Hydroxamic acid. Lossen rearrangement

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 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)... 

The Lossen rearrangement of an hydroxamic acid under basic conditions is a variant of the Hofmann reaction in which the aroyloxy group fills the role of the bromine.314... 

Originally, the Lossen rearrangement specifically referred to the conversion of a hydroxamic acid to an amine with the loss of carbon dioxide ... 

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). 

To improve the scope of the Lossen rearrangement, other structural analogous substrates to hydroxamic acids have been tested. Af-Phosphinoylhydroxylamines are the phosphorus analogues of hydroxamic acids and, when suitably activated, they undergo a Lossen-Uke rearrangement in the presence of base. 

Azine approach. DCC dehydration of the 3-oxoquinazoline-4-hydroxamic acid (602) gives an isocyanate (603) via a Lossen rearrangement addition of the AT-oxide oxygen to the isocyanate group effects the cyclization. The same product is formed by the phosgene reaction with 4-amino-2-methylquinazoline 3-oxide (76TL3615). 

However, hydroxamic acids, such as 474, react with carbodiimides to produce a nitrene intermediate 475, which undergoes the Lossen rearrangement to give an isocyanate 476." " The latter reacts with the starting hydroxamic acid to give the adduct 477. 

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. 

The Lossen reaction 4 5 is the rearrangement of hydroxamic acids, which are prepared from acids, acyl chlorides and esters. It is usually conducted under alkaline conditions. Initial attachment of electron-withdrawing groups to the oxygen atom of the hydroxamic acids is essential to conduct the reaction the... 

N// -Dicyclohexylcarbodiimide (DCC) also mediates the Lossen reaction of hydroxamic acids under neutral conditions.In the conversion of the hydroxamic acid (209) to the tricyclic compound (210), the Lossen rearrangement is accompanied by an intramolecular cycloaddition (equation 54). 

A combination of triphenylphosphine and diethyl azodicarboxylate (the Mitsunobu reagent) is useful for the rapid conversion of aromatic hydroxamic acids (211) to 0-(yV-arylcarbamyl)hydroxamates (212), products of the Lossen rearrangement. In some cases, a spontaneous second Lossen rearrangement occurs to give diarylureas (213), as shown in Scheme 33. The yields of (212) and (213) are 70-85%. The intermediacy of the phosphonium salts (214) has been suggested. 

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. 

Lossen rearrangement The O-acyl derivative of a hydroxamic acid gives an isocyanate when treated with a base or, sometimes, just heat. 

Lossen Rearrangement,78 The thermal decomposition of hydroxamic acid derivatives leads to isocyanates or, in aqueous solution, to amines. This reaction is usually called the Lossen rearrangement. Its mechanism... 

Lossen rearrangement. Conversion of a hy-droxamic acid, via a Hofmann-like arrangement, to an amine containing one less carbon than the original hydroxamic acid. 

Nucleophilic Attack at Other Atoms. A Lossen rearrangement occurs when aromatic hydroxamic acids are allowed to react with the triphenylphosphine-diethyl azodicarboxylate complex in the presence of ethanol, to give the hydroxamates (49). 

The hydroxamic acid function in most alicyclic and aromatic compounds is stable to hot dilute acid or alkali, and derivatives cannot undergo normal base-catalyzed Lossen rearrangement. Di Maio and Tardella,112,113 however, have shown that some alicyclic hydroxamic acids when treated with polyphosphoric acid (PPA) at 175°-195° undergo loss of CO, C02, or H20, in a series of reactions which must involve early fission of the N—0 bond, presumably in a phosphoryl-ated intermediate. Thus, l-hydroxy-2- piperidone 108) gave carbon monoxide, 1-pyrroline (119), and the lactams (120 and 121). The saturated lactam is believed to be derived from disproportionation of the unsaturated lactam. 

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