Isoxazolidines intermolecular reactions

Dipolar cycloaddition reactions occurreadily even with non-activated dipo-larophiles, such as isolated alkenes. This contrasts with the Diels-Alder reaction, particularly for intermolecular reactions, in which an activated alkene as the dienophile is required. Like the Diels-Alder reaction, [3+2] cycloaddition reactions of 1,3-dipoles are reversible, although in most cases it is the kinetic product that is isolated. For the intermolecular cycloaddition of nitrile oxides or nitrones, two of the most frequently used 1,3-dipoles, to monosubstituted or 1,1-disubstituted alkenes (except highly electron-deficient alkenes), the oxygen atom of the 1,3-dipole becomes attached to the more highly substituted carbon atom of the alkene double bond. Hence the 5-substituted isoxazolidine 206 is generated from the cycloaddition of the cyclic nitrone 205 with propene (3.136). Reductive... 

Isoxazolidines from Intermolecular Nitrone Cycloaddition Reactions. 59... 

Elsewhere, Heaney et al. (313-315) found that alkenyloximes (e.g., 285), may react in a number of ways including formation of cyclic nitrones by the 1,3-APT reaction (Scheme 1.60). The benzodiazepinone nitrones (286) formed by the intramolecular 1,3-APT will undergo an intermolecular dipolar cycloaddition reaction with an external dipolarophile to afford five,seven,six-membered tricyclic adducts (287). Alternatively, the oximes may equilibrate to the corresponding N—H nitrones (288) and undergo intramolecular cycloaddition with the alkenyl function to afford five,six,six-membered tricyclic isoxazolidine adducts (289, R = H see also Section 1.11.2). In the presence of an electron-deficient alkene such as methyl vinyl ketone, the nitrogen of oxime 285 may be alkylated via the acyclic version of the 1,3-APT reaction and thus afford the N-alkylated nitrone 290 and the corresponding adduct 291. In more recent work, they prepared the related pyrimidodiazepine N-oxides by oxime-alkene cyclization for subsequent cycloaddition reactions (316). Related nitrones have been prepared by a number of workers by the more familiar route of condensation with alkylhydroxylamines (Scheme 1.67, Section 1.11.3). 

In constrast with intermolecular nitrone cycloadditions to alkynes and allenes, very little work has been done on the corresponding intramolecular cycloadditions. The bicyclic isoxazolidines (65a-b) were reported as products from reaction of an alkynone with methylhydroxylamine in ethanol.26b Presumably the initial strained bridgehead C—C double bond of the AMsoxazoline added ethanol under the reaction conditions. Cyclization of an allenyl ketone with methylhydroxylamine in ethanol solution also led to isoxazolidines (65a-b) as the major products and isoxazolidine (66) as a minor product.266 Thus, preferential cyclization to the internal C—-C double bond of the allene occurred followed by addition of ethanol to the exocyclic C—C double bond of the methyleneisoxazolidine intermediate. 

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