Acyl hydroxamates amines

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). 

Amines from acyl hydroxamates CONHOAc CH2NH2... 

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. 

BrOP). These active esters react smoothly with amines at room temperature (reaction 9).42 Similarly, supported oximino esters 2743 and hydroxamic esters 2844 undergo facile acyl transfer reactions with amines at room temperature (reaction 10). The spent activating agent can be regenerated many times (by acylation with the appropriate acid chloride) without appreciable loss in activity. 

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). 

N,0-Acyltransferase. The /V-acyl transferase enzyme is believed to be involved in the carcinogenicity of arylamines. These compounds are first V-oxidized, and then, in species capable of their A-acetylation, acetylated to arylhydroxamic acids. The effect of N, O-transacetylation is shown in Figure 7.22. The A/-acyl group of the hydroxamic acid is first removed and is then transferred, either to an amine to yield a stable amide or to the oxygen of the hydroxylamine to yield a reactive N-acyloxyarylaminc. These compounds are highly reactive in the formation of adducts with both proteins and nucleic acids, and N, O -acy I Iransfcrasc, added to the medium in the Ames test, increases the mutagenicity of compounds such as A-hydroxy-2-acetylaminofluorine. 

In the presence of base, acyl derivatives of hydroxamic acids undergo the Lessen rearrangement to yield isocyanates or amines. 

Electrophilic N-aminations have been performed with hydroxylamine-O-sulfonic acid (HOSA)," O-(2,4-dinitrophenyl)hydroxylamine and C>-mesitylenesulfonylhydroxylamine. The use of HOSA is mainly restricted to aqueous reaction media. Imide sodium salts of some heterocycles such as theobromine (88) can be converted to hydrazine derivatives by treatment with 0-(diphenylphosphinyl)hydroxylamine (equation 35)." This reaction has been extended to synthesis of N-arylhyd ines, where R and R are hydrogen, alkyl or aryl (equation 36)." Similarly, trisubstituted hydrazines can be prepared by the use of N-aryl-O-acetylhy oxylamines and secondary amines." A recent publication" concerning the synthesis of l-acyl-2-dkylhydrazines from hydroxamic acids and amines in the presence of activating agents has been found to be erroneous no N—N bond formation occurs under these conditions." ... 

The fourth related rearrangement reaction is the Lossen reaction, which generally occurs by base treatment of 0-substituted hydroxamic acids which possess electron-withdrawing functions at the oxygen atom (e.g. O-acylhydroxamic acids), giving amines via isocyanates (equation 6). Preliminary 0-activation (e.g. O-acylation) of hydroxamic acids is essential for a smooth rearrangement, otherwise it will not occur, ilie Lossen reaction is not as useful as the other three rearrangements since hydroxamic acids are not readily available. 

A further example is the Lossen rearrangement, in which an O-acyl derivative of hydroxamic acid, RCONHOCOR, gives an isocyanate on treatment with hydroxide ion, which in turn may be hydrolysed to the amine. Illustrate this reaction pathway. 

Differently cross-linked poly(methyl methacrylate) (PMMA) (137) has been employed for the synthesis of supported hydroxamic acids 138 after treatment with hydroxylamine, and reacted with acyl chlorides in the presence of pyridine to give the supported hydroxamic acid esters 139, which are suitable as solid acyl transfer reagents when reacting with alkyl and aryl amines (Scheme 7.42) [143]. 

One important variation of this linker is Barany s B AL linker 13, which contains a formyl group [45-51]. Primary amines [45] and O-protected hydroxylamines [52] are attached to this linker by reductive animation. The resulting secondary amines can be acylated and the corresponding secondary amides or hydroxamates cleaved with TFA. Anilines [53] and enamines [54] can be cleaved without needing to be acylated. 

Trityl amine [78], -thiol, -hydrazine [86] and -hydroxylamine [87] linkers are sufficiently nucleophilic to be acylated or alkylated. Such supports are useful tools for the synthesis of amides, thiols, hydrazides and hydroxamates. 

Hydroxamic acids. Oximino esters (1) are reduced by 1 equiv. of BH3 in THF at -78 to hydroxamic acids (2). The reaction involves an O to N acyl thift, (a) (b). Ketoximes are reduced completely to amines by excess diborane... 

This reaction was first reported by Lossen in 1872. It is a thermal or alkaline conversion of hydroxamic acid into an isocyanate via the intermediacy of its O-acyl, sulfonyl, or phosphoryl derivative. In the presence of water, amine, or alcohol, the isocyanate is converted into amine, urea or urethane, respectively. Therefore, this reaction is generally known as the Lossen rearrangement. Occasionally, it is also referred to as the Lossen reaction, Lossen degradation, or Lossen transformation. ... 

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