Lossen rearrangements intermediates

Benzenesulfonyloxy-1 //-pyrrolo[3,4-/>]quinoxaline-1,3(2F/)-dione (591) gave //-phenyl-3-(A( -phenylureido)-2-quinoxalinecarboxamide (592) (PI1NH2, PhH, 20°C, 6 h 82% the mechanism probably involved Lossen rearrangement at an intermediate stage but remains unprove) A(-p-tolyl-3-(A( -p-tolyl-ureido)-2-quinoxalinecarboxamide (87%) was made similarly using p-toluidine. ... 

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. 

Compounds containing neutral, monovalent nitrogen atoms are known as nitrenes. The parent structure, NH, is also called imidogen. Because most stable compounds of neutral nitrogen have a valence of 3, it is no surprise that nitrenes typically are very short lived, reactive intermediates. A short history of nitrenes has been presented by Lwowski who points out that they were first proposed by Tiemann in 1891 as transient intermediates in the Lossen rearrangement. 

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. 

These reactive intermediates were proposed first for the Lossen rearrangements in 1891 by Tiemann b and for the photochemical decomposition of hydrazoic acid in 1928 by Beckman and Dickinson 2>. The chemistry in this field, which attracted little interest for a long time, was stimulated by the development of carbene chemistry. In the last fifteen years, beginning with a summary by Kirmse 3> in 1959, excellent reviews on nitrene chemistry appeared 4-12),... 

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. 

Nitrenes are also obtained as reaction intermediates in Hofmann, Schmidt and Lossen rearrangements. 

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. ... 

A -[(Methanesulfonyl)oxy]phthalimide undergoes a ring-expansion reaction with aqueous ammonia at room temperature to afford quinazoline-2,4(l//,3/f)-dione via a Lossen rearrangement. 2-Ureidobenzamide can be isolated as an intermediate when the reaction is performed under mild conditions and further cyclized to quinazoline-2,4(l//,3//)-dione by heating (cf. p 12). 

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. 

The ammonolysis of A-[(phenylsulfonyl)oxy]quinolinimide at room temperature yields, presumably via an intermediate Lossen rearrangement, a mixture of 3-pyridylurea-2-carboxamide and pyrido[3,2-t/]pyrimidine-2,4(177,3//)-dione. A similar reaction occurs with hydrazine or with hydroxylamine hydrochloride to give the 3-amino or 3-hydroxy compound.425... 

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. 

The reaction between the benzohydroxamate anion (109) and bis(2,4-dinitrophenyl)phosphate (110) has been examined kinetically, and the products were characterized by mass and NMR spectroscopies. The phosphate (110) underwent nucleophilic attack of (109) on phosphorus, giving 2,4-dinitrophenolate and an unstable intermediate (111) that underwent the Lossen rearrangement to alford phenylisocyanate, aniline, diphenylurea, and O-phenylcarbamyl benzohydroxamate and (ii) attack on the aromatic carbon, giving an intermediate (112) that was detected but slowly decomposed to aniline and 2,4-dinitrophenol (Scheme 25)." The benzohydroxamate anion represented a unique type of reactive nucleophile since it behaved as a one-cut self destructive molecular scissor, which lost its... 

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. 

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. 

Nitrenes were first proposed as reactive intermediates in the Lossen rearrangement by Tiemann in 1891, and subsequently by Stieglitz (1896) to account for the mechanisms of the related Hofmann, Curtius, and Beckmann rearrangements. Apart from an extensive amount of work by Curtius on the thermal decomposition of aryl and sulphonyl azides, interest in nitrenes declined until the reemergence of carbene chemistry in the 1950s. Reviews on nitrene chemistry by Kirmse (1959), Horner (1963), and Abramovitch (1964) reflected this renewed interest in nitrenes and provided a stimulus for the immense research effort undertaken in the 1960s, which has been surveyed in many reviews and two books.Of particular note are two chapters by Abramovitch" describing all facets of nitrenes, and an excellent chapter devoted specifically to aryl- and hetarylnitrenes by P. A. S. Smith. The present chapter is intended to update these reviews and it is hoped that it will stimulate further work, particularly on the synthetic aspects of intermolecular arylnitrene reactions. 

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. 

Identification of the site of hydroxamate incorporation. To identify which amino acids were involved in the incorporation of hydroxylamine and the concomitant loss of the enzyme activity, all modified pepsins containing from 1.2 to 3.8 mole of hydroxamate per mole of pepsin (Table I) were subjected to Lossen rearrangement, followed by acid hydrolysis. All samples contained 2,3-diamino-propionic acid, but no 2,4-diaminobutyric acid was found using the amino acid analyzer. Thus, the PTFS-pepsin intermediates trapped with hydroxylamine must have been formed at the B-carboxyl groups of aspartate residues and glutamate residues were not involved. 

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