Nitrones, addition from oximes

The electrophile-induced cyclization of heteroatom nucleophiles onto an adjacent alkene function is a common strategy in heterocycle synthesis (319,320) and has been extended to electrophile-assisted nitrone generation (Scheme 1.62). The formation of a cyclic cationic species 296 from the reaction of an electrophile (E ), such as a halogen, with an alkene is well known and can be used to N-alkylate an oxime and so generate a nitrone (297). Thus, electrophile-promoted oxime-alkene reactions can occur at room temperature rather than under thermolysis as is common with 1,3-APT reactions. The induction of the addition of oximes to alkenes has been performed in an intramolecular sense with A-bromosuccinimide (NBS) (321-323), A-iodosuccinimide (NIS) (321), h (321,322), and ICl (321) for subsequent cycloaddition reactions of the cyclic nitrones with alkenes and alkynes. 

BUzSnO catalyzes the formation of the nitrone 14 from benzaldehyde and the oxime 13. Addition of an olefin, followed by hydrolysis, gives a N-unsubstituted isoxazolidine (95CL357). 

Oxazines can also be synthesized by intramolecular addition of oximes to carbon-carbon double bonds. These reactions are not general nitrones and other products can be formed in competition with oxazines. There are examples of conjugate addition to activated alkenes <81TL2557, 91CPB2830> and of acid or Lewis acid-catalyzed addition to simple alkenes <88TL6805> or allenes <89JCS(P1)2415>. 3-Methyl-6-vinyl-5,6-dihydro-4//-1,2-oxazine was isolated in moderate yield from... 

Clerici and Porta reported that phenyl, acetyl and methyl radicals add to the Ca atom of the iminium ion, PhN+Me=CHMe, formed in situ by the titanium-catalyzed condensation of /V-methylanilinc with acetaldehyde to give PhNMeCHMePh, PhNMeCHMeAc, and PhNMeCHMe2 in 80% overall yield.83 Recently, Miyabe and co-workers studied the addition of various alkyl radicals to imine derivatives. Alkyl radicals generated from alkyl iodide and triethylborane were added to imine derivatives such as oxime ethers, hydrazones, and nitrones in an aqueous medium.84 The reaction also proceeds on solid support.85 A-sulfonylimines are also effective under such reaction conditions.86 Indium is also effective as the mediator (Eq. 11.49).87 A tandem radical addition-cyclization reaction of oxime ether and hydrazone was also developed (Eq. 11.50).88 Li and co-workers reported the synthesis of a-amino acid derivatives and amines via the addition of simple alkyl halides to imines and enamides mediated by zinc in water (Eq. 11.51).89 The zinc-mediated radical reaction of the hydrazone bearing a chiral camphorsultam provided the corresponding alkylated products with good diastereoselectivities that can be converted into enantiomerically pure a-amino acids (Eq. 11.52).90... 

Nitrones can be generated by Michael reaction of oximes with appropriate conjugated substrates.25 If a generated nitrone has a built-in dipolarophile, cyclization can ensue (Scheme 15). There are three synthetic variations on this theme.25a,b First, the oxime may contain the dipolarophile as in (56). Reaction of (56) with phenyl vinyl sulfone provided a quantitative yield of the tandem product as one stereoisomer. Alternatively, die dipolarophile can reside in the Michael substrate as in (57). Reaction of (57) with cyclohexanone oxime produced two isoxazolidines from competitive cyclization of the intermediate nitrone through six- and seven-membered carbocyclic transition states. It is also possible to carry out an intramolecular Michael addition followed by an intramolecular nitrone cyclization as in thermolysis of (58) to produce a tricyclic isoxazolidine. Very recently several examples of a tandem Diels-Alder, Michael addition, nitrone cyclization sequence have been reported.250... 

As described here, both enantiomers of 3 can be prepared In three steps from commercially available diethyl D- and L-tartrate in up to 70% over-all yield.2 3 5 Procedures to obtain the benzylidene acetal,11 12 with the ensuing reduction step,11. 2 are based on previous literature reports. Both enantiomers of 3 have been used in highly stereoselective nitroaldol additions.3 13 Imines, nitrones, oximes, and nitrile oxides derived therefrom were recently employed in a variety of additions/cycloadditions.14 15 (-)-2-0-Benzyl-L-glyceraldehyde has further been used... 

The chiral moiety of the nitrone can also be located at the carbon atom. Yokoyama et al. [50] used this approach in the asymmetric synthesis of spiro isoxazohdines (Scheme 10.21). The ribose-derived nitrone 62 is obtained from the corresponding oxime by Michael addition to methyl acrylate. With a second equivalent of methyl acrylate, the sugar nitrone 62 gave a single cycloadduct 63, which was converted into the corresponding pyrrolidine by reduction. 

In general, synthesis of 4-isoxazolines is accomplished via three routes 1,3-dipolar cycloaddition of nitrones to alkynes or by the oximation of a,i -ethylenic ketones, a-alkynic ketones and aldehydes or from the selective reduction of isoxazolium salts. The nitrone (262) underwent tandem cyclo-addition-[2,3]sigmatropic rearrangement with allenyl sulfoxide (263). And it resulted in 4-isoxazoline (264) (Equation (46)) <89TL663>. 

The Nef reaction1 2 is the conversion of nitroalkanes to ketones and aldehydes through treatment with base followed by acid.3 4,5,6 For example, deprotonation of 1-nitrobutane (1) with aqueous NaOH followed by addition of excess aqueous sulfuric acid afforded butyraldehyde (2) in 85% yield (isolated as the oxime derivative).7 These reactions proceed via intermediate nitronate anions, which are subsequently hydrolyzed to afford the carbonyl products. The overall transformation leads to formal polarity reversal of the carbon bearing the nitro group from a nucleophilic species to an electrophilic carbonyl carbon. Although the classical conditions for this process are quite harsh, a number of alternative procedures that employ mild reaction conditions have been developed. 

In addition to (aminoalkyl)phosphonic diesters, several other, well characterized products have been obtained from the oximes, or derivatives of oximes, of acylphosphonic diesters. Methylation of the oximes 283 [Z = CONHR, COOR (R = Et or Pr ), R = H of undefined geometry] with MeI-K2C03, or with Me2S04, yields the O-methyl oximes 283 (Z = CONHR R = Me) methylation with diazomethane also yields the latter but together with the phosphorylated nitrones 284 (Z = CONHR or COOR), which have been characterized in E and Z forms. The interaction of283 (R = Me) and diazomethane yields the corresponding 285 . Methylene insertion also occurs in reactions between diazomethane and 0-acylated oximes ... 

Another common example of kinetic currents is observed with reducible acids and substances that are reduced in protonized and unprotonized forms (e.g. some keto-acids< and other acids,oximes< nitrones ) etc.). For such substances two waves are observed on the polarographic curve, the ratio of which changes with the pH-value of the solution in the shape of a dissociation curve (Figs. 11 and 12). The more positive wave corresponds to the acidic form, and the more negative one to the reduction of the corresponding base. However, the ratio of the two waves does not correspond to the equilibrium conditions in the bulk of the solution. The height of the more positive wave is considerably higher than it would be if it corresponded to the equilibrium concentration of the acidic form. Additional acidic form is formed around the electrode by recombination from the... 

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