Acyl hydroxamates hydroxamic acids

Treatment of O-acylated hydroxamic acids with base provides isocyanates. 

A-Alkylhydroxylamines react with substituted allyl acetates (e.g. 15, equation 11) in palladium catalyzed addition-elimination reactions giving the corresponding A-alkyl, A-allylhydroxylamines 16. The reaction proceeds with high regioselectivity but complete racemization. A similar reaction with 0-acyl hydroxamic acids has been carried out using allylic a-alkoxycarbonyloxyphosphonates. ... 

A clear-cut molecular relay system is materialized with the combination of two nucleophile moieties such as hydroxamic acid and imidazole introduced in a polymer (38, 40, 82). Hydroxamate anion has a high nucleophilicity but deacylation of the acylhydroxamate is very slow. The significance of the deacylation step in the hydrolysis in polymer catalyst is pointed out in several works, for example, the deacylation of acetylated poly(4(5)-vinylimidazole) (83,84) and the aminolysis of nitrophenyl ester of poly(styrene-co-acrylic acid) (85—87). To promote the deacylation velosity of the acylated hydroxamic acid imidazole moiety is introduced in the hydroxamic acid-containing polymer. The polymers are shown in tire following page. 

In addition, as is shown in Table 13, the deacylation which is represented in kd is increased by a factor of more than 103 in poly(PHA-IM-am), compared with poly(PHA-am). As is observed in the deacylation which is catalysed by imidazole moiety in the case of a-chymotrypsin, the catalysis by imidazole moiety in the deacylation of the acylated hydroxamic acid is considered. The turnover number, turnover hi poly(PHA-IM-am) is also high. The deacylation rate of poly(PHA-IM-am)... 

Cyclocondensation of malonyl derived O-acyl hydroxamic acid derivatives 6, in the presence of phosphazene super base P2-r-Bu 7, gave rise to isoxazolone carboxylic esters 8 <03TL7763>. 

Rearrangement of O-acyl hydroxamic acid derivatives with base or heat to amines or urea derivatives (via isocyanates), or rearrangement of carboxylic acids via their hydroxamic acids to amines (see 1st edition). 

The most significant synthetic route to these compounds is the condensation of A-(a-hydroxy-acyl)hydroxamic acids with carbonyldiimidazole (Equation (23)) or aromatic aldehydes (Equation... 

Clark, A.J., Al-Faiyz, Y.S.S., Patel, D. and Broadhurst, M.J. (2001) Rearrangement of unactivated A-alkyl-O-benzoyl hydroxamic acid derivatives with phosphazene bases. Tetrahedron Letters, 42, 2007-2009 Clark, A.J., Patel, D. and Broadhurst, M.J. (2003) Base-mediated reaction of A-alkyl-O-acyl hydroxamic acids synthesis of 3-oxo-2,3-dihydro-4-isoxazole carboxylic ester derivatives. Tetrahedron Letters, 44, 7763-7765. 

Lessen (reaction of an 0-acyl hydroxamic acid with formation of an 0-leaving group)... 

Molz et al. synthesized monomers containing the cytostatic bis(2-chloroethyl)amino group linked via urethane or 0-acylated hydroxamic acid bonds to polymerizable methacrylic acid derivatives. Copolymers with hydrophilic monomers, e.g. 2-(methyl-sulfinyl)ethyl methacrylate, yielded biologically active compounds of the structure... 

Acyl derivatives, RCO—NH—OH and HjN—O—CO—R, are named as A-hydroxy derivatives of amides and as O-acylhydroxylamines, respectively. The former may also be named as hydroxamic acids. Examples are A-hydroxyacetamide for CH3CO—NH—OH and O-acetylhydrox-ylamine for HjN—O—CO—CH3. Further substituents are denoted by prefixes with O- and/or A-locants. For example, C5H5NH—O—C2H5 would be O-ethyl-A-phenylhydroxylamine or A-ethox-ylaniline. 

