N-Methyl nitrones

An identical rearrangment can be arrived at tiirou acylation of N-methyl nitrones," conveniently prepared from the kemne (155 to 156), althougb the process is apparently restricted to cyclic substrates, nnally a similar one-pot procedure for conversion of ketoximes to a-acetoxy ketones under the conditions shown (157 to 158), allows the transformation to be carried out simply and efficiently. In this case rearrangement produces a-acyloxyenimides, whose hydrolysis provides Ae keto equivalent. 

With C-phenyl-W-phenyl nitrones [iO] (equation 7) Similar reactions of N-methyl nitrone were also reported [10],... 

Occasionally, molecular mechanics calculations provide a rationale when FMO theory fails to account for a given regiochemical outcome. - For example, cycloaddition of C-phenyl-N-methyl nitrone to methyl 2-methyl-2,3-butadienoate leads exclusively to the S-exo-methylene cycloadduct, as one would expect based upon FMO theory. In contrast, C-phenyl-yV-f-butyl nitrone affords only the 4-exo-methylene isoxazolidine, a result which clearly cannot be in accord with the same principles (Scheme 12). Molecular mechanics calculations, carried out under the assumption that the relative energy differences between the products parallel the energy differences between transition states, were in accord with the experimental results, suggesting that the difference in behavior between the two nitrones may have a steric rather than an electronic origin (Table 10). ... 

N-Methyl nitrones -> N-methylamides (4, 510-511). Details are now available for the rearrangement of ketonic nitrones. ... 

Cycloadditions are stereospecific cis additions, as has been shown in several cases using geometric isomers as dipolarophiles . In addition to the rigid structure of norbornene, as well-defined approach is preferred, namely the one that gives an exo adduct, as is shown in (a) above for azides, but also occurs with C-phenyl-N-methyl-nitrone and for diphenylnitrilimine -. The alternative approach of the reactants is sterically hindered in the case of norbornene the steric course of reactions of norbornadiene can be different, as was found using phenyl azide as the 1,3-dipole . 

The cycloaddition of C-phenyl-N-methyl nitrone with a dipolarophile having an orf/to-hydroxy group is completely controlled by intermolecular hydrogen bonding between dipolar compound and dipolarophile leading to an E-endo transition state to give exclusively r-cycloadduct. 

For example, reaction of C-phenyl-N-methyl nitrone 125 with ort/to-hydro-xystyrene 137 gives only cw-adduct (100 %) in 92 % yield [112]. 

Tetramethylpiperidine, 192 Tetraphenyl phosphonium acetate, 224 Tetraphenyl phosphonium benzoate, 224 Tetraphenyl phosphonium phenolate, 225 4-(2-Thiazolyl)-phenyl-N-methyl-nitrilimine, 28 4-(2-Thiazolyl)-phenyl-N-methyl-nitrone, 28 4-(2-Thiazolyl)-phenyl-N-phenyl-nitrone, 28 3,3 -Thiodipropionic acid, 167... 

Chiacchio et al. (2007) have also demonstrated the synthesis of methylene-isoxazolidine nucleoside analogs by microwave-assisted nitrone cycloaddition. The insertion of a methylene isoxazolidine spacer unit between the nucleobase and the hydroxyl-methyl group in the N, O nucleoside analogs could control the conformational mobility of the system. The cycloaddition between a proper N-methylated nitrone and a suitably functionahzed allene, (often thymallene) in CCl or EtOH at 70°C for 10 min generated the methylene-isoxazolidine nucleoside ankogs with good yields (45-72%) and purity. The reaction rate was enhanced, when the reactions were ran under microwave irradiation, in comparison to conventional reaction conditions. 

Nitrones are among the most highly studied and useful reagents for the synthesis of five-membered-nng heterocycles. The first fluonnated nitrone, N-methyl-C-(trifluoromethyl)nitrone, was prepared recently and used to introduce Irifluoromethyl groups into such heterocycles... 

