Hydroxylamine sterically hindered

The main advantages of preparation of hydroxylamines through Af-alkylation of other hydroxylamines are versatility and predictable stereochemical outcome that allow the introduction of the hydroxyamino group at advanced stages of multistep syntheses. The use of nucleophilic displacement is however problematic for sterically hindered alkyl halides and sulfonates. Apart from several examples mentioned below, alkylation of hydroxylamines with tertiary alkyl halides does not take place. 

Intermolecular reactions of hydroxylamines with secondary alkyl halides and mesylates proceed slower than with alkyl triflates and may not provide sufficiently good yield and/or stereoselectivity. A nseful alternative for these reactions is application of more reactive anions of 0-alkylhydroxamic acids or 0-alkoxysulfonamides ° like 12 (equation 8) as nucleophiles. The resulting Af,0-disubstituted hydroxamic acids or their sulfamide analogs of type 13 can be readily hydrolyzed to the corresponding hydroxylamines. The same strategy is also helpful for synthesis of hydroxylamines from sterically hindered triflates and from chiral alcohols (e.g. 14) through a Mitsunobu reaction (equation 9). 

Direct oxidation of primary amines with peroxide oxidants does not provide appreciable yield of hydroxylamines. As was mentioned above, oxidation of secondary amines usually proceeds smoothly giving moderate to good yields of iV,iV-disubstituted hydroxylamines. Oxidation of sterically hindered secondary amines such as 125 (equation 88) can also be done with peracids . Further oxidation of the resulting Af,A-disubstituted hydroxylamines 126 with an excess of m-chloroperbenzoic acid is known to end up with the corresponding nitroxyl radicals of type 127 (equation 88) ° although the reaction can be stopped at the hydroxylamine stage. 

Hydroxylamines formed as metabolites of secondary alicyclic amines may also be converted to nitroxide radicals. For example, the sterically hindered 2,2,6,6-tetramethylpiperidine... 

A few observations can be made concerning the synthetic application of this fragmentation reaction. The hydroxylamine version seems to take place even in sterical hindered a,/8-epoxyketones. Precise reaction conditions, are also necessary to make the procedure successful [38]. 

Conversion of B0C2O (65) with hydroxylamine into the related B0C-ONH2 leads to a reagent of 1.5-2.5 enhanced reactivity. This reagent can be prepared in situ and used for acylating sterically hindered amino groups.b ... 

The most available and therefore the most widely used aminating agent is HOSA, obtained from hydroxylamine and oleum (82OPP265). However, it has some drawbacks. First, it can be used in aqueous media, but only occasionally in aqueous alcohol or in dimethylformamide (DMF), and in the latter cases, yields of N-aminoazoles are lower. Second, HOSA is readily decomposed by water and especially by alkali, and its anion, which takes part in the reaction, is not very electrophilic. For these reasons, HOSA does not give satisfactory results on amination of sterically hindered and slightly nucleophilic N-anions. 

In one approach (Fig. 2, route C) the resolution of the racemic anhydride 6 was attempted via the regioselective opening with various chiral auxiliaries, however, even with sterically hindered alcohols the diastereoisomeric esters could not be separated on a technical scale by crystallization. In contrast, good selectivity was obtained with (S)-phenylethyl hydroxylamine. This pathway, however, failed due to problems at a later stage. 

Oximes of sterically hindered ketones can be obtained, in very slow reactions but often in quantitative yield, by treatment with hydroxylamine hydrochloride in the presence of an excess of potassium tert-pentyl oxide at room temperature.950... 

Umpolung Cross-Coupling Johnson and coworkers reported electrophilic amination of organozinc nsing o-benzoyl hydroxylamine as electrophilic nitrogen (Scheme 20.26) [56]. This process allows the facile synthesis of sterically hindered amines via ort/io-metalation/frans-metalation/catalytic amination. 

