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Nitrone

A nitrone is a functional group in organic chemistry consisting of the N-oxide derivative of an imine, characterized by the general structure R¹R²C=N⁺(R³)−O⁻, where R¹, R², and R³ are typically hydrogen, alkyl, or aryl groups, and R³ is not hydrogen.^[1] Nitrones serve as versatile synthetic intermediates, particularly valued for their role as 1,3-dipoles in cycloaddition reactions that enable the construction of nitrogen-containing heterocycles such as isoxazolidines and isoxazoles.^[1] These reactions proceed with high regio- and stereoselectivity, making nitrones essential in the total synthesis of natural products, alkaloids, and amino acids.^[1] Common synthetic routes to nitrones include the condensation of N-substituted hydroxylamines with aldehydes or ketones and the oxidation of imines using mild oxidants such as peracids or hydrogen peroxide with catalysts, offering environmentally friendly methods for their preparation.^[2] Beyond synthesis, nitrones exhibit significant biological relevance as spin traps that react with free radicals to form stable adducts, facilitating the detection and study of reactive oxygen species in chemical and biochemical systems.^[3] This property underpins their antioxidant capabilities, with derivatives like α-phenyl-N-tert-butylnitrone (PBN) demonstrating neuroprotective effects in models of stroke, traumatic brain injury, and neurodegeneration by reducing oxidative stress and inflammation at low concentrations (10–50 µM).^[3] Ongoing research explores nitrones for therapeutic applications in cancer, hearing loss, and aging-related conditions, highlighting their potential to modulate nitric oxide pathways and inhibit cytokine expression.^[3]

Structure and Properties

Molecular Structure

The nitrone functional group is characterized by the general formula \ce{R1R2C=N^{+}(R3)-O^{-}}, where \ce{R1} and \ce{R2} are typically hydrogen, alkyl, or aryl substituents on the carbon atom, and \ce{R3} is an alkyl or aryl group attached to the nitrogen (distinct from oximes, which feature \ce{R3 = H}).^[1] This arrangement consists of a C=N double bond directly adjacent to an N-O single bond, forming a compact, polar unit that imparts unique electronic properties to the molecule.^[4] Resonance delocalization within the nitrone moiety significantly influences its bonding. The primary resonance structure is the zwitterionic form \ce{R1R2C=N^{+}(R3)-O^{-}}, with a contributing form \ce{R1R2C^{-}-N(R3)=O} that shifts electron density toward the carbon atom.^[5] A third minor contributor, \ce{R1R2C^{+}-N(R3)-O^{-}}, may also participate, but the dominant zwitterionic and carbanionic forms result in partial double bond character for the N-O linkage, enhancing its stability and polarity.^[5] This delocalization underscores the nitrone's hybrid nature, blending imine-like and oxide-like features. Due to the restricted rotation around the C=N double bond, nitrones exhibit stereoisomerism, existing as E and Z (or cis and trans) isomers depending on the relative positions of substituents \ce{R1/R2} and \ce{R3}. For instance, C-phenyl-N-methylnitrone (\ce{PhHC=N^{+}(CH3)-O^{-}}) demonstrates distinct E and Z configurations, where the phenyl and methyl groups can be on the same or opposite sides of the C=N bond, influencing the overall molecular geometry. Structurally, nitrones relate closely to imines (\ce{R1R2C=NR3}) as their N-oxide derivatives, with the added oxygen atom increasing electron withdrawal from the C=N unit.^[1] They also share the N-O motif with amine N-oxides (\ce{R3N^{+}-O^{-}}), but the conjugated C=N linkage differentiates them, creating a more rigid and dipolar system.^[1]

Physical and Spectroscopic Properties

Nitrones are typically colorless to pale yellow oils or low-melting crystalline solids at room temperature, depending on the substituents. More substituted derivatives like N-tert-butyl-α-phenylnitrone are solids with a melting point of 73–74 °C.^[6] Larger aromatic-substituted nitrones, such as N,α-diphenylnitrone, form crystalline solids with higher melting points of 113–114 °C.^[7] These physical states arise from the polar N-oxide functionality balanced against hydrophobic substituents. Solubility profiles of nitrones vary with structure but generally show limited aqueous solubility, often below 1–2 g/L at 25 °C, which restricts their direct use in biological assays without modification.^[8] For instance, N,α-diphenylnitrone has a solubility of 1120 mg/L in water, while many alkyl- or aryl-substituted analogs are more soluble in polar organic solvents like chloroform, ethanol, and acetonitrile.^[7] Phosphorylated or cyclodextrin-conjugated nitrones can enhance water solubility for therapeutic applications.^[9] Infrared (IR) spectroscopy provides key diagnostic features for nitrones, with characteristic absorption bands for the C=N stretch in the range of 1595–1650 cm⁻¹ and the N–O stretch at 1137–1186 cm⁻¹, confirming the presence of the nitrone moiety.^[10] These bands shift slightly with conjugation; for example, in α-organoelement nitrones, the C=N→O vibration appears intensely at approximately 1666 cm⁻¹.^[11] Nuclear magnetic resonance (NMR) spectroscopy further characterizes nitrones: in ¹H NMR, the =C–H proton typically resonates at 7–8 ppm due to deshielding by the adjacent N-oxide, while in ¹³C NMR, the nitrone carbon shifts to 117–152 ppm, influenced by substituents and ring strain in cyclic variants.^[12] Ultraviolet-visible (UV-Vis) spectra of nitrones display absorption maxima around 220–250 nm, attributed to π–π* transitions in the C=N chromophore, with extensions to longer wavelengths (up to 300 nm) in conjugated aryl-substituted systems.^[13] In mass spectrometry (MS), nitrones generally produce prominent molecular ions under electron ionization, alongside characteristic fragments from α-cleavage or hydrogen migration, such as loss of alkyl radicals or formation of iminium ions (e.g., m/z 106 for PhC≡N⁺• in phenyl-substituted cases). These patterns aid in structural confirmation without extensive derivatization.

