloaddition/[3,3]-rearrangement/retro-Mannich process. [ABSTRACT FROM AUTHOR]

The zwitterionic (zw-) type intramolecular [3 + 2] cycloaddition (IM32CA) reactions of C,N-disubstituted nitrones bearing acyclic and cyclic alkene functionalities have been studied from the molecular electron density theory (MEDT) perspective. The nitrones under study were classified as zwitterionic species from the topological analysis of the electron localization function (ELF). These IM32CA reactions show non-polar character and follow a non-concerted one step mechanism with activation free energies of 22.8--35.2 kcal mol-1 in toluene. When the N-butenyl system is attached to the nitrogen atom of the nitrone, the IM32CA reaction presents total regioselectivity with the terminal alkene carbon involved in C--C bond formation in complete agreement with the experimental findings. Interestingly, the activation free energy shows a sharp increase of 6.1 kcal mol-1 on dimethyl substitution of the terminal carbon owing to the considerable increase in the non-covalent strongly repulsive interaction revealed by the reduced density gradient scatter map of the NCI plot. This agrees well with the experiments showing no reaction of the corresponding nitrone. For the nitrones with a cyclic alkene functionality, the activation energies are decreased by 5.1--6.2 kcal mol-1 compared to the acyclic one, due to the relatively lower energy cost demanded for the similar bonding changes along the reaction path. [ABSTRACT FROM AUTHOR]

An unprecedented cascade strategy consisting of polarity reversal, normal electron-demand Diels-Alder cycloaddition and skeletal remodeling was developed to construct novel pyridine-fused nitrones in up to 82% yield. The key to the success was the umpolung process, which transformed the electron-deficient 3-nitropyridinium ring into a reactive, p-extended cyclic nitroalkene, serving as a rarely reported hetero-diene to participate in normal Diels-Alder cycloadditions. [ABSTRACT FROM AUTHOR]

A new copper-catalyzed aerobic hydroxyamination of alkenes of unsaturated keto oximes with O2 in EtOH for producing functionalized cyclic nitrones is presented. Mechanistic studies indicate that this method involves radical initiation from the oxime side and superoxide radical formation. This method is distinguished by its easy operation with the discharge of water as the attendant product, its use of green molecular oxygen as the oxygen atom source and terminal oxidant, inexpensive copper salt as the catalyst and low-cost environmentally benign EtOH as the medium, and its exquisite selectivity, broad substrate scope, and excellent functional group tolerance. [ABSTRACT FROM AUTHOR]

An efficient gold and chiral phosphoric acid cooperatively catalyzed enantioselective oxidative cyclization/Mannich-type addition reaction of homopropargyl amides with nitrones has been developed, which provides chiral pyrrolidin-3-ones in high yields with excellent enantioselectivities under mild conditions. This reaction employed stable and readily available alkynes as non-diazo carbene precursors, which provides a 100% atom economy method with high bond formation efficiency. [ABSTRACT FROM AUTHOR]

Cycloadditions are known to be one of the most abundant, versatile and valuable classes of chemical reactions. Among various efficient chemical processes, cycloaddition is an important route owing to its stereospecificity, ability to generate complex molecules and atom economy. Nitrone is one of the widely used dipoles in the 1,3-dipolar cycloaddition reaction, as it is stable and does not always require in situ generation. The 1,3-dipolar cycloaddition of nitrones with various dipolarophiles generates several heterocyclic rings having different sizes. These heterocycles have enormous applications in natural products, biologically active molecules and pharmaceuticals. This review is focused on nitrones that undergo cycloaddition with different substrates to generate various heterocyclic rings. [ABSTRACT FROM AUTHOR]

A new copper-catalyzed two-component amino-benzoyloxylation of unactivated alkenes of unsaturated ketoximes with O-benzoylhydroxylamines as the benzoyloxy sources is developed. Chemoselectivity of this method toward amino-benzoyloxylation or oxy-benzoyloxylation of alkenyl ketoximes relies on the position of the tethered olefins, and provides an external-oxidant-free alkene difunctionalization route that directly utilizes O-benzoylhydroxylamines as the benzoyloxy radical precursors and internal oxidants for the divergent synthesis of cyclic nitrones and isoxazolines. [ABSTRACT FROM AUTHOR]

