The involvement of 1,3-dipolar cycloaddition (1,3-DP), double bond migration, metathesis, and nitrile oxide (including in situ-generated nitrile oxide) as dipoles, together with the C=C bond containing dipolarophiles, in the syntheses of 2-isoxazolines is presented. Methods for synthesizing isoxazolines (other than 1,3-DP cycloaddition) were also presented briefly. Various methods of nitrile oxide preparation, especially in situ-generated procedures, are presented. Special attention was paid to the application of various combinations of 1,3-DP cycloaddition with double bond migration (DBM) and with alkene metathesis (AM) in the syntheses of trisubstituted isoxazolines. Allyl compounds of the type QCH2CH=CH2 (Q = ArO, ArS, Ar, and others) play the role of dipolarophile precursors in the combinations of DPC mentioned, DBM and AM. Mechanistic aspects of cycloadditions, i.e., concerted or stepwise reaction mechanism and their regio- and stereoselectivity are also discussed from experimental and theoretical points of view. Side reactions accompanying cycloaddition, especially nitrile oxide dimerization, are considered. 2-Isoxazoline applications in organic synthesis and their biological activity, broad utility in medicine, agriculture, and other fields were also raised. Some remaining challenges in the field of 1,3-DP cycloaddition in the syntheses of isoxazolines are finally discussed.

A new d-erythrose 1,3-dioxane derivative was synthesized from d-glucose and found to be a highly stereoselective template as a dipolarophile. Different 1,3-dipoles of allenyl-type were employed, giving different regioselectivities, depending on its nature; the regioselectivity is complete with alkyl azides and phenyldiazomethane, but is inexistence with nitrile oxides. Computational studies were performed to understand the mechanisms of cycloadditions. All the studied cycloadditions were found to be concerted involving small free activation energies and are all exoenergonic. The stereoselectivity is due to a combined result of the steric effect H-8a and the hyperconjugative effect of the *C-O to the incoming 1,3-dipole. The regioselectivity observed in alkyl azides and phenyldiazomethane is mostly dependent on the distortion effect during the cycloaddition process. This distortion effect is however higher in the alkyl azide compounds than in phenyldiazomethane.

Abstract 1,3-Dipoles, such as phenylglyoxylonitrile oxide (1), benzonitrile oxide, and phenyl azide, undergo cycloadditions to the more electron-rich double bond of 2,3-bis(methoxycarbonyl)bicyclo[2.2.2]octa-2,5-diene (5) to afford only endo adducts. The cycloadditions of these 1,3-dipoles to the more electron-rich double bond of 6,7-bis(methoxycarbonyl)bicyclo[3.2.2]nona-6,8-diene (6) give only exo adducts. Benzonitrile-N-phenylimine (4) undergoes cycloadditions to both the more electron-rich and the more electron-poor double bonds of 5 or 6. The reaction of 4 with 5 yields two endo adducts, and the reaction of 4 with 6 gives two exo adducts. However, the cycloaddition of 1 to 5,6-endo,endo-bis(methoxycarbonyl)bicyclo[2.2.2]oct-2-ene affords both the exo- and endo adducts. The reason for the predominant endo cycloadditions toward 5 and exo cycloadditions toward 6 is discussed.

Polar bimolecular reactions often begin as charge-transfer complexes and may proceed with a high degree of electron transfer character. Frontier molecular orbital (FMO) theory is predicated in part on this concept. We have developed an electron transfer model (ETM) in which we systematically transfer one electron between reactants and then use density functional methods to model the resultant radical or radical ion intermediates. Sites of higher reactivity are revealed by a composite spin density map (SDM) of odd electron character on the electron density surface, assuming that a new two-electron bond would occur preferentially at these sites. ETM correctly predicts regio- and stereoselectivity for a broad array of reactions, including Diels-Alder, dipolar and ketene cycloadditions, Birch reduction, many types of nucleophilic additions, and electrophilic addition to aromatic rings and polyenes. Conformational analysis of radical ions is often necessary to predict reaction stereochemistry. The electronic and geometric changes due to one-electron oxidation or reduction parallel the reaction coordinate for electrophilic or nucleophilic addition, respectively. The effect is more dramatic for one-electron reduction.