Chemical Stability and Reactivity Overview

Nitrones exhibit good thermal stability at room temperature, allowing them to be handled and stored under ambient conditions without significant degradation. However, upon heating above 100–150 °C, many nitrones undergo oligomerization or decomposition, often forming dimers through concerted cycloaddition pathways such as [3+3] processes leading to 1,4,2,5-dioxadiazinanes.^[14] For specific examples like chloro-substituted C-phenyl-N-phenylnitrones, thermal decomposition occurs in the 200–300 °C range following second-order kinetics, with activation energies varying based on substituent position.^[15] Nitrones show sensitivity to light and acidic conditions, influencing their practical applications. Photodecomposition under UV irradiation typically yields nitroso compounds and oximes via ring-opening or rearrangement mechanisms, particularly for cyclic and aromatic nitrones.^[16] In acidic media, nitrones undergo catalyzed hydrolysis to the corresponding carbonyl compounds and N-monosubstituted hydroxylamines, with the rate increasing at lower pH values; for instance, α-phenyl-N-t-butylnitrone hydrolyzes to benzaldehyde and N-t-butylhydroxylamine.^[17] This acid sensitivity arises from protonation of the oxygen atom, facilitating cleavage of the C=N bond. The stability of nitrones is markedly affected by pH and solvent environment. They remain stable in neutral aprotic solvents like dichloromethane or toluene, where hydrolysis and other degradative processes are minimized.^[18] In protic or acidic media, such as aqueous solutions at low pH, reactivity increases due to enhanced hydrolysis rates, though some derivatives maintain stability below pH 6.5.^[19] Overall, nitrones possess zwitterionic character from resonance between the C=N–O and C–N+=O forms, enabling their behavior as 1,3-dipoles in cycloadditions and as masked carbonyl equivalents in synthetic transformations.^[20] Tautomerism in nitrones is rare and typically requires specific conditions, such as photochemical activation, leading to keto-enol-like shifts toward oxaziridine isomers.^[21] This isomerization involves migration of the oxygen across the C=N bond but is reversible and uncommon thermally. Nitrones' inherent 1,3-dipolar nature predisposes them to cycloaddition reactions, a key aspect of their reactivity profile.^[20]

History and Discovery

Early Synthesis and Identification

The first synthesis of a nitrone was achieved by Ernst Beckmann in 1890 through the condensation of N-alkylhydroxylamines with carbonyl compounds, yielding what he termed "azomethine oxides," though he proposed cyclic structures for these products rather than the correct imine N-oxide formulation.^[20] In 1894, Alfred Werner and Hermann Buss reported the synthesis of C,N-diphenylnitrone via oxidation of the corresponding oxime derivative using mercuric oxide, providing one of the earliest examples of an aromatic nitrone and demonstrating its reactivity in cycloaddition reactions with alkynes, which they interpreted as a [2+2] process followed by rearrangement. These early preparations highlighted the compounds' tendency to form from hydroxylamine derivatives but also revealed identification challenges, as the products were initially misidentified as cyclic peroxides or anhydrides due to their instability and unexpected reactivity.^[22] The term "nitrone," derived from "nitrogen" and "ketone" to reflect the structural analogy with carbonyls, was coined around 1910 by Alfred Werner to standardize nomenclature for these imine N-oxides.^[22] In 1905, Jacob Meisenheimer extended nitrone synthesis to aliphatic systems by condensing N-alkylhydroxylamines with aliphatic aldehydes and ketones, yielding stable examples such as N-methyl-C-ethylnitrone and enabling further exploration of their properties beyond aromatic analogs.^[22] These developments laid the groundwork for understanding nitrones as distinct functional groups. Structural confirmation of nitrones progressed slowly amid early misconceptions; by the 1920s, elemental analysis and chemical degradation studies definitively established the imine N-oxide constitution, dispelling notions of peroxide-like or dimeric forms and aligning with Werner's nomenclature.^[22] Modern spectroscopic techniques, such as infrared spectroscopy revealing the characteristic N-O stretch around 1200 cm⁻¹, later corroborated these findings but were not available during initial characterization.^[22]

