Hofmann reaction of amides

This very inexpensive oxidant has been successfully used in the conversion of benzylic and benzhydrylic alcohols to aldehydes and ketones. a-Monosubstituted and a,a -disubstituted primary amines yield nitriles and aldehydes, and ketones, respectively Recently, the synthesis of aliphatic isocyanates via a two-phase Hofmann reaction of amides has been performed... 

Further pport for this conclusion is found in the results of studies on the Hofmann reaction of amides such as /3,/3,jS-triphenylpropionamide and j3,jS-dimethylbutyramide. Here the migrating groups R3(XH2, if free, are extremely susceptible of rearrangement. From these amides, however, only the expected amines, i.e., /3,/3,/3-triphenylethylamine and neopentylamine, are obtained. 

TABULAR SURVEY OF PRODUCTS AND YIELDS OBTAINED IN THE HOFMANN REACTION OF AMIDES... 

Prodtjcts and YibiiDS Obtained in Hofmann Reactions of Amides—Continued... 

Subsequent chlorination of the amide takes place ia a two-phase reaction mixture (a dispersion of diamide ia hydrochloric acid) through which a chlorine stream is passed. The temperature of this step must be maintained below 10°C to retard the formation of the product resulting from the Hofmann degradation of amides. Reaction of the A/,A/-dichloroamide with diethylamine [109-89-7] ia the presence of base yields /n j -l,4-cyclohexane-bis-l,3-diethylurea (35), which is transformed to the urea hydrochloride and pyroly2ed to yield the diisocyanate (36). 

Our recent studies on effective bromination and oxidation using benzyltrimethylammonium tribromide (BTMA Br3), stable solid, are described. Those involve electrophilic bromination of aromatic compounds such as phenols, aromatic amines, aromatic ethers, acetanilides, arenes, and thiophene, a-bromination of arenes and acetophenones, and also bromo-addition to alkenes by the use of BTMA Br3. Furthermore, oxidation of alcohols, ethers, 1,4-benzenediols, hindered phenols, primary amines, hydrazo compounds, sulfides, and thiols, haloform reaction of methylketones, N-bromination of amides, Hofmann degradation of amides, and preparation of acylureas and carbamates by the use of BTMA Br3 are also presented. 

The N-bromination of amides with bromine and alkali has been extensively researched as the first step of the Hofmann degradation. However, it is difficult to isolate the N-bromoamides because of their subsequent reaction to produce amines, which proceeds very readily under excessive alkaline conditions. Now, the reaction of amides with a stoichiometric amount of BTMA Br3 and sodium hydroxide in ice-water gave N-bromoamides in fairly good yields. Our method can be applied to various types of aliphatic, aromatic, and heterocyclic amides (Fig. 31) (ref. 39). 

Fig. 32. Reaction scheme of the Hofmann degradation of amides with BTMA Br3 BTMA Bfj, rt or 70 C...

The Hofmann reaction of an amide with bromine and alkali apparently goes by way of the iV-bromoamide and unicovalent electron-deficient nitrogen. 

The above procedure is essentially that of Ullmann and Bleier.2 2-Aminobenzophenone has also been prepared by reduction of 2-nitrobenzophenone,3 by the Hofmann reaction of the amide of o-benzoylbenzoic acid with sodium hypobromite,4 by the action of an excess of benzoyl chloride on aniline at 220°,6 and by hydrolysis of the acetyl derivative which is obtained by the action of phenylmagnesium bromide on 2-methyl-3,l,4-benzoxaz-4-one (from anthranilic acid and acetic anhydride).6 Various methods for the preparation of 2-aminobenzophenones have been summarized critically by Simpson, Atkinson, Schofield, and Stephenson.7... 

Scheme 2.11 Effect of variations in reaction conditions in the Hofmann rearrangement of amides 26.

The Hofmann and Curtius reactions as applied to both the mono-and diamides and hydrazides have been reported. Marquardt found that a low yield of the amine can be obtained in the Hofmann reaction of l,2,5-thiadiazole-3-carboxamide. The main side reaction was hydrolysis of the electron-deficient amide to the carboxylic acid. Under the same conditions the dicarboxamide (78) formed the amino acid (16b). Attempts to prepare diaminothiadiazole via the Hofmann reaction of the amino amide (16a) resulted only in amide hydrolysis and the formation of the same amino acid. 

Hoesch-Houben reaction, 321 Hofmann degradation of amides, 103, 296, 674... 

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. 

As a method of synthesis of amines, the Hofmann degradation of amides has the special feature of yielding a product containing one less carbon than the starting material. As we can see, reaction involves migration of a group from carbonyl... 

Let us begin with a reaction that we encountered earlier as a method of synthesis of amines the Hofmann degradation of amides. Whatever the mechanism... 

This means the synthesis must employ a reaction that generates an amine of 1 less carbon from succinic anhydride. Such a reaction is the Hofmann degradation of amides. As seen below, the reaction involves the migration of a group from carbonyl carbon to the adjacent nitrogen atom. It is therefore an example of a molecular rearrangement. ... 

Reactions of Amides Because amides are the most stable acid derivatives, they are not easily converted to other derivatives by nucleophilic acyl substitution. From a synthetic standpoint, their most important reaction is the reduction to amines, which is one of the best methods for synthesizing amines. The Hofmann rearrangement (Section 19-19C) also converts amides to amines, with loss of one carbon atom. Amides are hydrolyzed by strong acid or strong base. Just as nitriles can be hydrolyzed to amides, amides can be dehydrated to nitriles. 

Hofmann (reaction of a primary amide with alkaline bromine solution) o... 

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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