Enones reaction with hydroxylamine

Alternatively, Shibata and coworkers first realized the catalytic enantioselective synthesis of trifluoromethyl-substituted 2-isoxazolines 69 in 2010 by developing a cinchona-alkaloid-catalyzed asymmetric conjugate addition/cyclization/dehydration cascade reaction with hydroxylamines 67 and enones 68 (Scheme 2.19). A wide range of substrates could be employed in this reaction to give the desired cyclized products with excellent enantioselectivities [33]. 

A2-Isoxazolines are readily available from the 1,3-dipolar cycloaddition of nitrile JV-oxides with alkenes and from the condensation reaction of enones with hydroxylamine. Therefore, methods of conversion of A2-isoxazolines into isoxazoles are of particular interest and of synthetic importance. 

A modification of the above route to the A4 alkaloid and its 3 -demethoxy analog has recently been reported by the Wiechers group (60). In a series of reactions which directly parallel those reported by Stevens et al., Wiechers and co-workers react the synthon 62 and its 3 -demethoxy analog in separate reaction schemes with the enone acetal 114 to give 115 (R = H or OMe) they converted the latter compounds directly to the pyridine alkaloid and its 3 -demethoxy base with hydroxylamine hydrochloride (see Scheme 29). 

The 1,5-dicarbonyl functionality is also represented by 2-alkoxy-3,4-dihydro-2H-pyrans (e.g., 162, a masked 5-ketoaldehyde), which are obtained by hetero-DiELS-ALDER reaction of enones and vinyl ethers (c p. 315). On treatment with hydroxylamine, they afford pyridines (e.g., 163) ... 

Reaction of the enone (60) with a variety of IV-substituted hydroxylamines gave the conjugate addition products (61), whereas the analogous reaction with 0-methylhydroxylamine gave a mixture of oximino-derivatives (62) and (63) (Scheme 6). Reduction of uloses (61) with sodium borohydride gave predominantly products with the D-araWno-configuration the e.s.r. spectroscopy of free radicals produced on spontaneous oxidation of such products is covered in Chapter 22. The condensation of... 

Next came the challenging task of introducing the hydroxylamine moiety in an asymmetric fashion. To acconplish this we fbrst needed access to enantiomerically enriched/pure 3-iodocyclopent-2-enol (24), then we needed to establish that this allylic alcohol would undergo Sk2 reaction with a protected hydroxylamine nucleophile without loss of stereochemical integrity. We found that racemic 3-iodo-cyclopent-3-enol 23 could be prepared in high yield by Luche reduction (17) of enone 22. After screening a number of lipases we found... 

Since heterocycles containing a trifluoromethyl group are representatives of a major structure type in agricultural and medicinal chemistry, Shibata ct al. have developed a novel enantioselective synthesis of trifluoromethyl-substituted 2-isoxazolines 46 on the basis of a domino oxa-Michael-intramolecular hemi-aminahzation-dehydration reaction of hydroxylamine with a range of ( )-trifluoromethylated enone derivatives 47 [81]. This process, which employed N-3,5-bis(trifluoromethyl)benzyl-quinidinium bromide 48 as a chiral phase-transfer catalyst combined with CsOH as a base provided a series of trifluoromethyl-substituted 2-isoxazolines 46 in high yields and enantioselectivities of up to 94% ee (Scheme 37.8). 

Enehydroxylamine 0-derivatives 149 and 151, prepared from the reactions of A-alkyl-3-(hydroxyamino)cyclohex-2-enone (148, R = H) and iV-alkyl-3-(hydroxyamino)-5,5-dimethylcyclohex-2-enone (148, R = Me) with MsCl (equation 41) and Mc2NC(S)Cl (equation 42), respectively, in the presence of base rearrange spontaneously providing the corresponding [3,3]-sigmatropic rearranged products 150 and 152 in moderate to excellent yield . However, the diethyl phosphate 153 (equation 43) and the O-benzoyl hydroxylamine 154 rearrange under reflux in toluene (equation 44). 

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