By cycloaddition of nitrile oxides

The reaction of benzonitrile oxide with (447) or (448) produced only (449). No isoxazoline (450) was observed in the reaction with (447) (80MI41601). 

The first isolated isoxazoline was obtained by this method in 1895, and it has been found to be a highly complicated reaction which yields a variety of products depending on, among other conditions, the pH, concentration, temperature and solvent (62HC(i7)l). 

The reaction of a dibromochalcone with hydroxylamine hydrochloride in pyridine gave three products with the expected 2-isoxazoline product as the predominate compound. A ring bromination product and an isoxazole were also isolated (70IJC796). The reaction of hydroxylamine with/3-thiosulfates of propiophenone at reflux produced 3-phenyl-2-isoxazo-line (455). At room temperature a bis-Michael product (456) was produced. The reaction with Af-phenylhydroxylamine yielded a mono-Michael type product (457) (74CPB1990). 

Reacting hydroxylamine with the corresponding trichloro derivative (462) under acidic conditions gave an oxazinone (463) while under basic conditions the 2-isoxazoline (464) was produced (80ZC19). 

The action of benzoylmethylides (471) and (472) with nitrosyl chloride produced the 2-trans products (473) and (474) (72T3845). 

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The process has been applied to the synthesis of a A9-19-nor-10-azatesto-sterone 378 by cycloaddition of nitrile oxide 377 to MCP followed by thermal rearrangement of the adduct (Scheme 52) [94]. 

Polymeric isoxazolines were prepared by cycloaddition of nitrile oxides to norbomadiene followed by ring-opening metathesis polymerization (ROMP) <06PLM3292 06MM3147>. 

Azine approach. Substituted 6,7,8,8a-tetrahydro-5H-[l,2,4]oxadiazolo[4,5-a]-pyrimidines (613) have been prepared by cycloaddition of nitrile oxides or their chloro-oxime equivalents to a tetrahydro pyrimidine (73GEP2155753). 

Vinyl isoxazolines 48 can be prepared by cycloaddition of nitrile oxide to 1,3-butadiene. An alternative synthetic approach has been recently described. The method is based on domino nucleophilic addition-anionic C-O-heterocyclization of nitrile oxides with allyl organometallics derived from trans-1,4-dihalobutene and a metal such as zinc, magnesium or indium. In the case of indium an aqueous media could be used <07SL1449>. 

Although isoxazoles can be obtained by cycloaddition of nitrile oxides to alkynes (Scheme 74), they are also accessible via the corresponding isoxazolines. Dehydrogenation of isoxazolines has been carried out... 

Dihydrospiro[cyclopropane-l,5 -isoxazoles] 41 can be prepared by cycloaddition of nitrile oxides to methylenecyclopropanes 40. Thermolysis of the spiro-compounds led, in general, to the formation of mixtures of enaminones 42 and pyridones 43. However, the proportion of the enaminone 42 was much reduced when the rearrangements were carried out by flash-vacuum pyrolysis at 400 °C, and good yields of pyridones 43 were isolated (see Section 1. A.5.2.3.1 ... 

Contrary to earlier reports,1 3a,4,5,6,7,7a-hexahydroindoxazenes can be prepared by cycloaddition of nitrile oxides to cyclohexene.102,103 Similar cycloadditions with 1,2-dihydronaphthalene produce a mixture of the regioisomers 91a and 91b, and with cyclohex-2-en-l-one a mixture of 3-aryl-4-oxo- and 3-aryl-7-oxo-3a,4,5,6,7,7a-hexahydroindoxazenes, the former predominating.104... 

Studies detailing the thermal and photochemical reactions of these compounds are rare. The l-oxa-2,4-diazine 63 is known, from H NMR, to be in equilibrium with the spiro isomer 64, with the former predominating. Heating this mixture above 40 °C results in decomposition to acetonitrile, methyl isocyanate, and benzene (Scheme 4) <1995H(40)619>. The formation of compounds such as 63 (and 64) by cycloaddition of nitrile oxides to 8-azahepta-fulvenes is discussed in Section 9.05.10. 

Syntheses of isoxazoline-based amino acids by cycloaddition of nitrile oxides and their conversion into highly functionalized bioactive amino... 

A 1,3-dipolar cycloaddition using a nitrile oxide dipole was described by Roth and Singh as an approach to the 3-hydroxy-3-alkyl oxindole scaffold (2011OL2118). Spirocychc isoxazoline 307 was obtained by cycloaddition of nitrile oxide 305 with 3-methylene oxindole 306 and was further elaborated to 3-hydroxy-3-cyanomethyl oxindole 308. This novel protocol was then used to synthesize the tricyclic pyrrolidinoindohne natural product ( )-alline 310 via the tricycHc intermediate 307 (Scheme 55). Thus... 

A wide variety of 2-isoxazolines is available by cycloaddition of nitrile oxides to alkenes. Now it has been shown that isoxazolines can be converted into a -unsaturated ketones in two simple steps representing a straightforward method of acylation of an alkene unit (Scheme 47). ... 

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