Key Developments in Nitrone Chemistry

In the mid-20th century, nitrones gained recognition as versatile 1,3-dipoles, largely due to the pioneering work of Rolf Huisgen, who established the framework for 1,3-dipolar cycloadditions in the 1950s and 1960s. Huisgen's studies demonstrated that nitrones react with alkenes and other dipolarophiles to form isoxazolidines, providing a stereocontrolled route to five-membered heterocycles. A seminal 1963 publication outlined the general mechanism and kinetics of these cycloadditions, emphasizing nitrones' role in pericyclic reactions. This was followed by a 1964 report detailing the addition of C-phenyl-N-methylnitrone to various olefins, yielding isoxazolidines in high yields and highlighting regioselectivity patterns that became foundational for synthetic applications.^[23] The 1970s marked a shift toward nitrones' utility in radical chemistry, particularly through spin trapping for electron spin resonance (ESR) spectroscopy. Researchers, including Keith U. Ingold, explored nitrones as traps for short-lived radicals, enabling their detection and identification in biological and chemical systems. A key advancement was the introduction of α-phenyl-N-tert-butylnitrone (PBN) in 1972, which formed stable nitroxide adducts with carbon- and oxygen-centered radicals, facilitating studies of oxidative processes. Ingold's group further refined this technique in the late 1970s by measuring rate constants for PBN's reactions with peroxyl and alkoxyl radicals, establishing quantitative benchmarks for spin trapping efficiency in lipid peroxidation and enzymatic reactions.^[24] During the 1980s and 1990s, focus turned to asymmetric synthesis, leveraging chiral nitrones to achieve enantioselective 1,3-dipolar cycloadditions. Early efforts involved auxiliaries derived from amino acids or sugars, enabling diastereoselective additions to alkenes with high ee values (often >90%). For instance, N-(glyoxyloyl) nitrones with chiral auxiliaries provided access to enantiopure isoxazolidines, precursors for alkaloids and amino sugars. Reviews from the period highlight how these developments expanded nitrones' role in total synthesis, with metal-catalyzed variants emerging by the late 1990s to enhance stereocontrol.^[25] The 2000s saw nitrones enter biomedical applications and sustainable synthesis. NXY-059, a disulfonated phenylnitrone, advanced to phase III clinical trials for acute ischemic stroke, demonstrating neuroprotective effects via free radical scavenging in animal models, though human trials showed limited efficacy in reducing disability. Concurrently, green synthesis methods proliferated, including one-pot condensation-oxidation protocols using urea-hydrogen peroxide to generate nitrones from amines and aldehydes in high yields under mild, metal-free conditions. These approaches minimized waste and solvents, aligning with principles of sustainable chemistry.^[26]^[27] In the 2020s, phosphorylated nitrones have emerged as promising scaffolds for bioactive heterocycles. These compounds, featuring phosphorus substituents on the nitrone carbon or nitrogen, undergo cycloadditions to yield phosphorus-containing isoxazolidines and pyrrolidines with potential antimicrobial and anticancer properties. Recent syntheses via oxidation of α-hydroxyphosphonates or condensations with phosphylated carbonyls have enabled access to diverse libraries, with applications in drug discovery highlighted in comprehensive reviews.^[28]

Synthesis

Oxidation of Hydroxylamines and Oximes

The oxidation of N,N-disubstituted hydroxylamines serves as a cornerstone method for nitrone synthesis, transforming precursors of the general form R₂CH–N(R')–OH into nitrones R₂C=N⁺(R')–O⁻ through dehydrogenation. This process involves the removal of two hydrogen atoms—one from the N–OH group and one from the α-carbon adjacent to the nitrogen—resulting in the formation of the characteristic C=N double bond and overall loss of H₂.^[22]^[29] A classic reagent for this transformation is yellow mercuric oxide (HgO), which provides high regioselectivity and compatibility with sensitive functional groups, making it particularly valuable in natural product synthesis. For instance, the oxidation of N-benzyl-N-methylhydroxylamine with HgO in ether at room temperature yields C-phenyl-N-methylnitrone effectively.^[22] Typical conditions involve stirring the hydroxylamine with 1–2 equivalents of HgO in diethyl ether or dichloromethane (DCM) at ambient temperature, often achieving yields of 70–90% after filtration and evaporation.^[22] Milder alternatives include manganese dioxide (MnO₂), which delivers comparable efficiency and regioselectivity to HgO while avoiding mercury residues.^[30] Lead tetraacetate also facilitates this oxidation under mild conditions, though it is less commonly employed due to toxicity concerns. While nitrones can be accessed indirectly from oximes through N-alkylation followed by rearrangement, the direct oxidation of N-alkylhydroxylamines remains the preferred route owing to its simplicity and higher efficiency.^[22] A representative equation for the process is:

\ce{R^1R^2CH-N(R^3)-OH ->[oxidation] R^1R^2C=N^{+}(R^3)-O^{-} + H2}

Side reactions, such as formation of azoxy compounds from overoxidation, can occur but are minimized under controlled conditions.^[22]

