O-Acylated hydroxamic acids

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

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). 

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. 

Hence, the implication of combinatorial chemistry for high throughput generation of structurally diverse hydroxamic acids is self-evident. Several solid-phase approaches for their syntheses have been reported,1 7-11 the majority of which are based on the anchoring of iV-hydroxyphthalimide onto an appropriate solid support. After hydrazine-mediated /V-dcprotcction, /V-acylation of the resin-bound hydroxylamine would yield the desired O-anchored hydroxamic acid, which is typically released by acidolysis. 

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). 

P-Lactams.1 A biomimetic synthesis of /3-lactams from chiral amino acids such as L-serine has been developed by Mattingly and co-workers. The protected amino acid (1) is first converted into the O-alkyl or O-acyl hydroxamate (2), which undergoes cyclization to derivatives of l-hydroxy-2-azetidinones on treatment with triphenylphosphine-carbon tetrachloride. This cyclization is also possible with triphenylphosphine-diethyl azodicarboxylate.2 The final step involves reduction of the N—OH group with TiClj.3 The advantage of this method over that of Wasserman (9,428), which involves cyclization of /3-haloamides, is that a strong base such as NaH is not required. 

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. 

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. 

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. 

What about the isomers of the hydroxamic acids, the 0-acyl derivatives of hydroxy-lamine Having mentioned early in this study that N-methylhydroxylamine is more stable than its O-isomer, we are thus intrigued by the finding that iV-benzoylhydroxylamine (benzohydroxamic acid), or at least its A -f-butyl derivative, is less stable than its corresponding O-benzoyl isomer as shown by the thermal isomerization of the former to the latter, equation 55. 

Preparation of hydroxamic acids through acylation of hydroxylamines is a common and straightforward reaction. However, acylation of iV-alkylhydroxylamines is known to proceed on both the oxygen and nitrogen atoms and can result in mixtures of N- and 0-acylation products . In iV-alkylhydroxylamines possessing a bulky " or an electron-poor substituent on nitrogen atom, O-acylation is predominant. 

Intramolecular addition of hydroxylamines and hydroxamic acids to the non-activated double bonds is possible through oxidative cyclization. Reaction of O-Acyl fi,y-unsaturated hydroxamates (e.g. 56, equation 38) with bromine provides 3,4-substituted iV-hydroxy -lactams such as 57 with high diastereoselectivity. Analogous reaction of O-benzyl hydroxylamine 58 (equation 39) with iodine results in five-membered cyclization with 2 1 ratio of diastereomers. ... 

Multicomponent reactions have recently become one of the favored methods to prepare pharmacologically important compounds. Ugi condensations with O-protected hydroxylamines have been successfully performed in THE using ZnCl2 as activating agent (Scheme 56). This synthetic strategy opens up the route to a very convergent assembly of internal hydroxamic acid derivatives (A-acyl-A-hydroxypeptides 109)" . 

O-linked polymer-bound Af-substituted hydroxylamines are prepared by reduction of resin-bound oximes with borane-pyridine complex in the presence of dichloroacetic acid (Scheme 94). Other reducing systems commonly used for imine or oxime reduction are ineffective, including borane-pyridine in the presence of acetic acid. Subsequently, the A-substituted products are acylated and cleaved from the resin to afford Af-substituted hydroxamic acids 220. ... 

To improve the product yields in Lossen rearrangement, mesyloxycarbamates have been used as alternative reagents . The use of A-acyl-O-mesylhydroxamic acids (558) avoids the competing formation of self-condensation by-products (560). These are obtained from the accumulation of isocyanate (559) before complete consumption of the hydroxamic acid (557) as observed in the classical Lossen rearrangement (equation 249). 

Hydroxamic acids 1 (Scheme 1) present both N- and O-centers in their reactions with electrophilic centers. However, commonly alkylation/acylation/phosphorylation occur via the O-center. The ionized hydroxamate is of course more reactive than the unionized form, as is the case with oximes and the corresponding oximates. 

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