Regio- and stereo-selective synthesis of carbohydrate isoxazolidines by 1,3-dipolar cycloaddition of nitrones to 5,6-dideoxy-1,2-O-isopropylidene- alpha-D-xylo-hex-5-enofuranose. The synthesis of 2-phenyl-3-aryl and 2-phenyl-3-aroyl derivatives 5-(1,2-O-isopropylidene-alpha-D-xylo-tetrofuranos-4-yl)isoxazolidi ne (3) from nitrones and 5,6-dideoxy-1,2-O-isopropylidene-alpha-D-xylo-hex-5- enofuranose (1) is described. The 1,3-dipolar cycloaddition reactions given mainly anti adducts 3 and 4 (greater than or equal to 95% pi-facial stereoselectivity). The cycloadducts 3 with H-3,5 cis are formed either exclusively or preponderate over the trans diastereoisomers 4. Published in Carbohydrate research (1992)

Abstract Die 1,3‐Dipole (II) bzw. (VI) addieren sich an die elektronenreichere Doppelbindung der Bicycloalkadiene (I) unter Bildung der Addukte (III) bzw. (V).

Nitrones (azomethine <i>N</i>-oxides) are among the most versatile intermediates in organic synthesis, enabling the efficient construction of heterocyclic frameworks that underpin advances in medicinal chemistry, materials science, and chemical biology. Over the past few years, transition-metal-catalyzed strategies have delivered remarkable control over regio- and stereoselectivity, yet their cost and limitations in substrate scope have encouraged the search for alternatives. In this context, transition-metal-free protocols, including [3 + 2], [2 + 2] and [4 + 2] cycloadditions, have emerged as sustainable and economical approaches. Complementing these methods, new developments such as asymmetric click reactions, deoxygenative cyclizations, silylacetate-promoted addition reactions, photoredox catalysis, and self-oxidative cyclizations further broaden the synthetic toolbox, enabling access to structurally complex and biologically relevant scaffolds. By integrating these diverse methodologies, nitrone chemistry continues to evolve as a dynamic platform for heterocycle construction. This review highlights recent synthetic strategies for nitrone-derived heterocycles reported from 2021 to 2025, critically evaluating their advantages and limitations while outlining promising directions toward greener, more versatile, and practically useful methodologies.

The 1,3-dipolar cycloaddition is a chemical reaction between a 1,3-dipole and a dipolarophile to form a five-membered ring. The earliest 1,3-dipolar cycloadditions The 1,3-dipolar cycloaddition is a chemical reaction between a 1,3-dipole and a dipolarophile to form a five-membered ring. The earliest 1,3-dipolar cycloadditions were described in the late 19th century to the early 20th century, following the discovery of 1,3-dipoles. Mechanistic investigation and synthetic application were established in the 1960s, primarily through the work of Rolf Huisgen. He Lack of solvent effects in 1,3-dipolar cycloaddition is clearly demonstrated in the reaction between enamines and dimethyl diazomalonate (see scheme below). The polar reaction, N-cyclopentenyl pyrrolidine nucleophilic addition to the diazo compound, proceeds 1,500 times faster in polar DMSO than in non-polar decalin. On the other hand, a close analog of this reaction, N-cyclohexenyl pyrrolidine 1,3-dipolar cycloaddition to dimethyl diazomalonate, is sped up only 41-fold in DMSO relative to decalin. 1,3-Dipolar… However, it is uncertain whether the metallocarbene intermediate generates the carbonyl ylide. In some cases, metallocarbenes can also react directly with dipolarophiles. In these cases, the metallocarbene, such as the dirhodium(II)tetracarboxylate carbene, is stabilized through hyperconjugative metal enolate-type interactions. Subsequent 1,3-dipolar cycloaddition reaction occurs through a transient metal-complexed carbonyl ylide. Therefore, a persistent metallocarbene can influence the stereoselectivity and regioselectivity of the 1,3-dipolar cycloaddition reaction based on the stereochemistry and size of the metal ligands. The mechanism of the 1,3-dipolar cycloaddition reaction between the carbonyl ylide dipole and alkynyl or alkenyl dipolarophiles has been extensively investigated with respect to regioselectivity and stereoselectivity. As symmetric dipolarophiles have one orientation for cycloaddition, only one regioisomer, but multiple stereoisomers can be obtained. On the contrary, unsymmetric dipolarophiles can have multiple regioisomers and stereoisomers. These regioisomers and stereoisomers may be predicted based on frontier molecular orbital (FMO) theory, steric interactions, and stereoelectronic interactions. Regioselectivities of 1,3-dipolar cycloaddition reactions mediated by metal catalysis of diazocarbonyl compounds may also be influenced by the metal through formation of stable metallocarbenes. Stabilization of the metallocarbene, via metal enolate-type interactions, will prevent the formation of carbonyl ylides, resulting in a direct reaction between the metallocarbene dipole and an alkynyl or alkenyl dipolarophile (see image of The…