Condensation with Carbonyl Compounds

One of the primary methods for synthesizing nitrones involves the condensation of N-monosubstituted hydroxylamines with carbonyl compounds, such as aldehydes or ketones, to form the characteristic C=N⁺-O⁻ functionality.^[2] This approach is particularly valued for its simplicity and direct construction of the nitrone core, often proceeding under mild conditions without the need for strong oxidants.^[2] The mechanism proceeds via nucleophilic addition of the hydroxylamine nitrogen to the electrophilic carbonyl carbon, yielding a tetrahedral carbinolamine intermediate, followed by dehydration to afford the imine N-oxide (nitrone).^[2] The dehydration step is typically rate-determining, facilitated by acid catalysis or intramolecular proton transfer, and exhibits general acid and specific base catalysis depending on pH.^[31] This condensation is most effective with aldehydes, where high yields (typically 85–95%) are achieved due to lower steric demands at the carbonyl.^[2] For example, the reaction of benzaldehyde with N-methylhydroxylamine in toluene at room temperature yields the corresponding C-phenyl-N-methylnitrone in 90% yield.^[2] Ketones, however, require activated conditions such as Lewis acid catalysis (e.g., TiCl₄) to overcome steric hindrance, resulting in moderate yields of 50–70%.^[2] Common reaction conditions include acid catalysis with p-toluenesulfonic acid in ethanol under reflux, or solvent-free methods in glycerol at 60–80 °C, affording yields of 75–98% for aromatic and aliphatic aldehydes.^[32] The general equation is:

\ce{R-CHO + R'-NH-OH -> R-CH=N^{+}-O^{-}-R' + H2O}

^[2] Limitations include reduced efficiency with bulky substituents, which exacerbate steric issues in the addition step and lead to lower yields, particularly for ketones.^[2] Additionally, N-unsubstituted hydroxylamines (with H on N) must be avoided, as they preferentially form oximes rather than nitrones.^[2] Spectroscopic monitoring, such as IR or NMR, can track the reaction progress via the disappearance of the carbonyl stretch.^[32]

Other Synthetic Routes

One notable alternative route to nitrones involves the reaction of nitrosoarenes with alkenes, often facilitated by metal catalysts to generate nitrone intermediates in situ. For instance, gold-catalyzed addition of nitrosobenzenes to styrene derivatives proceeds via initial ene-type reaction followed by rearrangement, yielding β-arylated nitrones such as Ar-N(O)=CH-CH₂-Ph, with yields up to 85% under mild conditions. This method leverages the electrophilic nature of nitroso compounds and is particularly useful for accessing functionalized nitrones without preforming hydroxylamine precursors.^[33] Transition-metal-free coupling of N-nosylhydrazones with nitrosoarenes provides another efficient access to (Z)-N-arylnitrones. This process, conducted at room temperature, delivers products in good to excellent yields (70-95%) through diazo intermediate formation and subsequent [3+2] cycloaddition/rearrangement, compatible with electron-rich and -poor substituents.^[34] Complementary visible-light-promoted reactions of nitrosoarenes with aryl diazoacetates also form α-arylated nitrones under metal-free conditions, achieving 60-90% yields in green solvents like water or ethanol.^[35] Metal-catalyzed approaches extend to copper-mediated hydroamination of propargyloxyamines, yielding N-alkylated unsaturated ketonitrones via electrocyclic ring opening. This regioselective method, using CuI (10 mol%) in toluene at 80°C, provides 75-92% yields and is scalable for synthetic applications.^[36] Similarly, DMAP-catalyzed reactions of benzyl halides with nitrosoarenes generate keto- and aldonitrones, such as from methyl 2-bromo-2-phenylacetate, in 80-95% yields under mild aerobic conditions.^[37] For cyclic nitrones, sugar-derived precursors offer stereocontrolled routes, particularly in carbohydrate chemistry. Aldohexose-based piperidine nitrones are synthesized from protected glucopyranose via dithioacetal formation, oxidation to ketone, acetal protection, hydroxylamine condensation, and intramolecular cyclization, affording diastereomeric nitrones in 73-84% yields per step with high purity. Azepane nitrones from aldohexoses proceed through analogous intramolecular aldehyde-hydroxylamine condensation, yielding pairs of epimeric nitrones (e.g., from D-glucose) in 70-85% overall efficiency, serving as versatile synthons for iminosugars. From pyrrolines, enantiopure hydroxylated pyrroline N-oxides are accessed via ω-oxo enoate formation from D-ribose followed by cyclization, enabling diastereoselective functionalizations.^[38] Emerging green methods emphasize sustainability, such as microwave-assisted synthesis of hydroxyphenyl nitrones from aldehydes and N-substituted hydroxylamines under solvent-free conditions, completing in 5-15 minutes with 80-95% yields and reduced energy use. One-pot assembly in aqueous media using a self-assembled tetrahedral Ga³⁺-based nanoreactor encapsulates reactants, accelerating condensation/oxidation to nitrones (70-83% yields) at room temperature while avoiding organic solvents and chromatography for facile isolation.^[39] Enzymatic oxidations with flavin-dependent monooxygenases represent a biocatalytic alternative, selectively converting hydroxylamine precursors to nitrones in aqueous buffers with >90% ee and turnover numbers exceeding 1000, highlighting biocompatibility since the 2010s.^[40]