An original approach to achieve the C(sp2)–H azolation of cyclic aldonitrones mediated by Selectfluor® has first been employed. By exploiting a metal-free, visible-light-promoted cross-dehydrogenative C–N coupling reaction between model aldonitrones, 2H-imidazole 1-oxides, and NH-containing azoles, a series of novel azaheterocyclic derivatives have been obtained in yields up to 94%. The elaborated protocol has proved to be appropriate for gram-scale processes and displayed potential for utilization in the synthesis of novel structural analogues of lanabecestat. Besides, mechanistic studies have revealed that this coupling reaction is likely to proceed via a nitroxide-involving radical pathway, encompassing a chain of electron transfer events, such as hydrogen atom transfer (HAT) and single electron transfer (SET). [ABSTRACT FROM AUTHOR]

The straightforward preparation of new 3-furanyl isoxazolidines by 1,3-dipolar cycloaddition of 5-hydroxymetylfurfural (HMF)-derived nitrones with electro-deficient olefins is investigated. The study addresses the stepwise reaction, with isolation of the intermediate nitrone, and the multicomponent protocol involving directly HMF and other reaction partners and reagents. The optimal reaction parameters (solvent, temperature, stoichiometry) for the stepwise and multicomponent reactions are defined, resulting in a choice of clean and direct conditions leading to cycloadducts in good yields. Isopropanol is found to be the most appropriate solvent in terms of both acceptability and efficiency depending on the solubility of the different substrates and on specific requirements for the stepwise and multicomponent protocols. The stereochemical outcome of the reaction and the structural scope with respect to various dipolarophiles (acrylates, cycloalkenones, acrylamides, acrylonitrile) and variously substituted hydroxylamines, using HMF and O-substituted HMF analogs are also fully assessed. The structural considerations allowing more regioselective reactions are also defined. This study provides the basic elements necessary for considering the use of HMF in such strategies. [ABSTRACT FROM AUTHOR]

CuFe2O4 nanoparticles acted as a highly efficient heterogeneous catalyst in the reaction of alkynes and nitrones (Kinugasa reaction) for the synthesis of various 2-azetidinones. In all cases, the reactions proceeded conveniently under mild conditions with good-to-excellent yields and with a wide range of functional-group tolerance. The catalyst could be separated readily using an external magnet. [ABSTRACT FROM AUTHOR]

The use of functional groups as internal ligands for assisting C–H functionalization, termed the chelation assisted strategy, is emerging as one of the most powerful tools for construction of C–C and C–X bonds from inert C–H bonds. However, there are various directing groups which cannot be either removed after functionalization or require some additional steps or reagents for their removal, thereby limiting the scope of structural diversity of the products, and the step and atom economy of the system. These limitations are overcome by the use of the traceless directing group (TDG) strategy wherein functionalization of the substrate and removal of the directing group can be carried out in a one pot fashion. Traceless directing groups serve as the most ideal chelation assisted strategy with a high degree of reactivity and selectivity without any requirement for additional steps for their removal. The present review overviews the use of various functional groups such as carboxylic acids, aldehydes, N-oxides, nitrones, N-nitroso amines, amides, sulfoxonium ylides and silicon tethered directing groups for assisting transition metal catalyzed C–H functionalization reactions in the last decade. [ABSTRACT FROM AUTHOR]

A new organocatalytic bicyclization of α-alkynylnaphthalen-2-ols with nitrones was first reported, leading to the convergent synthesis of polycyclic indoles with substantial substitution diversity in generally good yields through scission of the N–O bond of nitrones via [3,3]-sigmatropic rearrangement. This transformation showcases the use of a quinine catalyst in a complicated cascade system that has been shown to effectively construct polycyclic heterocycles via alkyne difunctionalization. [ABSTRACT FROM AUTHOR]

We report a relay catalysis for the highly stereoselective synthesis of densely substituted oxazonine-fused endoperoxides in good yields. This domino reaction is based on an Yb(OTf)3 and visible light promoted [3 + 2] cycloaddition/[3,3]-rearrangement, and in situ [4 + 2] cycloaddition with air in one pot under mild reaction conditions from N-vinyl-α,β-unsaturated nitrones and methylenecyclopropanes, leading to a practical assembly of densely substituted oxazonine-fused endoperoxides containing five stereocenters with a wide substrate scope and excellent diastereoselectivity. Mechanistic studies reveal that the O–O bond of the endoperoxide ring is derived from singlet oxygen (1O2) generated by air under a white LED. Moreover, such an asymmetric relay catalyst has also been realized to afford chiral endoperoxides in good enantioselectivity. Biological tests show that the designed oxazonine-fused endoperoxides significantly inhibited nitric oxide (NO) generation in LPS-stimulated RAW264.7 cells and exhibited their bioactivity as good anti-inflammatory agents. [ABSTRACT FROM AUTHOR]

