Nitrenes Hofmann 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-... 

Overall, then, the Curtius rearrangement converts an acid chloride to an amine with loss of a car- tk>n atom—very useful. Also useful is the related Hofmann rearrangement, which turns an amide ito an amine with loss of a carbon atom. This time we start with a primary amide and make a trene by treatment with base and bromine. Notice how close this nitrene-forming reaction is to the tarbene-forming reactions we talked about on p. 1072. The nitrene rearranges just as in the Curtius reaction, giving an isocyanate that can be hydrolysed to the amine. 

Conversion of acid derivatives into amines with the loss of the carbonyl group can be done in various ways. In chapter 36 we recommended the Curtius and the Hofmann. The Hofmann degradation is the easier if we start with an ester, converting into the amide with ammonia and then treating with bromine in basic solution. The N-bromo amide undergoes a-elimination to a nitrene that rearranges to an isocyanate. 

The Hofmann rearrangement, commonly referred to as the Hofmann degradation, converts a primary carboxamide to a primary amine fScheme 4.25T After formation of an N-bromoamide 66 under base-mediated bromination conditions, a nitrene 67 is generated via a-elimination of HBr. Subsequent rearrangement of the nitrene results in the formation of an isocyanate 68 which is hydrolyzed to a primary amine 69 after CO2 extrusion. 

In Summary Treatment of primary and secondary amides with base leads to deprotonation at nitrogen, giving amidate ions. Bases abstract protons from the a-carbon of tertiary amides. In the Hofmann rearrangement, primary amides react with halogens in base to furnish amines with one fewer carbon. In the conrse of this process an alkyl shift takes place, which converts an acyl nitrene into an isocyanate. 

Preparation from Nitrene Intermediates. A convenient, small-scale method for the conversion of carboxyhc acid derivatives into isocyanates involves electron sextet rearrangements, such as the ones described by Hofmann and Curtius (12). For example, treatment of ben2amide [55-21-0] with halogens leads to an A/-haloamide (2) which, in the presence of base, forms a nitrene intermediate (3). The nitrene intermediate undergoes rapid rearrangement to yield an isocyanate. Ureas can also be formed in the process if water is present (18,19). 

It was assumed that the rearrangement of N-anionic intermediate 181 into isocyanate 182 occurs as a synchronous process including the formation of a new C—N bond and the withdrawal of the anion acid (X ), but without formation of the intermediate nitrene. According to early papers, information about yields of naphthostyryl 174 (R = H), which is obtained from naphthaloimide 178 (R = H) by the Hofmann reaction, is contradictory. The procedure has been checked and developed preparatively by... 

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

A number of methods involve the rearrangement of carboxylic acid derivatives via nitrenes. The best known of these is the Hofmann degradation of amides. This involves treating an amide with bromine and alkali. The A-bromo compound undergoes an a-elimination in the presence... 

Hie Hofmann, Losseir and Curtins rearrangements (Scheme 6.38) are also thought to occur via an acyl nitrene-type intermediate and involve the migration of an R group to form an isocyanate. In the related Schmidt... 

Nitrenes take part in Curtius, Schmidt, Hofmann, and Lossen rearrangements. 

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. 

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