The main building block of PEDC (1 -phenyl-2-[(S)-l-aminoethyl] -N,N -di-ethylcyclopropanecarboxamide), a potent NDMA (N -methyl-D-aspartic acid) receptor antagonist of a cyclopropane structure, N -benzyl-C-cyclopropyl nitrone... 

This series of rearrangements includes the dithia-Claisen rearrangement mentioned above (Section IV.E.l) as well as the palladium-catalyzed [3,3]-sigmatropic isomeriza-tions of allyl methyl N-aryldithiocarbonimidates 627 (refluxing dioxane, 20 h, 62-90%) (equation 275)376 and a Pd11-catalyzed tandem [2,3]-sigmatropic shift, followed by 1,3-dipolar cycloaddition which takes place at equilibrium between O-allyl ethers of oximes 628 and the corresponding N-allyl nitrones 629 (equation 276)377. 

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 all of the above reactions, a chiral center of the alkene was located in the allylic position. However, as shall be demonstrated next, more distant chiral centers may also lead to highly selective cycloadditions with 1,3-dipoles. In two recent papers, the use of exocyclic alkenes has been applied in reactions with C,N-diphenylnitrone (165,166). The optically active alkenes 109 obtained from (S)-methyl cysteine have been applied in reactions with nitrones, nitrile oxides, and azomethine ylides. The 1,3-dipolar cycloaddition of 109 (R=Ph) with C,N-diphenyl nitrone proceeded to give endOa-1 Q and exOa-110 in a ratio of 70 30 (Scheme 12.36). Both product isomers arose from attack of the nitrone 68 at the... 

Ein analoger Reaktionsweg wird bei der Cyclisierung des N-Aryl-nitrons IV mit Bromcyan zu I-(Ethoxycarbonyl-imino-methyl)-2-hydroxy-benzimidazol(66% Schmp. 127-132°) beobachtet591 ... 

Imidazole synthesis. A new synthesis of 4,5-diarylimidazoles (2) involves reaction of catalytic amounts of aqueous elhanolic K.CN with N-methyl-C-aryl nitrones (1), prepared by condensation of aryl aldehydes with N-methyl-hydroxylamine. The reaction involves an intermediate cyanoimine (n). 

F3C—CN + R — ONa) Nitrone N-Methyl-C-trifluoro-mcthyl- ElOb,. 548F (Educt)... 

Nitrones.1 O-Trimethylsilyloximes undergo N-methylation on reaction with Meerwein s reagent or methyl trifluoromethanesulfonate. The products are converted into nitrones on addition of KF or Bu4NF. Although both (E)- and (Z)-nitrones are formed initially, purification results in isolation of the more stable (Z)-nitrones. 

This 1,3-dipolar cydoaddition not only gave excellent results but was also found to be very general with regard to the nitrone component. Several types of aryl- and alkyl-substituted nitrone have been applied successfully. Irrespective of the substitution pattern, high diastereomeric ratios and enantioselectivity were obtained (see Scheme 8.9, products 35a,d,f,g). Variation of the N-alkyl group is also possible. As can be see from Scheme 8.9 (see, e.g., products 35a-c), the reactions also proceed well when an N-allyl and N-methyl-substituted nitrone is used. Acrolein, 32b, and crotonaldehyde, 32a, were used as the aldehyde component. It is noteworthy that this reaction is also suitable for use on a larger scale, as has been demonstrated by the 25 mmol-scale preparation of endo-35a (98% yield, 94% ee) starting from nitrone 31a and crotonaldehyde. 

An outstanding comparison was made with the best known dipolarophi-le, dimethyl acetylenedicarboxylate (DMAD). The cycloaddition of N-methyl-C-phenylnitrone to adamantanethione is 1500 times faster than the addition to DMAD. As indicated in Scheme 74 the reaction is an equilibrium, leading to 56 44 ratio of product vs starting material. This equilibrium is shifted towards the left side for thiobenzophenones, as the cycloadduct formation breaks the conjugation, and thus these thiones do not appear to react with nitrones. Ab initio calculations were carried out to model the high reactivity of nitrones with thiocarbonyl compounds [257]. 

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