Amines from Hofmann rearrangement

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. 

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. 

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. 

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 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). 

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. 

Arylfurazancarboxamides on treatment with alkaline hypochlorite undergo Hofmann degradation to the amines likewise carbamates result from Curtius rearrangement of furazanylacyl azides in the presence of alcohols. 

In both of these reactions, the product amine is formed from a carboxylic acid derivative precursor that has one more carbon than the amine. In the Hofmann rearrangement, the precursor is an amide, which is treated with Br2, NaOH and H2O. In the Curtius rearrangement, the precursor is an acid chloride, which is treated with NaN3, then with H2O and heat. 

The Hofmann rearrangement is the conversion of primary amides into primary amines by the action of sodium hypohalite (usually generated in situ from halogen and sodium hydroxide). The most important feature of the rearrangement is that the amine formed has... 

A -Haloamides also undergo the Hofmann rearrangement This reaction provides a useful method of making amines from amides with the loss of the carboxyl carbon atom. 

The enantioselective total synthesis of (-)-epibatidine was accomplished in the laboratory of D.A. Evans." The key steps in the synthetic sequence included a hetero Diels-Alder reaction and a modified Hofmann rearrangement. The primary carboxamide was subjected to lead tetraacetate in fert-butyl alcohol that brought about the rearrangement and gave the corresponding A/-Boc protected primary amine in good yield. A few more steps from this intermediate led to the completion of the total synthesis. 

From B 1. SOCI2. 2. NH> 3. Cl2, NaOH (Hofmann rearrangement, loses CO2 and makes simple amine),... 

Bis(trifluoroacetoxy)iodo]benzene has also been used as a reagent for the Hofmann rearrangement, as illustrated by the conversion of amide 404 into the respective amine 405 (Scheme 3.162) [503], A similar [bis(trifluoroacetoxy)iodo]benzene-induced Hofmann rearrangement has been used for the preparation of both enantiomers of trfl 5 -2-aminocyclohexanecarboxylic acid from fran5-cyclohexane-l,2-dicarboxylic... 

Scheme 9.103. The Hofmann rearrangement, which results in the loss of carbon dioxide (CO2) and the production of an amine from oxidation of an amide with bromine (Br ) or chlorine (CI2).The oxidation produces the A -halo-compound, which, on treatment with base, undergoes rearrangement to generate the N-alkylisocyanate (cyclohexylisocyanate in this case). Treatment of the Af-alkyhsocyanate with water, produces the transient carbamic acid. The carbamic acid undergoes spontaneous decarboxylation in water to carbon dioxide (CO2) and cyclohexylamine (Chapter 10). Details of the Hofinann rearrangement will be discussed subsequently. But see Hofmann, A. W. Chem. Ber., 1881,7 /, 2725.

Two new syntheses of hydrazines from secondary amines have been reported. In one 1,1-diarylhydrazines are the products of the Hofmann rearrangement of the corresponding ureas (Scheme 33), and in the other ... 

For the next two retrosynthetic steps, we need new knowledge related to the Hofmann rearrangement of amides to amines with the loss of one C atom, discussed in Sect. 8.3. This rearrangement enables the introduction of an amino group in TM 7.3b starting from the corresponding carboxylic amide. The high value of this retrosynthetic approach becomes obvious on the next disconnection steps, refro-cyclization to p-ketoxime and its interconversion to easily available diketo-carboxylic acid. 

Synthetic application of this reaction extends from rearrangements of aliphatic amides to aromatic and heterocyclic amides. Results of the Hofmann rearrangement are primary amines or their A -acyl derivatives. 

Secondary or tertiary amides are prepared in good yield from amines and alcohols using an in situ generated N-bromophosphonium salt from the reaction of NBS and PPhs. " Benzylamines are debenzylated by NBS and AIBN and the conversion of amides into carbamates was achieved in a Hofmann rearrangement using NBS/NaOMe, or NBS/DBU/MeOH. ... 

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