Hofmann amides

HOFMANN Amide Degradation Degradation o( amides to amines by means of hypohaiides... 

The Hofmann amide rearrangement is a conversion of a primary carboxamides 230 into amines using aqueous NaOH and bromine (see review in Reference 330). This reaction is, in effect, an elimination of the carbonyl group from the amide and is therefore usually... 

HOFMANN Amide degradation 173 HOFMANN IsonitrHe synthesis 173 HOFMANN Elimination 174 HOFMANN LOEFFLER - FREYTaG Pyrrolidine synthesis 175... 

II. Migration from carbon to nitrogen 1. Hofmann amide degradation118... 

Hofmann s amine synthesis can be applied to both aliphatic and aromatic carboxylic acid amides, benzamide, C HsCONH, thus giving aniline, C4H5NH,. 

This compound is similar in type to the sodium acet-bromoamide, CHjCONNaBr, which is an intermediate compound in Hofmann s amine synthesis (p. 127). If a weak acid (such as acetic acid) is now added to the solution of the chloro-sodio-amide, the latter compound reacts with the hypo-chlorous acid giving the sulphon-dichloro amide, which being insoluble in water, rapidly separates ... 

The conversion of an amide into an amine in this way is termed the Hofmann reaction or the Hofmann rearrangement. 

We have meet NO2 and CN before, but a primary amine can also be made from an amide by the Hofmann degradation (see Norman p.446-7 or Tedder, vol.2, p.281-2). 

Diamides and triamides have been obtained from the action of an aqueous saturated solution of ammonia on the corresponding ester (Scheme 18) (88). Amides can also be obtained by the Curtius (16) or Hofmann reactions (80). Thus the Curtius reaction with 2-substituted 4-thiazolecarboxylic acids gives the 4-acetamido compounds (16). 

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). 

Amides. Because amides are less basic, they chlorinate less rapidly than amines. A/-Halamides are converted to amines in basic solution via intermediate formation of an isocyanate (Hofmann reaction) (91). 

Ureas. Chlorination of aqueous urea yields unstable A/-chloro compounds. With excess C10 decomposition yields CO2, N2O, and NCl the latter decomposes further to NO (96). Only two soHd derivatives have been isolated A/-chlorourea [3135-74-8] mp 74—76°C, and N,lSf-dichlorourea [2959-01-5] which decomposes at its mp of 83°C with evolution of NCl. As an amide, urea also undergoes the Hofmann reaction yielding hydrazine. This route to hydrazine was once employed commercially. 

The synthesis of meconin has been referred to already (p. 201). Cotarnine has been synthesised by Salway from myristicin (I) as a starting-point. This was transformed into jS-3-methoxy-4 5-methylenedioxy-phenylpropionic acid (II), the amide of which was converted by Hofmann s reaction into )S-3-methoxy-4 5-methylenedioxyphenylethylamine, and the phenylacetyl derivative (HI) of this condensed, by heating it in xylene solution with phosphoric oxide, giving rise to the two possible dihydroiso-quinoline derivatives. The first of these substances, 8-methoxy-6 7-methylenedipxy-1-benzyl-3 4-dihydroiioquinoline (IV), on conversion into the methochloride and reduction with tin and hydrochloric acid, gave... 

White s observations on the pharmacological activity of the lysergic acids and their simple amides are of practical, therapeutic interest in view of the possibility of preparing from natural supplies of these acids, partially synthetic oxytocic substances of which a first series by Stoll and Hofmann has been described (p. 528), including d-lysergic-(-t-)-jS-butanolamide, already the subject of promising clinical trials. ... 

Most aminothiophenes are prepared by the reduction of nitrothio-phenes. Aminothiophenes or their derivatives have also been obtained through the Hofmann rearrangement of the acid amides, which, however, fails with 2-thenamide, in contrast to the 3-isomer. The Beckmann rearrangement of the oxime of 2-acetylthiophene has been applied successfully to the preparation of 2-acetamidothiophene. The free aminothiophenes are very unstable compounds and it has not been possible to distil 3-aminothiophene. They are best stored as the stannic-chloride double salts and give stable acetyl derivatives. 

The Hofmann and Curtius rearrangements have been applied to 2-thienylacryl amides for the preparation of 2-thiophene acetaldehydes. The Hofmann rearrangement proceeds also with 3-thenamides but fails with 2-thenamide. ... 

Carboxylic acid derivatives can be converted into primary amines with loss of one carbon atom by both the Hofmann rearrangement and tire Curtius rearrangement. Although the Hofmann rearrangement involves a primary-amide and the Curtius rearrangement involves an acyl azide, both proceed through similar mechanisms. 

Figure 24.5 MECHANISM Mechanism of the Hofmann rearrangement of an amide to an amine. Each step is analogous to a reaction studied previously.

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