Prochiral N-alkyltrifluoromethylmethylene nitrones reacted smoothly with piperine, an α,β,γ,δ-unsaturated natural amide, to afford novel corresponding cycloadducts in moderate yields. This non-catalysed 1,3-dipolar cycloaddition was an entirely chemo- and regioselective reaction, and its stereoselectivity was strongly dependent on both the steric hindrance of the nitrone and the effects of the electron-withdrawing CF3 group. The major products 6a–6c were found to have the C3/C4 trans relative configuration of the protons in the isoxazolidinyl ring. In contrast, the 1,3-dipolar cycloaddition of unsubstituted N-methylmethylene nitrone to piperine led to two regioisomeric cycloadducts 7 and 8. The major cycloadducts underwent N–O cleavage todiastereoselectively pure 1,3-aminoalcohols 10a, 10c and 10d. The structure of the products was established by spectroscopic techniques, and the stereochemical aspects were discussed based on 1D/2D NMR relationships. [ABSTRACT FROM AUTHOR]

A general protocol for the construction of novel densely functionalized γ-lactones was developed in good to excellent yields with high diastereoselectivity from easily available N-vinyl-α,β-unsaturated nitrones and ketenes. The reaction involves copper-catalyzed [5 + 2] cycloaddition, N–O bond cleavage, 6π electron cyclization, and aromatization to afford various γ-(pyridin-2-yl)lactones over four step transformations in a single flask. The present method features mild reaction conditions, high atom economy, high regio- and diastereoselectivity, diversity of γ-lactones, and a new application of the O-transfer reaction. [ABSTRACT FROM AUTHOR]

In this work, α-phenyl-N-tert-butylnitrone (PBN), N-benzylidene-1-diethoxyphosphoryl-1-methylethylamine N-oxide (PPN) and N-benzylidene-1-ethoxycarbonyl-1-methylethylamine N-oxide (EPPN) derivatives bearing methoxy groups (MeO-) on the phenyl ring were synthesized. Their electrochemical properties were studied by cyclic voltammetry and the results showed that the position and the number of methoxy substituents influence the redox potential of the nitronyl group. The spin-trapping ability of the derivatives was next investigated by electron paramagnetic resonance spectroscopy for the hydroxymethyl radical (˙CH2OH). The ortho, meta and para mono-substituted-PBN derivatives exhibited similar trapping rates to the parent PBN while surprisingly, nitrones with two MeO-substituents on the ortho-position failed to trap ˙CH2OH. The trapping rates of the parent compounds were ranked as follows: PPN > EPPN > PBN, indicating that the presence of diethoxyphosphoryl and ethoxycarbonyl electron withdrawing groups on the N-tert-butyl group significantly enhanced the reactivity towards hydroxymethyl radicals. The effect of the substitutions on the atomic partial charges of the nitronyl-moiety and on the ionization potential was computationally rationalized and showed a strong correlation between the ionization potential and the experimentally measured oxidation potential. [ABSTRACT FROM AUTHOR]

The first chemo-, regio-, and enantioselective rhodium-catalyzed addition of oximes to allenes is reported. Using a Rh(i)/Josiphos catalyst system under mild conditions, the construction of allylic C–N bonds instead of C–O bonds was achieved. This method permits the atom-economic synthesis of branched allylic nitrones in good to quantitative yields with excellent enantioselectivities. [ABSTRACT FROM AUTHOR]

Efficient synthesis of 2-naphthols was realized by Ru(ii)-catalyzed C–H activation of aryl nitrones and intermolecular [3+3] annulation with α-diazo sulfonyl ketones under redox-neutral conditions. Easily available α-diazo sulfonyl ketones act as a three-carbon component in the reaction. [ABSTRACT FROM AUTHOR]

A new and environmentally benign protocol aimed at the generation of triarylated (Z)-nitrones in generally good yields has been developed via metal- and catalyst-free H2O-mediated 1,3-dipolar transfer reaction of para-quinone methides (p-QMs) with diarylated nitrones under aerobic conditions. The purification of these products only needs to be recrystallized by a mixed solvent comprising small amounts of petroleum ether and ethyl acetate, thereby avoiding the requirement of traditional chromatography. This new 1,3-dipolar strategy features broader substrate scope, green process, and mild conditions. [ABSTRACT FROM AUTHOR]