Reactions

1,3-Dipolar Cycloadditions

Nitrone cycloadditions represent a cornerstone of 1,3-dipolar cycloaddition chemistry, wherein nitrones act as 1,3-dipoles reacting with unsaturated dipolarophiles to form five-membered heterocycles. These reactions proceed via a concerted pericyclic mechanism, characterized by suprafacial addition and high stereospecificity.^[20] The process involves the alignment of the nitrone's C=N-O unit with the π-bond of the dipolarophile, leading to the formation of two new σ-bonds in a single step without intermediates.^[41] Frontier molecular orbital (FMO) theory elucidates the reactivity, with the interaction between the highest occupied molecular orbital (HOMO) of the nitrone dipole and the lowest unoccupied molecular orbital (LUMO) of the dipolarophile dominating in normal electron-demand scenarios, particularly with electron-deficient alkenes.^[42] This HOMO(dipole)-LUMO(dipolarophile) overlap facilitates regioselectivity and rate enhancement when substituents modulate orbital energies.^[43] Common dipolarophiles include alkenes, which yield isoxazolidines, and alkynes, producing Δ²-isoxazolines. For instance, the reaction of a nitrone with ethylene forms a simple isoxazolidine ring:

\ce{R^1R^2C=N^{+}(R^3)-O^{-} + CH2=CH2 ->[cycloaddition] 2-R^3-3-R^1-3-R^2-isoxazolidine}

^[44] Electron-deficient alkenes, such as acrylates, react preferentially due to lowered LUMO energies, often achieving yields exceeding 90% under mild conditions.^[45] With terminal alkenes, regioselectivity favors the 5-substituted isoxazolidine isomer, where the oxygen of the nitrone ends up adjacent to the substituted carbon of the alkene, as predicted by FMO coefficients.^[46] Alkynes similarly provide aromatic-like isoxazolines with high efficiency. Reactions with other dipolarophiles like imines are less common but can yield 1,2,4-oxadiazolidines. The stereochemistry of these cycloadditions is governed by the concerted nature of the reaction, resulting in retention of the dipolarophile's alkene geometry in the product.^[47] Diastereoselectivity often follows the Alder endo rule, where the endo transition state—placing electron-withdrawing groups on the dipolarophile proximal to the nitrone's oxygen—is energetically favored due to secondary orbital interactions, leading to cis-fused or syn diastereomers in many cases.^[48] Exo selectivity can predominate with bulky substituents or specific catalysts, but endo products are typical in uncatalyzed reactions with cyclic dipolarophiles.^[49] Lewis acid catalysis enhances both rate and selectivity in nitrone cycloadditions by coordinating to the nitrone oxygen, lowering the LUMO energy and promoting asymmetric induction. For example, ZnBr₂ accelerates reactions with enol ethers, improving endo/exo ratios and enabling >90% yields with moderate diastereoselectivity.^[50] Chiral Lewis acids, such as those derived from iron or ruthenium complexes, achieve enantioselectivities up to 99% ee in intermolecular additions to α,β-unsaturated carbonyls, facilitating access to enantioenriched isoxazolidines.^[51] These catalyzed variants maintain the concerted mechanism while allowing precise control over regiochemistry, often reversing selectivity compared to thermal conditions.^[52]

Reduction Reactions

Reduction of nitrones typically involves the addition of hydrogen across the C=N bond and cleavage of the N–O bond, yielding amines, imines, or hydroxylamines depending on the conditions and reducing agent employed. These transformations are valuable for synthesizing nitrogen-containing compounds, particularly in the context of natural product synthesis. The general reaction for complete deoxygenation can be represented as:

R^1_2C=N^+(R^3)-O^- + H_2 \to R^1_2CH-NH-R^3 + H_2O

This process often proceeds via an intermediate hydroxylamine or imine stage.^[2] Catalytic hydrogenation represents a common method for reducing nitrones, often achieving complete deoxygenation to secondary amines under appropriate conditions. Using palladium on carbon (Pd/C) or Raney nickel with hydrogen gas, nitrones are converted to amines, particularly when conducted in acidic media such as acetic acid or under high pressure to facilitate N–O bond cleavage. For instance, microwave-assisted hydrogenation with Pd/C at 150 °C and 7 bar H₂ in AcOH/HCl provides efficient access to amines from chiral nitrones derived from amino acids.^[53] In cases where selective N–O reduction is desired, milder conditions with iridium catalysts like [IrCl(cod)]₂/(S)-BINAP yield optically active N-hydroxylamines with up to 83% ee. These reductions exhibit syn stereoselectivity due to concerted addition mechanisms, leading to cis diastereomers in cyclic systems.^[2]^[54] Metal hydrides offer selective reduction pathways, primarily targeting the N–O bond to produce N-alkylhydroxylamines (R¹₂CH–NH–OR³). Sodium borohydride (NaBH₄) in protic solvents effectively reduces nitrones to hydroxylamines without affecting the C=N bond, providing yields up to 90% for aliphatic and aromatic substrates. Stronger reducing agents like lithium aluminum hydride (LiAlH₄) can achieve further reduction to amines under anhydrous conditions, though selectivity may vary with substrate sterics. Asymmetric variants using ruthenium-catalyzed hydrosilylation with chiral phosphine ligands deliver enantioenriched hydroxylamines with 85% ee, highlighting the method's utility for chiral pool synthesis.^[2] Dissolving metal reductions, such as with zinc in acetic acid (Zn/AcOH), are employed to convert intermediate hydroxylamines to imines, which can be further hydrolyzed or reduced to amines. This method preserves sensitive functional groups like aldehydes or nitriles, yielding imines in 70–90% efficiency from nitrone precursors. Iron in AcOH similarly provides direct access to secondary amines from nitrones and nitroxides, demonstrating chemoselectivity in multifunctional molecules. Emerging enzymatic bioreductions using systems like Baker's yeast enable stereoselective production of chiral hydroxylamines or amines from nitrones, offering mild, environmentally benign alternatives with high enantioselectivity for complex substrates. These methods are particularly promising for asymmetric synthesis, though structural limitations persist.^[55] Such reduction strategies find key applications in alkaloid synthesis, where nitrones serve as versatile intermediates. For example, hydrogenation and hydride reductions have been pivotal in constructing the polyhydroxylated frameworks of (-)-lentigirosine and indolizidine 205A, enabling efficient routes to bioactive heterocycles with controlled stereochemistry.^[2]

