Hofmann amide rearrangement

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

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.

When an a-hydroxy amide is treated with Br2 in aqueous NaOH under Hofmann rearrangement conditions, loss of C02 occurs and a chain-shortened aldehyde is formed. Propose a mechanism. 

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. 

The NHase and amidase from Rhodococcus rhodochrous IFO 15 564 was studied using a series of a,a-disubstituted malononitriles. This amidase preferentially hydrolyzes the pro (R) amide of the prochiral di-amide, which is an intermediate resulting from the nonenantiotopic NHase activity on the dinitrile substrate. This transformation was combined with a Hofmann rearrangement to generate a key precursor of (A)-methyldopa in 98.2% ee and 95% yield (Figure 8.5) [41],... 

The amides undergo a rearrangement resembling Hofmann rearrangement and give isocyanate. 

Benzyltrimethylammonium tribromide has been used for the A -bromination of amides in good yield [54]. Under basic conditions, Hofmann rearrangement to amines is also possible (see Section 9.3). 

Electrolysis of amides in MeOH containing the bromide ion efficiently led to products of the Hofmann rearrangement (for example, 119 to 120 Scheme 43) [131]. This reaction, named the electrochemically induced (E-I) Hofmann rearrangement, is achieved without any bromine and base under mild and neutral reaction conditions. 

A potential versatile route into a-amino acids and their derivatives is via a combination of (i) nitrile hydratase/amidase-mediated conversion of substituted malo-nonitriles to the corresponding amide/acid followed by (ii) stereospecific Hofmann rearrangement of the amide group to the corresponding amine. Using a series of a,a-disubstituted malononitriles 14, cyanocarboxamides 15 and bis-carboxamides 16, the substrate specificity of the nitrile hydratase and amidase from Rhodococcus rhodochrous IF015564 was initially examined (Scheme 2.7). The amidase hydrolyzed the diamide 16 to produce (R)-17 with 95% conversion and 98%e.e. Amide 17 was then chemically converted to a precursor of (S)-a-methyldopa. It was found... 

Hofmann Rearrangement A useful means of converting an amide to an amine. 

For the Hofmann rearrangement reaction, a carboxylic amide 1 is treated with hypobromite in aqueous alkaline solution. Initially an A-bromoamide 4 is formed. With two electron-withdrawing substituents at nitrogen the A-bromoamide shows NH-acidity, and can be deprotonated by hydroxide to give the anionic species 5. 

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-... 

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). 

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

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