Hofmann rearrangement, preparation

In addition to the nitrile and alcohol routes for fatty amine preparation, processes have been described by Unocal and Pennwalt Corporation, using an olefin and secondary amine (14—16) by Texaco Inc., hydrogenation of nitroparaffins (17—20) by Onyx Corporation, reaction of an alkyl haUde with secondary amines (21,22) by Henkel Cie, GmbH, reduction of an ester in the presence of a secondary amine (23) by catalytic hydroammonolysis of carboxyhc acids (24) and by the Hofmann rearrangement (25). 

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. ... 

The Curtius rearrangement, like the Hofmann rearrangement, involve migration of an -R group from the G-O carbon atom to the neighboring nitro gen with simultaneous loss of a leaving group. The reaction takes place on heat ing an acyl azide that is itself prepared by nucleophilic acyl substitution of m acid chloride. 

This procedure permits the synthesis of cyclobutylamine from cyclobutanecarboxylic acid in one step and in high yield. The procedures involving the Hofmann rearrangement require the preparation of the amide from the acid and afford lower yields of the amine. 

Amines are prepared by aminolysis of alkyl halides, and also reductive amination (reduction in the presence of ammonia) of aldehydes and ketones (see Section 5.7.19). They are obtained conveniently from Hofmann rearrangement of amides. 

Hofmann rearrangement In this reaction, amines (with one less carbon) are prepared from amides by the treatment of halides (Br2 or CI2) in aqueous sodium or potassium hydroxide (NaOH or KOH). 

Amides are the least reactive of the carboxylic acid derivatives, and undergo acid or base hydrolysis to produce the parent carboxylic acids, and reduction to appropriate amines (see Section 4.3.10). They can also be dehydrated to nitriles, most commonly with boiling acetic anhydride, (AcO)20, sulphonyl chloride (SOCI2) or phosphoms oxychloride (POCI3) (see Section 4.3.18). Amines (with one less carbon) are prepared from amides by the treatment of halides (Br2 or CI2) in aqueous NaOH or KOH. This reaction is known as Hofmann rearrangement (see Section 4.3.10). 

Acetaminothiophene has been prepared by a Hofmann rearrangement of thiophene-3-carboxamide (equation 49), or by a Beckmann rearrangement of the 3-acetylthiophene oxime (Section 3.14.3.4). Dimethyl 4-amino-2,3-thiophenedicarboxylate was formed in excellent yield from the oxime of the 4-ketotetrahydrothiophene diester, which is readily available by addition of thioglycolate to dimethyl fumarate, followed by a Dieckmann cyclization (equation 50 Section 3.15.2.2.2). 

These derivatives may be obtained by reduction of the appropriate nitro derivative catalytically or with a metal-acid system, or by Beckmann or Hofmann rearrangements of suitable acyl or carboxamido derivatives. 4-Aminobenzo[6]thiophene has also been prepared by means of a Bucherer reaction with 4-hydroxybenzo[6 Jthiophene. Several 5-aminobenzo[6]thiophenes have been prepared by cyclization reactions of p-acetamino-phenylthio derivatives. 6-Acetaminobenzo[6 Jthiophenes may be obtained from the corresponding 6-acetyl derivative by Schmidt or Beckmann rearrangements. 7-Aminobenzo[6 ]thiophene can also be prepared from 7-hydroxybenzo[6 ]thiophene by a Bucherer reaction (70AHC(ll)l77). 

Scheme 2 Preparation of gem-Diaminoalkyl Derivatives by Curtius or Hofmann Rearrangement from Acyl Azides or Acyl Amides...

A synthetic scheme becomes apparent when we recognize that a primary amine may be obtained by Hofmann rearrangement of the primary amide having one more carbon in its acyl group. This amide may, in turn, be prepared from the corresponding carboxylic acid. 

Despite its mechanistic complexity, the Hofmann rearrangement often gives high yields of both aryl- and alkylamines. For example, the appetite-suppressant drug phentermine is prepared commercially by Hofmann rearrangement of a primary amide. Commonly known by the name /cn-phen, the combination of phentermine with another appetite-suppressant, fenfluramine, is suspected of causing heart damage. 

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