Hydroxamic halides

Rearrangement of hydroxamic acids and acyl halides (Lossen)... 

Formally, they can all be viewed as derivatives of hydroxylamine, H2N—OH indeed, oximes can be prepared by the addition of hydroxylamine to aldehydes and ketones (equations 1 and 2), and hydroxamic acids by its reactions with acetyl halides and esters (equations 3 and 4). ... 

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). 

Hydroxamic acids undergo facile nucleophilic Ai-arylation with activated aryl halides such as 31 (equation 22). While hydroxamates are known to be ambident nucleophiles in alkylation reactions, arylation of hydroxylamines results exclusively in Ai-substituted hydroxamates of type 32 (equation 22)". ... 

The general approach to 0-arylation of hydroxylamines involves N-protection followed by O-arylation. Activated aryl halides and heteroaryl halides easily alkylate oxime salts (equation 25), N-aUcyl hydroxamic acids and N-hydroxysuccinimide . N-Hydroxyph-thalimide can be also 0-phenylated through a reaction with diphenyliodonium salt, although in lower yield . ... 

As illustrated by the examples in Table 3.9, resin-bound 4-alkoxybenzylamides often require higher concentrations of TFA and longer reaction times than carboxylic acids esterified to Wang resin. For this reason, the more acid-sensitive di- or (trialkoxy-benzyl)amines [208] are generally preferred as backbone amide linkers. The required resin-bound, secondary benzylamines can readily be prepared by reductive amination of resin-bound benzaldehydes (Section 10.1.4 and Figure 3.17 [209]) or by A-alkyla-tion of primary amines with resin-bound benzyl halides or sulfonates (Section 10.1.1.1). Sufficiently acidic amides can also be A-alkylated by resin-bound benzyl alcohols under Mitsunobu conditions (see, e.g., [210] attachment to Sasrin of Fmoc cycloserine, an O-alkyl hydroxamic acid). 

Hydroxylamines and hydrazines can be acylated on insoluble supports using the same type of acylating agent as is used for the acylation of amines [146-149]. Because of their higher nucleophilicity, hydroxylamines or hydrazines can be acylated more readily than amines, and unreactive acylating agents such as carboxylic esters can sometimes be successfully employed (Table 13.10). Polystyrene-bound O-alkyl hydroxamic acids can be N-alkylated by treatment with reactive alkyl halides and bases such as DBU (Entry 5, Table 13.10). 

The simpler examples are readily hydrolysed in aqueous solution, and therefore react with sodium hydrogen carbonate and also give the ester test they may be confirmed by applying the hydroxamic ester test (Section 9.5.3, p. 1222). Carbonyl adsorption is apparent in the infrared spectrum at about 1820 cm-1 and at about 1760cm-1. It should be noted that aromatic anhydrides and higher aliphatic anhydrides are not readily hydrolysed with water and are therefore effectively neutral (Section 9.5.3, p. 1218). The final characterisation of the acid anhydride is achieved by conversion into a crystalline carboxylic acid derivative as for add halides. 

The 1,4-dinucleophilic building blocks used most are 1,2-disubstituted ethanes of the type HXCHiCHjYH, semicarbazides, thiosemicarbazides, hydroxamic acid amides, amidrazones, and 1,2-disubstituted aromatic and heteroaromatic compounds. 1,1-Dielectrophilic building blocks preferentially used are perfluorinated carboxylic acids and their derivatives, such as acid halides, anhydrides, imidoesters, nitriles, perfluoroalkyl chlorosul-... 

Hydroxamic acids may sometimes be prepared from acyl halides and hydroxy lamine... 

Hydroxamic acid halides (a-halooximes) are readily dehydrohalogenated by bases, generating the nitrile oxides. Sodium carbonate or alkali hydroxides,156,222 225 amines,85,225-230 and sodium acetate28 are common... 

The Fukuyama amine synthesis can also be applied to protected hydroxylamines and hydroxamates.33 Various protected hydroxylamines 54 undergo clean reaction with NsCl giving 55. This N, O-protected hydroxylamine 55 may then react with a variety of alkyl halides to give fully protected hydroxylamines 56. 

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