Hofmann rearrangement primary amides

Hofmann rearrangements Primary amides are converted into amines in high yield by reaction with this owdant at room temperature in aqueous acetonitrile (equation I). The reaction is rslated to a recent method using lead tetraacetate (6, 316) however, the intermet iate isocyanate in this case is not trapped as the carbamate, but is hydrolyzed alirectly to the amine. 

Hofmann rearrangement Primary amides are transformed into methyl carbamates by NBS-DBU in refluxing methanol. 

Hofmann rearrangement. Primary amides such as protected asparagines are degraded by Phl(OAc)j in one operation. 

In Summary Treatment of primary and secondary amides with base leads to deprotonation at nitrogen, giving amidate ions. Bases abstract protons from the a-carbon of tertiary amides. In the Hofmann rearrangement, primary amides react with halogens in base to furnish amines with one fewer carbon. In the conrse of this process an alkyl shift takes place, which converts an acyl nitrene into an isocyanate. 

Section 20.17 The Hofmann rearrangement converts amides of the type RCNH2 to primary amines (RNH2). The carbon chain is shortened by one carbon with loss of the carbonyl group ... 

Hofmann rearrangement of amides (Hofmann degradation) Treatment of a primary amide with sodium hydroxide and bromine or chlorine gives a primary amine, (p. 919)... 

Hofmann rearrangement of amides Conversion of a primary amide to an amine (with one less carbon) by treatment with a basic bromine solution. The C=0 group is lost as CO2. (pp. 919, 1023)... 

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. 

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-... 

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. 

Hofmann-type rearrangement of primary amides (107) into the corresponding amines (108) using PIFA [79-81] was used for the initial reaction toward the total synthesis of the potent thrombin inhibitor cyclotheonamide A (109) [Eq. (25)]. 

Hofmann rearrangementTwo laboratories4 5 have reported that this hyper-valent iodine reagent is useful for rearrangement of primary amides to primary amines, without effect on a secondary sulfonamide group. In the example cited here, the Hofmann rearrangement failed completely under usual conditions. 

Overall, then, the Curtius rearrangement converts an acid chloride to an amine with loss of a car- tk>n atom—very useful. Also useful is the related Hofmann rearrangement, which turns an amide ito an amine with loss of a carbon atom. This time we start with a primary amide and make a trene by treatment with base and bromine. Notice how close this nitrene-forming reaction is to the tarbene-forming reactions we talked about on p. 1072. The nitrene rearranges just as in the Curtius reaction, giving an isocyanate that can be hydrolysed to the amine. 

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 variation of the Hofmann rearrangement treated a p-hydroxy primary amide with PhI(02CCF3)2 in aqueous acetonitrile, giving an isocyanate via -CON-I, which reacts with the hydroxyl group intramolecularly to give a cyclic carbamate. Note that carbamates are converted to isocyanates by heating with Montmorillonite KIO. ... 

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. 

The Hofmann reaction involves the conversion of carboxylic primary amides to primary amines or their derivatives. Generally, alkaline hypohalites or a combination of halogens and alkaline hydroxides are used in aqueous solutions. The rearrangement generally occurs by heating. The intermediate isocyanates are easily hydrolyzed to amines under the reaction conditions, as shown in Scheme 3. When sodium methoxide in methanol is used in place of aqueous alkaline hydroxide, the corresponding methylurethanes are formed and may be hydrolyzed to yield amines. 

The first asymmetric total synthesis of the hasubanan alkaloid (+)-cepharamine was completed by A.G. Schultz et al. In order to construct the c/s-fused A/-methylpyrrolidine ring, the advanced tetracyclic lactone was first converted to the primary carboxamide by treatment with sodium amide in liquid ammonia. Next the Hofmann rearrangement was induced with sodium hypobromite in methanol initially affording the isocyanate, which upon reacting with the free secondary alcohol intramolecularly gave the corresponding cyclic carbamate in excellent yield. 

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