A series of novel Au(i)–nitrone complexes with specific catalytic properties were prepared. Furthermore, Au(i)– and Au(iii)–oxadiazole complexes were formed by a novel Au-generated nitrile–nitrone [3 + 2] cycloaddition, and the crystal structures of Au(i)–nitrones as well as the Au(i)– and Au(iii)–oxadiazole complexes were studied (X-ray). A useful one-pot Au(iii)-mediated cycloaddition method was developed for the formation of a number of dihydro-1,2,4-oxadiazoles, involving in situ formation of Au(iii)–oxadiazole complexes. The observed Au(i) and Au(iii) dual selective reactivity gives new understanding about the Au(i)– and Au(iii)–nitrone chemistry. [ABSTRACT FROM AUTHOR]

A novel synthesis of five-membered cyclic nitrones has been developed based on the Lewis acid-catalysed [3+2]-annulation reaction of D–A cyclopropanes with 1,4,2-dioxazoles. Broad substrate scope and generally good yield make this reaction useful in the preparation of nitrones. When a suitable 1,4,2-dioxazole was used, nitrone and tetrahydrofuran could be prepared in one pot with high atom economy. [ABSTRACT FROM AUTHOR]

An efficient Rh-catalyzed site-selective amidation of nitrones with 1,4,2-dioxazol-5-ones has been developed. The reaction can tolerate a number of groups and generates functionalized aldehydes in good yields. The significance of the amidation is highlighted by the late-stage transformation of the formed aldehydes. [ABSTRACT FROM AUTHOR]

An efficient and redox-neutral naphthol synthesis has been realized via rhodium(iii) catalyzed C–H activation of α-carbonyl nitrones and annulation with alkynes, where the nitrone group functioned as a traceless directing group. [ABSTRACT FROM AUTHOR]

A chiral N,N′-dioxide/Co(BF4)2·6H2O complex catalytic system has been developed to efficiently catalyze the asymmetric 1,3-dipolar cycloaddition of nitrones with methyleneindolinones. The corresponding chiral multisubstituted spiroisoxazolidines with three contiguous quaternary–tertiary stereocenters were obtained in moderate to high yields with excellent dr and ee values (up to 97% yield, ＞19 : 1 dr and 98% ee). [ABSTRACT FROM AUTHOR]

An efficient and green “on water” regio- and stereoselective synthetic route to chiral 1,2,4-oxadiazinanes and 1,4,2-dioxazinanes with excellent yields (up to 99%) and de/ee (＞99%) has been developed for the first time via the domino ring-opening cyclization (DROC) of N-activated aziridines and epoxides with nitrones using LiClO4/Bu4NBF4 a dual catalyst system. The developed green strategy features a broader substrate scope and mild reaction conditions, and successfully overcomes the competitive oxidative ring opening of aziridines. Further synthetic significances of this green protocol are the formation of the products (i) as single diastereomers starting from a mixture of cis/trans disubstituted aziridines via dynamic kinetic epimerization (DKE) and (ii) via a multicomponent approach starting from N-methyl hydroxylamine hydrochloride, benzaldehyde and aziridine. [ABSTRACT FROM AUTHOR]

The cycloaddition of nitrones with α,β-unsaturated carbonyl compounds (enones) afforded predominantly 4-acylisoxazolidines, whereas the cycloaddition of the corresponding oximes afforded 5-iminoisoxazolidines. This inverse regioselection is due to HOMO activation by the oxime functionality. [ABSTRACT FROM AUTHOR]

The manuscript describes a facile and highly diastereoselective synthesis of cis-3-(hydroxy/bromo)methyl-1-aryl-4-(-styryl)azetidin-2-ones via copper(i) mediated Kinugasa reactions of previously unexplored functionalized α,β-unsaturated nitrones. A variety of functionalized acetylenes and α,β-unsaturated nitrones were studied to yield cis-3-(hydroxy/bromo)methyl-1-aryl-4-(-styryl)azetidin-2-ones in good yields (82%). [ABSTRACT FROM AUTHOR]

