Nucleophilic addition of hydroxylamines

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 carbonyl function can undergo the usual addition reactions (Section 17-5). Thus, nucleophilic addition of hydroxylamine (Section 17-9) results in the expected condensation product (see, however, the next section). 

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. 

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). 

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). 

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. 

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. 

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. 

The nucleophilic addition of lithiated allyl phenyl sulfone to nitrones at 0 °C afforded 4-(phenylsulfonyl)isoxazol-idines as major products. The process probably involves the isomerization of the allylsulfonyl moiety of the initially formed hydroxylamine anion to vinylsulfone which then undergoes intramolecular Michael addition. For example, the chiral nitrone 536 afforded isoxazolidine 537 with high diastereoselectivity (Equation 88) <2005T3335>. When the same reaction was carried out in the presence of hexamethylphosphoramide (HMPA) at —80°C, the anti-a-sulfonyl homoallyl hydroxylamine was obtained. 

Alternatively, isoxazolidin-5-yl acetates were obtained by reduction and acetylation of suitable isoxazolidin-5-ones, which, in turn, were prepared by diastereoselective Michael addition of hydroxylamines to unsaturated esters or by nucleophilic addition of enolates to nitrones and subsequent cyclization of the resulting hydroxylamines. For example, the two diastereomeric isoxazolidinones 552 were converted into thymidine analogues 590 (Scheme 146) <1997JOC7430, 1998T6587, 2000TL9239, 2005CRC775>. 

Cyclization by Addition of Amines to Multiple Bonds of Carbohydrate Substrates. A versatile unsaturated aldehydic intermediate derived from D-ribose has been used to synthesize a number of potential glycosidase inhibitors (Scheme 13). Addition of hydroxylamine and then bromine to the enal resulted in the formation of nitrone 57 with 66% diastereoselectivity, and this in turn was readily transformed into various imino-alditols (e.g. 5R-60) by nucleophilic attack followed by reduction. A number of these compounds proved to be good inhibitors of a-L-fucosidases. ... 

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