Hydroxylamines nucleophilic addition

The reaction is thought to occur by nucleophilic addition of the N-alkyl-hydroxylamine to the keto acid as if forming an oxime (Section 19.8), followed by decarboxylation and elimination of wrater. Show the mechanism. 

An illustrative example of the Michael reaction is that of the thiirene dioxide 19b with either hydroxylamine or hydrazine to give desoxybenzoin oxime (87) and desoxybenzoin azine (88), respectively, in good yields6 (see equation 29). The results were interpreted in terms of an initial nucleophilic addition to the a, j8-unsaturated sulfone system, followed by loss of sulfur dioxide and tautomerization. Interestingly, the treatment of the corresponding thiirene oxide (18a) with hydroxylamine also afforded 86 (as well as the dioxime of benzoin), albeit in a lower yield, but apparently via the same mechanistic pathway6. 

Amongst other N-nucleophilic species, hydroxylamine exhibits some abnormal behavior besides oxime formation (p. 25). Thus it reacts with diphenyl cyclopropenone42 probably by 1,4-addition and subsequent oxidation and/or decarboxylation giving rise to 3,4-diphenyl isoxazolone (328) and desoxybenzoin oxime. With pentyl cyclopropenone48 hydroxylamine undergoes addition followed by normal oxima-tfon after ring fission yielding 2,3-dioximino octane (329). 

Nucleophilic addition of organometalic reagents occurs when the nitrone form is in equilibrium with the hydroxylamine form, for instance, in the case of N -benzyl-/V-glycosyl hydroxylamines (Scheme 2.130) (213). 

Addition of organometalic compounds to nitrones is known as an efficient method of enantioselective synthesis of primary amines that can be easily obtained by the reduction of hydroxylamines which are the products of nucleophilic addition. 

Nucleophilic addition of metallated heterocyclic derivatives to AMetrahydro-pyranyl (THP) protected nitrones (361) makes it possible to synthesize a-branched hydroxylamines (362) (Table 2.13) (597). 

Addition of 2-Alkyl-2-Oxazolines All of the above mentioned reactions of nucleophilic addition of nitrones give the corresponding hydroxylamines. In this chapter, the reactions of nitrones and nucleophiles and their conversions to compounds of other structures are considered. 

Addition of Lithiated Sulfoxides and Sulfones Nucleophilic addition of lithiated methylaryl sulfoxides (384) to nitrones of various structures proceeds easily and in good yields (622). The reactions are applied to the synthesis of optically active a-substituted and a,a-disubstituted hydroxylamines, to secondary amines (623), and to enantioselective syntheses of alkaloids (624). The preferred approach to (+ )-euphococcinine is based on the use of homochiral 3-sullinyl nitrones (385) (Scheme 2.167). 

This scheme, set up with reactions in dichloromethane, gave spin adducts from several of the nucleophiles discussed above (F, Cl", AcO, CN, tetramethylsuccinimide anion and triethyl phosphite), provided UV light was employed. With filtered light of A > 435 nm, no spin adducts were detected. This is expected, since PBN cannot then be excited. With water as the nucleophile, only benzoyl nitroxide [9] was seen, indicating that any HO-PBN" disappears too rapidly to be detectable 10 s in acetonitrile) and/or that its rate of formation from PBN +ConW is too low (see above). The complication that nucleophilic addition-oxidation might compete was ruled out experimentally in dichloromethane, but detected for fluoride ion in chloroform, using dioxygen to oxidize the intermediate hydroxylamine anion. 

A new semipinacol rearrangement mediated by Sn(IV) was proposed by Bates and to explain the formation of 579 from 578 (equation 256). As stated by the authors, the mechanism of formation of 579 most likely involves an intermediate hydroxylamine 580 (equation 257). Nucleophilic addition of the hydroxylamine to the ketonic carbonyl leads to 581, which may undergo a tin-mediated pinacol-type rearrangement with preferred migration of the phenyl substituent to produce amide 582. 

Adducts 119 are of relevance as reaction intermediates in the chemistry of several uracil and cytosine derivatives, which show a strong tendency to undergo covalent nucleophilic addition across the 5,6 double bond with such reagents as water, alcohols, hydroxylamine, and bisulfite ion. 

The versatility of 5-nitrosopyrimidines in pteridine syntheses was noticed by Pachter (64MI21603) during modification of the Timmis condensation between (262) and benzyl methyl ketone simple condensation leads to 4-amino-7-methyl-2,6-diphenylpteridine (264) but in the presence of cyanide ion 4,7-diamino-2,6-diphenylpteridine (265) is formed (equation 90). The mechanism of this reaction is still uncertain (63JOC1187) it may involve an oxidation of an intermediate hydroxylamine derivative, nitrone formation similar to the Krohnke reaction, or nucleophilic addition of the cyanide ion to the Schiff s base function (266) followed by cyclization to a 7-amino-5,6-dihydropteridine derivative (267), oxidation to a quinonoid-type product (268) and loss of the acyl group (equation 91). Extension of these principles to a-aryl- and a-alkyl-acetoacetonitriles omits the oxidation step and gives higher yields, and forms 6-alkyl-7-aminopteridines, which cannot be obtained directly from simple aliphatic ketones. 

In the course of redox pyrrolization of the oxime 39 with X = OH, the hydroxyl group in position 5 is vinylated to a slight extent to form 1-vinyl-5-vinyloxy-4,4,6,6-tetramethyl-4,5,6,7-tetrahydro-5-azaindole (40, X = OCH=CH2). This was the first example of nucleophilic addition of hydroxylamine to a triple bond not activated by strong electron-withdrawing substituents. x... 

The molecular mechanisms for the nucleophilic addition of lithium enolates and silyl ketene acetals to nitrones in the absence and in the presence of a Lewis acid catalyst to give isoxazolidin-5-ones or hydroxylamines have been investigated by DFT methods at the B3LYP/6-31G level.13 An analysis of the global electrophilicity of the reagents accounts for the strong electrophile activation of the Lewis acid-coordinated nitrone, (g) and the analysis of the local indices leads to an explanation for the experimentally observed regioselectivity. 

Nucleophilic additions to chiral a-alkoxy and a-amino nitrones have been reviewed, focusing on tuning of Lewis acid catalysts and protecting groups so as to exert stereocontrol in producing hydroxylamines and ultimately useful amino acids, amino alcohols, and nucleoside analogues.96... 

Although there is ample evidence for nucleophilic additions to benzyne la> and some other unstable angle strained cycloalkyne intermediates 15,27,31,205 207), only a few addition reactions to isolable angle strained cycloalkynes are known which can be classified as nucleophilic. Hydroxylamine and hydrazine add to (31) to yield the corresponding oxime and hydrazone, resp. 208). 

Syntheses include nucleophilic addition or substitution of a binucleophilic reagent to perfluoroolefins followed by an intramolecular nucleophilic cyclization to afford seven-membered heterocycles. Thus, with the reaction of perfluoro-2-methylpent-2-ene with hydroxylamine, the major product is compound 131, whereas the expected compound 132 is obtained in a low yield (01 JFC(110)11). 

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