The reversible reaction of an aldehyde with a hydroxylamine affords a nitrone which is capable of forming a stiff gel with chloroform at concentrations as low as 0.20 wt% (6 mM). The gelator forms dynamically from its constituents and the gel assembly can be degraded in a controlled manner through a recognition-mediated reaction that targets the nitrone component of the gel network. [ABSTRACT FROM AUTHOR]

A heterocyclic, sp3-rich chemical scaffold was synthesised in just 6 steps via a highly regio- and diastereo-selective tandem nitrone formation/intramolecular nitrone–alkene [3+2] cycloaddition reaction. A library of 543 lead-like compounds based on the scaffold core has been produced. [ABSTRACT FROM AUTHOR]

The first NHC–copper(i)-halide catalyzed addition of terminal alkynes to enantiomerically pure nitrones on water is described. This reaction provides a straightforward access to propargylic N-hydroxylamines in excellent yield and with excellent stereoselectivity (up to 97%). The presented methodology was applied as a key step in the formal synthesis of (−)-lentiginosine. [ABSTRACT FROM AUTHOR]

An umpolung approach toward nitrone construction utilizing a phosphine-mediated addition of 1,2-dicarbonyls to nitroso compounds is reported. The reaction exhibits a high degree of chemo-selectivity and provides direct access to isoxazolidines, imines, and trisubstituted alkenes. [ABSTRACT FROM AUTHOR]

The IPrAuNTf2/HNTf2 co-catalyzed cyclization of N-(2-perfluoroalkyl- 3-alkynyl) hydroxylamines produces pyrroles in moderate to excellent yield, whereas the AgOTf-catalyzed reaction affords cyclic nitrones in high yields. [ABSTRACT FROM AUTHOR]

The detection and identification of transient radicals in biological systems is of importance for the understanding of their roles in a variety of biological processes. Electron paramagnetic resonance spectroscopy coupled with the use of the spin trapping technique has been an indispensable tool for this application owing to its high specificity. In this study, we developed a general method using dual function free radical probes (GS-PBN and its phosphorylated analogue GS-PPN) for the simultaneous determination of transient radicals and the microenvironment where the corresponding spin adducts are situated. This conception was initially proved by high spectral sensitivity of the p-ClPhṖ spin adduct of GS-PBN towards its rotational motion in the glycerol–water system. Results showed that a relatively bulky glutathionyl group in the spin adduct plays an important role in its high sensitivity to the molecular motion. This was further verified by high sensitivity of the p-ClPhṖ spin adduct of the newly synthesized probe GS-PPN to its molecular motion. Unlike GS-PBN, GS-PPN can be used to detect O2Ṗ− generated in the enzymatic system and PSII membranes of chloroplasts. Based on the relationship between the τC values of the superoxide spin adduct and the medium viscosity, the local environment of the adduct in the PSII membranes was determined to be similar to that of the aqueous solution containing ∼15% glycerol (η≈ 1.33 p). [ABSTRACT FROM AUTHOR]

By a ring expansion reaction of boroles with nitrones a straightforward route to eight-membered O,N,B-containing ring systems was developed, which present a new structural motif in heterocyclic chemistry. Formally, these compounds can be considered as BN-analogues of eight-membered ring ethers containing three double bonds. The X-ray crystallographic data of a series of these oxazaborocine derivatives show that they adopt a boat conformation in the solid state. [ABSTRACT FROM AUTHOR]

Silver(i)-catalyzed asymmetric formal [3+3]-cycloaddition of nitrones with a donor–acceptor cyclopropene, formed in situ from dirhodium acetate-catalyzed dinitrogen extrusion/intramolecular cyclization of enoldiazoacetates, effectively generates 3,6-dihydro-1,2-oxazine derivatives in high yield and with exceptional stereocontrol. [ABSTRACT FROM AUTHOR]

We found, unexpectedly, that the radical form of the carbon-centered quinone ketoxy radical adduct with a recently developed spin-trapping agent BMPO can not only be directly detected and identified using HPLC/high resolution MS, but can also be isolated and purified using semi-preparative HPLC, enabling direct observation of its clean 6-line ESR signal. [ABSTRACT FROM AUTHOR]

A gold catalyzed enantioselective [3+2] dipolar cycloaddition of N-allenyl amides with nitrones was developed to give chiral 4-alkylidenyl isoxazolidine derivatives in high yields and excellent enantioselectivities by using BINOL derived chiral phosphoramidate Au(i) catalysts. [ABSTRACT FROM AUTHOR]