Isocyanates Lossen rearrangement

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 ... 

The amidase from Rhodococcus erythopolis strain MP50 was nsed to selectively convert racemic 2-phenylpropionamide into 5 -2-phenylpropiohydroxamate. This was converted into the isocyanate by Lossen rearrangement and then by hydrolysis to S-( )-phenylethyl-amine (Hirrlinger and Stolz 1997). 

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). 

The migration of the 0-r-butoxy group with concomitant generation of the 0-t-butoxy isocyanate 562 was observed in the Lossen rearrangement of 561 induced by base deprotonation " (equation 250). 

The hydroxamate anion 566 is invoked as intermediate in the formation of urea 568 from the iV-tosylated /3-lactam 564 by a Lossen rearrangement in the presence of a secondary amine 565 (equation 252). Apparently, attack of amine in an S/v2 fashion at the C(4) carbon of the /3-lactam 564 opened the ring to form hydroxamate anion 566, which then initiated a facile Lossen rearrangement to isocyanate 567 trapped with another molecule of base to give 568. 

Treatment of amides with bromine in alkaline medium promotes the Hofmann rearrangement, which may or may not involve a free nitrene intermediate." The oxidation of primary amides with lead tetraacetate and the resulting Lossen rearrangement also produces isocyanates, with the possible intervention of an acylni-... 

As with thtHofmann, Schmidt and Lossen Rearrangements, there is a common isocyanate intermediate. 

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. 

Amides react with alkaline hypochlorite or hypobromite solutions to form primary amines having one less carbon atom. The reaction involves the hydrolysis of an isocyanate, which is seldom isolated. Isocyanates are also intermediates in the Curtius and Lossen rearrangements (methods 447 and 448). Although diese methods have a common mechanism and intermediate, they involve three separate and distinct types of starting materials and are, therefore, treated individually. A comparison of these reactions has been made. A detailed discussion of the Hofmann reaction, which includes conditions, typical procedures, and compounds prepared thereby, has been presented. ... 

The acyl azide undergoes a rearrangement similar to the Hofmann rearrangement (method 446) and to the Lossen rearrangement (method 448). This step is carried out in inert solvents like benzene and chloroform to give the isocyanate directly or in solvents like alcohol and water which will react with the isocyanate to form urethanes and ureas. 

The rearrangement has a mechanism similar to those of the Hofmann rearrangement of amides, the Lossen rearrangement of acylhydroxamic esters, the Schmidt rearrangement of carbonyl compounds and the Wolff rearrangement of diazoketones. Evidence concerning the mechanism of one can often be applied to the others, and the whole family has been reviewed briefly . Sometimes the distinction is made that the conversion of an acyl azide into an isocyanate or urethane is the Curtius rearrangement whereas the overall sequence is the Curtius reaction, but usually the former name is used for both processes. 

The Hofmatm, Curtius, Schmidt and Lossen rearrangements generally involve nucleophilic migrations from a carbon to an electron deficient nitrogen center (Scheme 5), giving isocyanates as the initial products, which undergo further reactions as already shown in Scheme 2. 

The Lessen reaction of peptide carboxylic acids has teen investigated in order to determine the carboxy terminal amino acid residue of peptides." The procedure first involves the formation of 0-pivaloylhydroxamic acids (187) by condensation of peptide carboxylic acids (184) with 0-pivaloylhy-droxylamine (185) using a water soluble carbodimide, l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (186). The Lossen rearrangement of (187) occurs at pH 8.5 and 50 C to give a mixture of isocyanates (188) and their reaction products, which, on acidic hydrolysis, afford the aldehydes (189), ammonia and amino acids, as shown in Scheme 30." Identification of aldehydes determines the C-terminal amino acids of the original peptides. 

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... 

Other lH-2,3-dihydro 2-oxo compounds have been prepared by more specialized routes. Reaction of quinoxaline N-oxide (61) with phenyl isocyanate gives a mixture of anilinoquinoxaline 62 and the (presumably) derived diphenyl oxo compound 63. Recently it has been shown that the alloxazine derivative (64) on treatment with di-n-butylamine undergoes a Lossen rearrangement to give the 2-oxo compound 65. Alkali treatment of compound 65 gives the 1,3-unsubstituted product 59. 

A practical and general strategy towards such heterocycles from penam precursors was recently disclosed [129, 130] (Scheme 73). Hydroxamic acids 249, formed by cleavage of the P-lactam ring of the penicillinates 248 with hydroxylamine, underwent a smooth Lossen rearrangement in the presence of A/, iV-diethylaminopropyne. The isocyanate intermediates 250 immediately cyclised to give the desired compounds 251 without racemization. 

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. 

The use of azides in the Curtius reaction is hazardous and the utility of the Hoffman and Lossen rearrangements is limited to preparation of aliphatic isocyanates, as aqueous media are employed (aromatic isocyanates react readily with water to form substituted ureas). Tertiary butyl hypochlorite can be used for non-aqueous Hoffman rearrangements but is costly. In practice mostly phosgenation of a primary amine is commercially important ... 

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. 

Unlike hydroxamic acids, A -hydroxyimides form stable 0-phosphoryloxy and O-sulfonyl derivatives. These hydroxyimides can be prepared from hydroxamic acid and isocyanates. As an example, cyclic A/-hydroximide 22 was prepared from dihydroxamic acid 20 through Lossen rearrangement and followed by self-condensation of intermediate 21. 

Carbamates are also formed by one-stage, two-step processes involving isocyanates as intermediates and precursors. Thus, carbamates are prepared under modified Hofmann rearrangement conditions, using NBS/NaOMe as the reagent [443], by Curtius rearrangement of the acyl azide if the reaction is carried out in alcohol, by the reaction of amides with lead tetraacetate [444], or by the Lossen rearrangement, if the carbamates are not sensitive to the presence of base. 

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