Rearrangements and Isomerizations

Nitrone molecules exhibit geometric isomerism about the C=N bond, existing as E or Z isomers, with the Z configuration generally being thermodynamically favored due to reduced steric hindrance between substituents. The interconversion between these isomers occurs through thermal activation via a bimolecular diradical mechanism involving initial C–C coupling to form a dimer intermediate, followed by bond breaking and reformation, with an activation barrier of approximately 26–30 kcal/mol depending on substituents such as methyl or methoxycarbonyl groups.^[56] Acid catalysis, including Lewis acids like MgBr₂·OEt₂ or Brønsted acids, accelerates the E to Z isomerization by protonating the oxygen, lowering the barrier and promoting rotation around the C=N bond, particularly in carbonyl-conjugated nitrones.^[57] The equilibrium between the Z and E isomers is described by:

\text{Z-nitrone} \rightleftharpoons \text{E-nitrone}

This process favors the Z-isomer in acyclic nitrones, with the energy difference typically 1–2 kcal/mol in favor of Z for aldonitrones, as determined by DFT calculations, allowing facile interconversion at room temperature in solution.^[49] ^[56] A Cope elimination-like process in γ-alkenyl nitrones involves a neutral thermal [3,3]-sigmatropic rearrangement, known as the 2-aza-Cope rearrangement, which proceeds through a concerted pericyclic transition state to form an α,β-unsaturated imine intermediate.^[58] This rearrangement, occurring at elevated temperatures (100–150 °C), can be followed by deoxygenation under light or further thermal conditions to yield amides, particularly in systems where the imine hydrolyzes or tautomerizes to the carbonyl form, providing a route to γ-ketoamides.^[59] Visible light promotion enhances this cascade, enabling mild deoxygenation without metal catalysts, as seen in one-pot nitrone formation and rearrangement sequences.^[60] Nitrone-oxaziridine tautomerism involves reversible cyclization to a three-membered oxaziridine ring, often facilitated under basic conditions where deprotonation aids ring closure via nucleophilic attack of the oxygen on the carbon. This equilibrium is dynamic, with the nitrone form predominating, but the oxaziridine can rearrange back or forward to imines or amides upon heating or irradiation, serving as an intermediate in skeletal changes.^[56] ^[61] Photoinduced rearrangements of nitrones upon UV irradiation typically proceed via initial formation of the oxaziridine tautomer, which then opens to imines or, under prolonged exposure, to amides through C–N or N–O bond cleavage. In some cases, especially with electron-deficient substituents, this leads to nitrile oxides via dehydration-like processes, though imine formation is more common. These transformations occur efficiently in continuous flow setups for synthetic scalability.^[60] ^[61] In synthetic applications, the controlled E/Z isomerization of cyclic nitrones, such as those derived from sugars or pyrrolidines, enables stereocontrol in subsequent reactions like 1,3-dipolar cycloadditions, where the Z-form directs exo selectivity for trans-fused heterocycles. For instance, thermal isomerization in five-membered cyclic nitrones has been exploited to access stereodefined alkaloids with high diastereoselectivity.^[62]

Hydrolysis and Cleavage

Nitrones are susceptible to hydrolytic cleavage, particularly under acidic conditions, which regenerates the parent carbonyl compound and an N-substituted hydroxylamine. This reaction proceeds via protonation of the oxygen atom, facilitating nucleophilic attack by water on the carbon-nitrogen double bond, followed by bond scission.^[55] Typical conditions involve treatment with hydrochloric acid (HCl) or trifluoroacetic acid (TFA) in aqueous dioxane, often achieving quantitative yields for simple alkyl- or aryl-substituted nitrones such as C,N-diphenylnitrone.^[55] The process is reversible, positioning nitrones as effective protecting groups for aldehydes and ketones during multi-step syntheses where umpolung reactivity at the carbonyl carbon is desired.^[63] The general reaction for acid-catalyzed hydrolysis is represented as:

