Isoxazoline formation, dipolar addition

Fig. 15.43. Isoxazoline formation by way of a 1,3-dipolar addition of an in situ generated nitrile oxide to trans-butene.

Phase-transfer addition (c/. Vol. 6, p. 31) of dibromocarbene to carvone and reduction to a monobromo-ketone by tributyltin hydride, or to a dibromo-alcohol with lithium aluminium hydride, is reported/ 1,3-Dipolar cycloaddition of acetonitrile oxide occurs exclusively at the exocyclic double bond in limonene to give (155 R = Me, X = Hi), whereas isoxazoline formation with carvone yields (155 R = Me, X —O) and the isomeric product from attack at the C-6 double bond benzonitrile oxide, however, only yields (155 R = Ph, X = 0 or NOH). A re-investigation of aqueous chlorination of a -terpineol indicates that the diequator-ial chlorohydrin (156) and the corresponding diaxial chlorohydrin are the major... 

The 3 + 2-cycloaddition of nitrile oxides to 2-crotyl-l,3-dithiane 1-oxides produces exclusively 5-acyldihydroisoxazoles.92 Lewis acid addition to 1,3-dipole cycloaddition reactions of mesityl nitrile oxide with a, /i-unsaturated 2-acyl-1,3-dithiane 1-oxides can reverse the sense of induced stereoselectivity.93 The 1,3-dipolar cycloaddition of 4-t-butylbenzonitrile oxide with 6A-acrylainido-6A-deoxy-/i-cyclodextrin (68) in aqueous solution favours the formation of the 4-substituted isoxazoline (69) rather than the 5-substituted regioisomer (Scheme 24).94 Tandem intramolecular cycloadditions of silyl nitronate, synthons of nitrile oxides, yield functionalized hydrofurans.95... 

Michael addition of diethyl cyanomethylphosphonate to a-nitroalkenes in the presence of LDA (1 eq) followed by treatment with Mc,SiOI provides a one-pot synthesis of 2-isoxazoline derivatives. The reaction proceeds through a 1,3-dipolar cycloaddition of trimethylsilyl nitronate with an a-cyanovinylphosphonate. Similarly, the 1,4-addition of the sodium diethyl cyanomethylphosphonate to the azo-ene system of conjugated alkenes results in the formation of l,2-diamino-3-(dietlioxyphosphinyl)pyrroles in moderate to good yields via a hydrazonic intermediate. - In a route to phosphonylated pyrones, the sodium diethyl cyanomethylphosphonate reacts with 3-anilinometliylene derivatives of 4-hydroxycouinaiins in DMF with displacement of aniline. ... 

The first synthesis of this compound to be completed was the result of studies by Smith and co-workers in 1982. The readily available flavor constituent cyclotene (368) (Scheme 2.28) was reduced and isomerized to 2-methyl-2-cyclopenten-l-one (369) in 64% yield. Addition of dimethyl cuprate followed by isomerization and Baeyer-Villiger oxidation gave the racemic 8-lactone 370 (86%). Addition of allyl Grignard reagent followed by formation of the methyl ketal provided a 71% yield of 371, which possesses the expected axial methoxy group. Conversion of the terminal olefin into the functionalized isoxazoline 373 was accomplished in 68% by the 1,3 dipolar cycloaddition of nitrile oxide 372. 

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