Deprotonation of Al,<9-bis(trimethylsilyl)hydroxylamine with n-butyllithium or potassium hydride at low temperature yields the nitrogen centered anion Al,<9-bis(trimethylsilyl)hydroxyl-amide. At higher temperatures the oxyanion Al,A -bis(tri-methylsilyl)hydroxylamide is formed by rearrangement. Each reacts with acyl chlorides chemospecifically by M-acylation and 0-acylation, respectively. The oxyanion also reacts with silyl halides, methyl iodide, and sulfonyl chlorides chemospecifically on oxygen. In a Peterson-type one-pot reaction, oximes and oxime derivatives can be prepared effectively from the N-anion of iV,0-bis(trimethylsilyl)hydroxylamine and an aldehyde or ketone (eq 5). Oximes of sterically hindered ketones can be formed in high yields by this procedure. 

Hydroxylamines are multifunctional. They can act both as C-radical scavengers and as hydroperoxide decomposers. They reach full effect even in low concentrations without negative effects on color. That is why hydroxylamines are mainly used as processing stabilizers for color-critical applications. Generally, hydroxylamines are combined with sterically hindered amines [538]. 

Interception of free radicals by radical scavengers and/or hydroperoxide decomposers, such as sterically hindered amines and hydroxylamines... 

Another related class to sterically hindered amines are sterically hindered amine ethers. These compoimds are equally capable of forming nitroxyl radicals, as shown in Figure 20.4. Moreover, for example, the ethyl ethers decompose thermally into a hydroxylamine compound and ethene. 

In this case, differences in the reaction directions conld be explained by steric hindrances relative to attack of the triple bond by nitrogen atom when R =Me, as it takes place, for example, in acylation of N-monosubstituted hydroxylamine [407], In this process, nitrogen is usually a more active nucleophilic center, but if the access to it is sterically hindered, the acylation can occur at the oxygen atom also. However, actually, the situation is even more complicated when R =Ph, that is, in the case of even higher steric encumbrances, the same reaction leads to a mixture of N- and O-adducts (Schane 1.202) [406],... 

In 1998, Dankwardt used for the first time ester linkers for the synthesis of hydroxamates [116]. The synthesis of hydroxamates and hydroxamic acids is a known synthesis on solid supports but former approaches used special hydroxamate linkers that had to be synthesized in previous reactions. The methodology published by Dankwardt is very simple because ArgoGel-OH resins can be used without further derivatization to bind protected amino acids 88 in the presence of coupling reagents. Hydroxamic acids 90 were cleaved by the addition of hydroxylamine in 21% (sterically hindered amino acids) to quantitative yields (glycin. Scheme 12). 

For color-critical applications requiring phenol-free stabilization synergistic mixtures of sterically hindered amines (HA (L)S) and a hydroxylamine-based stabilizer, used during melt processing, with or without an organophosphate or organo-phosphonite, can be used to avoid the undesired discoloration typically associated with the oxidation of the phenolic antioxidants into products with quinoid stmctures. ... 

In the case of the acyclic hydrazine 141, 142 and hydroxylamine 144 derivatives, both nitrogen inversion and hindered rotation is present. The results have been interpreted in terms of nitrogen inversion 85,86,92) in agreement with the magnitude of the substituent effects in the series 141, 143—145 which are similar to those obtained for the corresponding pyrrolidine derivatives (95—97, 99). However, steric effects would favour hindered rotation about the N—0 bond as the observed (NMR) process in acyclic hydroxylamines 112>. 

The Schmitz reaction can be unsuccessful in sterically demanding environments in such circumstances, the electrophilic aminating agent reacts faster with ammonia than with hindered ketones <1965JA2665>. Consequently, the synthesis of 2-azi-camphane 64, a compound which is unobtainable under standard conditions <1996TL6647>, was achieved by slow diaziridination of camphor imine hydrochloride 63 (rather than camphor itself) with hydroxylamine-O-sulfonic acid (HOSA)-ammonia, followed by iodine-mediated oxidation (Scheme 22) <2001S379>. 

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