In 2000, an efficient three-step procedure for the synthesis of 5-substituted 3-isoxazolols (without formation of undesired 5-isoxazolone byproduct) was published. The method uses an activated carboxylic acid derivative to acylate Meldrum s acid, which is treated with A,0-bis(ten-butoxycarbonyl)hydroxylamine to provide the N,0-di-Boc-protected P-keto hydroxamic acids 14. Cyclization to the corresponding 5-substituted 3-isoxazolols 15 occurs upon treatment with hydrochloric acid in 76-99% yield. 

Because of the great range of structures containing cyclic hydroxamic acid functions it is difficult to give a concise summary of the available synthetic methods. Nevertheless, the vast majority of published syntheses depend on condensation reactions involving only familiar processes of acylation or alkylation of hydroxylamine derivatives. The principles of such syntheses are outlined in a number of typical examples in Section III, A but no attempt has been made to cover all reported cases. 

Quinazoline hydroxamic acids (26) can be prepared by acylation of an o-aminobenzohydroxamic acid (25). An alternative procedure... 

In one particular example, an interesting intramolecular acylation occurred. Reduction of cis-iVi-acetyl-o-nitrobenzylideneoxindole (55) gave rise to a cyclic hydroxamic acid, assigned structure 56. 

Acyl derivatives of cyclic hydroxamic acids, like all 0-acyI derivatives of hydroxylamine, show infrared absorption because of the acjd carbonyl at characteristically high frequencies, generally near 1800 The range of frequencies is similar to that found for... 

A mixture of 3-hydroxy-4-phenylfurazan and 1,2,4-oxadiazole 243 was prepared from a-phenyl-a-hydroximino hydroxamic acid by acylation and subsequent treatment with 15% aqueous NaOH (Scheme 164) (25G201). The reaction of tetraacetate 244 with sodium acetate hydrate in glacial acetic acid at 70°C gives 3,4-dihydroxyfurazan (9%) (92URP1752734). a-Hydroximino ester 245 reacts with hydroxylamine to form furazan 246 in 25% yield (Scheme 164) (79JHC689). 

Some hydroxamic acids of the isoxazole series also display a marked antituberculosis activity. The penicillin derivatives, acylated with isoxazole carboxylic acids possess an antibacterial activity similar to that of penicillin, against resistant species.Among other isoxazole derivatives possessing activity one should especially mention the sulfonamides of this series, and 4-hydroxyiminoisoxazol-5-... 

In the Lossen reaction a hydroxamic acid derivative (usually an 0-acyl derivative) is deprotonated by base, and rearranges via migration of the group R to give an isocyanate 2. Under the usual reaction conditions—i.e. aqueous alkaline solution—the isocyanate reacts further to yield the amine 3. The Lossen reaction is closely related to the Hofmann rearrangement and the Curtins reaction. 

The intramolecular /zetero-Diels-Alder reactions of 4-O-protected acyl-nitroso compounds 81, generated in situ from hydroxamic acids 80 by periodate oxidation, were investigated under various conditions in order to obtain the best endo/exo ratio of adducts 82 and 83 [65h] (Table 4.15). The endo adducts are key intermediates for the synthesis of optically active swainsonine [66a] and pumiliotoxin [66b]. The use of CDs in aqueous medium improves the reaction yield and selectivity with respect to organic solvents. 

The 0-acyl derivatives of hydroxamic acids give isocyanates when treated with bases or sometimes even just on heating, in a reaction known as the Lossen rearrangement. The mechanism is similar to that of 18-13 and 18-14 ... 

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

Much more important than these reactions, however, are the reactions of CDI and its analogues with carboxylic acids, leading to AAacylazoles, from which (by acyl transfer) esters, amides, peptides, hydrazides, hydroxamic acids, as well as anhydrides and various C-acylation products may be obtained. The potential of these and other reactions will be shown in the following chapters. In most of these reactions it is not necessary to isolate the intermediate AAacylazoles. Instead, in the normal procedure the appropriate nucleophile reactant (an alcohol in the ester synthesis, or an amino acid in the peptide synthesis) is added to a solution of an AAacylimidazole, formed by reaction of a carboxylic acid with CDI. Thus, CDI and its analogues offer an especially convenient vehicle for activation of... 

---