Hydroxamic acids Lossen reaction

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 Lossen reaction is of limited importance in synthetic organic chemistry one reason for that is the poor availability of the required hydroxamic acid derivatives. Some hydroxamic acids are even unreactive." ... 

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 ... 

As early as 1899, 8tieglitz proposed a tetrahedral intermediate for the hydrolysis of an imino ether to an amide. Thns it was clear qnite early that a complicated overall transformation, imino ether to amide, would make more sense as the result of a series of simple steps. The detailed mechanism proposed, althongh reasonable in terms of what was known and believed at the time, wonld no longer be accepted, but the idea of tetrahedral intermediates was clearly in the air. 8tieglitz stated of the aminolysis of an ester that it is now commonly snpposed that the reaction takes place with the formation of an intermediate prodnct as follows referring to work of Lossen. (Note that the favored tautomer of a hydroxamic acid was as yet unknown.)... 

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... 

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). 

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 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,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... 

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. 

An earlier proposed structure for the bis oxime of N-acetylisatin was shown to be erroneous. The correct structure (60) was deduced from its chemical reactions and by synthesis from methyl o-N-acetamidobenzoyl-formate and hydroxylamine.162 The hydroxamic acid (60) underwent a Lossen reaction to form the 4-isocyanato derivative, which cyclized to the oxadiazoloquinazoline 61. The structure of the latter was confirmed by an X-ray analysis.163... 

Conversions of compounds 116, 120 and 123 into IP-2-ones described above belong to Hofmann-, Curtius- and Lossen-type reactions. Therefore the parent amides, hydroxamic acids and o-aminopyridinecarboxylic acid azides, may formally be regarded as derivatives of monoaminopyridines. The above compounds rearrange into o-diamines with various degrees of ease, while benzenesulphonate 121 is transformed into intermediate isocyanate 122 under extremely mild conditions (68JOC2543). 

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. ... 

The Lossen rearrangement, discovered in 1872, is the transformation of a hydroxamic acid derivative to an isocyanate by using an activated hydroxamic acid 71 as the key intermediate tScheme 4.27)Z This activation can be achieved by O-acylation, O-arylation, or O-sulfonylation. From a mechanistic point of view, a base or a thermal treatment can initiate the reaction, giving a rearrangement of the corresponding anion 72 via a three-membered ring transition state 73. 

Hydroxamic acid 3 can be converted to activated hydroxamate 2 via reaction with a variety of electrophilic reagents. The Lossen rearrangement is then initiated by exposure of 2 to base or heat resulting in anion 10. Through a fast subsequent transformation via cyclic intermediate 12, isocyanate 1 is generated. This isocyanate 1 can be further converted to urea 13 or amine 15. 

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