\ce{R^1_2C=N^{+}(R^3)-O^{-} + H_2O ->[H^{+}] R^1_2C=O + R^3-NHOH}

This cleavage highlights the nitrone's role in carbonyl umpolung chemistry, enabling the carbon (typically electrophilic in carbonyls) to behave nucleophilically in reactions like 1,3-dipolar cycloadditions prior to deprotection.^[55] Base hydrolysis of nitrones occurs more slowly than the acid variant and typically requires stronger conditions such as sodium hydroxide (NaOH) in aqueous media. Under mild basic conditions, the reaction can divert toward oxime formation rather than full cleavage to hydroxylamine, depending on the nitrone substitution and pH.^[55] For instance, treatment with potassium carbonate (K₂CO₃) in refluxing methanol has been employed to hydrolyze ester-containing nitrones to phenolic or carboxylic acid derivatives, indirectly regenerating carbonyl equivalents.^[55] Oxidative cleavage provides an alternative degradative pathway, fragmenting the nitrone into a nitroso compound and a carbonyl derivative. Periodate (NaIO₄) effectively cleaves cyclic nitrones, such as 5,5-dimethyl-1-pyrroline 1-oxide, to yield nitroso acids via selective oxidation of the C=N bond. Ozone (O₃) performs similarly on acyclic nitrones, as demonstrated with C,C,N-triphenylnitrone, producing acetophenone and a nitroso intermediate that tautomerizes or further oxidizes to nitrobenzene. These methods are particularly useful for structural elucidation or when hydroxylamine byproducts are undesirable, with reactions often conducted in aqueous or organic solvents at low temperatures to control reactivity.

Applications

In Organic Synthesis of Heterocycles

Nitrones serve as versatile 1,3-dipoles in the synthesis of isoxazolidines, which are key intermediates for constructing heterocyclic frameworks found in natural alkaloids. The 1,3-dipolar cycloaddition of nitrones with alkenes provides stereocontrolled access to these five-membered rings, which can be further elaborated into complex structures. For instance, in the total synthesis of biotin, an intramolecular nitrone-olefin cycloaddition has been employed to form the tetrahydrothiophene-fused isoxazolidine core with high stereospecificity starting from cycloheptene derivatives.^[64] Similarly, nitrone cycloadditions have been utilized to build the bicyclic tropane skeleton characteristic of alkaloids like cocaine and pseudotropine, where the reaction enables the formation of the bridged pyrrolidine system through regioselective addition to cyclic alkenes.^[65] These approaches highlight the utility of nitrones in mimicking the nitrogen-oxygen connectivity in alkaloid backbones while allowing for subsequent functional group manipulations. Tandem reactions involving nitrone cycloadditions followed by ring-opening steps extend their synthetic value by generating acyclic amino alcohol motifs embedded in larger heterocycles. The isoxazolidine products from the initial [3+2] cycloaddition can undergo reductive N-O bond cleavage, often with Raney nickel or catalytic hydrogenation, to yield β-amino alcohols that serve as precursors to piperidines or pyrrolidines. This sequence has been applied in the synthesis of trifluoromethyl-substituted amino alcohols, where the cycloaddition to electron-deficient alkenes provides diastereoselective adducts amenable to regioselective ring opening.^[66] Such tandem processes are particularly efficient for constructing polyfunctionalized chains that cyclize into heterocycles, avoiding stepwise isolations and enhancing overall yields in alkaloid analog synthesis. Asymmetric variants of nitrone cycloadditions, developed prominently in the 1990s, employ chiral auxiliaries to access enantiopure heterocycles with high diastereoselectivity. Chiral sultams derived from camphorsulfonic acid, such as Oppolzer's bornane-10,2-sultam, have been attached to the nitrone carbonyl equivalent to induce facial selectivity in additions to alkenes, yielding isoxazolidines that are convertible to enantiomerically pure amino sugars or alkaloid fragments. For example, in the synthesis of pumiliotoxin C, a sugar-based chiral auxiliary on the nitrone directed the cycloaddition to afford the trans-fused bicyclic system with >95% diastereomeric excess.^[67] These methods have become staples for stereocontrolled heterocycle assembly, with auxiliaries recyclable post-reaction to improve atom economy. Nitrones have played a pivotal role in the total synthesis of numerous natural products, particularly through intramolecular cycloadditions that forge polycyclic frameworks. In terpenoid chemistry, exocyclic nitrones tethered to olefinic chains undergo thermal cycloaddition to generate bridged carbocycles, as demonstrated in syntheses of sesquiterpenes like bisabolol, where the reaction establishes the angular fusion with complete stereocontrol.^[68] Recent advances include formal [3+3] cycloadditions of nitrones with allylsilanes, catalyzed by Lewis acids, to directly access piperidine rings via sequential addition and cyclization, offering a streamlined route to azacycloalkanes with quaternary centers for alkaloid diversification.^[69] A 2025 review highlights the continued use of intramolecular nitrone cycloadditions in the total synthesis of diverse natural products, including alkaloids and terpenoids, emphasizing improvements in regioselectivity and stereoselectivity.^[70] These developments continue to expand nitrones' scope beyond traditional [3+2] pathways.

