By the activation of alkyl nitro compounds

Rahman and Clapp decomposed dinitromethane derivatives in DMF in the presence of alkenes to obtain 2-isoxazolines. Without any alkene present, an acid and KNO2 were obtained. They proposed a mechanism which proceeded via a three-membered ring or a nitrocarbene which rearranged to a nitrile oxide (76JOC122, 75MI41612). 

Oximes with a displaceable group in the /3-position cyclize in the presence of base to produce 2-isoxazolines as exemplified in the conversion of (480) into (481) (62HC(l7)l, 78JOC2020, 66JAP6616384, 70JOC2065). 

N-Oxides are commonly reduced by a variety of reagents including PC1S and H2, as shown by the reaction of (482) with H2 to give (483) (69JOC984). 

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The two major methods of preparation are the cycloaddition of nitrile oxides to alkenes and the reaction of a,/3-unsaturated ketones with hydroxylamines. Additional methods include reaction of /3-haloketones and hydroxylamine, the reaction of ylides with nitrile oxides by activation of alkyl nitro compounds from isoxazoline AT-oxides (methoxides, etc.) and miscellaneous syntheses (62HC(i7)i). 

Alkoxyl tion. The nucleophilic replacement of an aromatic halogen atom by an alkoxy group is an important process, especially for production of methoxy-containing iatermediates. Alkoxylation is preferred to alkylation of the phenol wherever possible, and typically iavolves the iateraction of a chloro compound, activated by a nitro group, with the appropriate alcohol ia the presence of alkaU. Careful control of alkaU concentration and temperature are essential, and formation of by-product azoxy compounds is avoided by passiag air through the reaction mixture (21). 

Activated nitro and halo substituents have been efficiently replaced by a variety of alkyl groups via SsAx reaction with carbanions. Examples include the displacement of the nitro group in compounds (10 X = 4-PhCO, 4-MeOCO, 4-CN, 4-N02, 4-PhS02, 3,5-(CF3>2) by the anion of 2-nitropropane in HMPA at room temperature (equation 2),83 and the reaction of p-dinitrobenzene with several ketones, esters and nitriles (RH equation 3) in Bu OK/liquid NH3 at -70 C.84 Interestingly, under the latter reaction conditions, p-chloronitrobenzene gave the product of alkylation rather than of SNAr displacement of chloride, as in equation (4).85 Further examples include the dehalogenation of p-halonitrobenzenes by 9-fluorenyl anions in DMSO at room temperature,34 and dehalogenation and denitration reactions by the carbanions of phenyl- and diphenyl-acetonitrile in DMSO or under PTC conditions.86... 

As would be expected, deuterium exchange between nitromethane and D2O is catalyzed by acetate ions, and the rate of exchange is equal to the rate of bromination under the same conditions (Reitz, 43). Similar correspondences would be expected in the rate of racemization of optically active nitro compounds, but here the position has been complicated by reports (Kuhn and Albrecht, 45 Shriner and Young, 46) that these compounds do not lose their activity completely on conversion to the ion. However, it has recently been shown (Kornblum et al., 47, 48) that the residual activity in these observations was due to the presence of alkyl nitrate as an impurity. The mutarotation of a-nitro camphor represents a similar type of reaction it is catalyzed both by acids and bases (Lowry, 49), and a quantitative study of acid catalysis in chlorobenzene solution has been made (Bell and Sherred, 50). Lowry and most subsequent writers have supposed that the observed change of rotation is due to conversion to the aci-nitro form (II), i.e.,... 

The result is encouraging, since it suggests this approach to the design of hypoxia-selective compounds (the use of cellular nitro-reduction to activate an alkylating moiety) has potential. However, the ratio of 3.2-fold is small compared to the difference in aerobic toxicities between the 4-NO compound (3) and its potential end-stage metabolite, the 4-NH compound (15) actually measured (220-fold) or computed by Equation 6 (3500-fold). Although this ratio must be seen as the theoretical maximum for the hypoxia-selective toxicity of the corresponding nitro compound (it is unlikely that there will be complete reduction to the 6-electron product), the hypoxic selectivity shown by the nitro compounds (3 and 4) are very small fractions of this maximum. 

There is much evidence to suggest that carcinogenic N-nitros-amines are metabolised by an oxidative process to produce an alkylating agent (J f2) One potential metabolite is therefore the corresponding N-nitrosamide resulting from 2-electron oxidation at the oc-carbon atom, and, indeed, such compounds appear to induce tumours at the site of application without metabolic activation (3) It follows that the chemical properties of N-nitrosamides are relevant to the etiology of cancer ... 

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