Spin Trapping and Radical Detection

Nitrones function as spin traps in electron spin resonance (ESR) spectroscopy, enabling the detection and characterization of short-lived free radicals that are otherwise difficult to observe directly. The core principle relies on the nucleophilic addition of a transient radical (R•) to the electrophilic carbon of the nitrone's C=N⁺-O⁻ moiety, yielding a persistent nitroxide radical adduct. This adduct exhibits a detectable ESR signal due to the unpaired electron on the nitrogen-oxygen group, with the spectral hyperfine splitting patterns providing structural information about the original radical. The reaction is represented as:

\ce{R2C=N^{+}-O^{-}-tBu + R^\bullet -> R2(R)C-N(O^\bullet)-tBu}

This approach was pioneered with nitrones in the late 1960s, marking a significant advancement in radical chemistry.^[71] Among the most widely used nitrone spin traps are α-phenyl-N-tert-butylnitrone (PBN) and 5,5-dimethyl-1-pyrroline N-oxide (DMPO), along with DMPO analogs. PBN, first introduced as a spin trap in 1968, excels at capturing carbon-centered radicals, producing adducts with characteristic ESR hyperfine splittings such as a_N ≈ 14.5–15.0 G and a_H^β ≈ 1.5–4.0 G for alkyl radicals, though oxygen-centered radical adducts are less stable. DMPO, developed in the 1970s, is particularly effective for trapping reactive oxygen species like hydroxyl (•OH) and superoxide (O₂⁻•), yielding adducts with distinct patterns, including a_N ≈ 14.7 G and a_H^β ≈ 14.9–16.0 G for the hydroxyl adduct. These splitting constants, typically in the 14–16 G range for β-hydrogens in oxygen adducts, allow for radical identification by comparison to known spectra.^[71]^[72]^[73] Since the 1970s, nitrone spin trapping has been instrumental in biological research, particularly for investigating oxidative stress and lipid peroxidation processes. In these applications, PBN and DMPO have detected carbon-centered radicals from lipid degradation and peroxyl radicals (ROO•) in cellular and tissue models, providing evidence of radical-mediated damage in conditions like ischemia-reperfusion injury. Water-soluble traps such as DMPO enable in vivo studies, where they are administered to trap radicals in real-time, revealing pathways of reactive species formation in living systems. The stability of the nitroxide adducts—often persisting for minutes to hours—enhances sensitivity, allowing detection at micromolar concentrations.^[73]97984-6/fulltext) Despite these strengths, nitrone-based spin trapping has limitations, including poor specificity for certain species like superoxide, where DMPO-OOH adducts decompose rapidly (half-life ~14 minutes) to form misleading hydroxyl-like signals via mechanisms such as adduct rearrangement. Additionally, non-specific trapping and potential artifacts from trap decomposition can complicate interpretations, necessitating complementary techniques for validation. Nonetheless, ongoing developments in trap design, such as charged or cyclic analogs, continue to improve selectivity and applicability in complex biological environments.^[72]^[73]

Biomedical and Therapeutic Uses

Nitrones function as therapeutic antioxidants by scavenging reactive oxygen and nitrogen species (ROS/RNS), including superoxide anions and peroxynitrite, thereby mitigating oxidative stress in pathological conditions such as ischemia and neurodegeneration.^[74] This radical-quenching mechanism parallels their role in laboratory spin trapping but is optimized for in vivo applications to quench harmful radicals and reduce inflammation.^[74] Prominent nitrone derivatives include α-phenyl-N-tert-butylnitrone (PBN) and its analogs, which have demonstrated neuroprotection in models of cerebral ischemia by reducing infarct volume and oxidative damage.^[75] A key example is disufenton sodium (NXY-059), a sulfonated PBN derivative with improved solubility, which showed neuroprotective effects in rodent stroke models but failed to demonstrate efficacy in Phase III clinical trials for acute ischemic stroke in 2006 due to lack of functional improvement despite safety.^[76] More recently, tetramethylpyrazine nitrone (TBN) has exhibited neuroprotective benefits in Parkinson's disease models by activating the PGC-1α/Nrf2 pathway to alleviate mitochondrial dysfunction and dopaminergic neuron loss.^[77] In amyotrophic lateral sclerosis (ALS) models, TBN and the nitrone OKN-007 delay motor neuron degeneration and slow disease progression.^[78] Additionally, PBN has anti-inflammatory effects in arthritis models, reducing joint inflammation through ROS scavenging.^[79] As of 2025, nitrone-based therapies remain investigational with limited regulatory approvals; for instance, a Phase II trial of oral TBN in 155 ALS patients (doses of 1200 mg or 2400 mg daily versus placebo) confirmed good safety and tolerability over 180 days but showed no significant change in ALS Functional Rating Scale–Revised scores, though high-dose TBN slowed grip strength decline, particularly in younger patients with slower progression.^[80] Ongoing research explores nitrone derivatives as superoxide dismutase (SOD) mimics for neuroprotection, with preclinical data supporting their use in ischemia and neurodegeneration, but no FDA-approved nitrone therapeutics exist for these indications.^[78] Structure-activity relationships highlight that cyclic nitrones, such as phosphorylated variants like DEPMPO, offer enhanced stability and bioavailability compared to acyclic counterparts, potentially improving tissue penetration for therapeutic applications.^[9] Nitrones generally exhibit low toxicity, with adverse events in trials being mild and comparable to placebo, though metabolism often yields hydroxylamines that contribute to their antioxidant activity but require monitoring for potential redox cycling.^[80]^[81]

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