The Hofmann Rearrangement of Amides

In the presence of a strong base, primary amides react with chlorine or bromine to form shortened amines with loss of the carbonyl carbon atom. This reaction, called the Hofmann rearrangement, is used to synthesize primary alkyl and aryl amines. 

Part 1 Deprotonation of the amide and nucleophilic attack on bromine. 

Part 2 Second deprotonation. The presence of a leaving group (bromine) allows the alkyl group to migrate and the leaving group to leave 

Part 3 Isocyanates react rapidly with water to give carbamic acids. Hydroxide ion attacks the carbonyl group of the isocyanate. 

Part 4 Carbamic acids tend to lose CO2 spontaneously. Decarboxylation (loss of CO2) gives the amine 

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Scheme 2.11 Effect of variations in reaction conditions in the Hofmann rearrangement of amides 26.

The rearrangement has a mechanism similar to those of the Hofmann rearrangement of amides, the Lossen rearrangement of acylhydroxamic esters, the Schmidt rearrangement of carbonyl compounds and the Wolff rearrangement of diazoketones. Evidence concerning the mechanism of one can often be applied to the others, and the whole family has been reviewed briefly . Sometimes the distinction is made that the conversion of an acyl azide into an isocyanate or urethane is the Curtius rearrangement whereas the overall sequence is the Curtius reaction, but usually the former name is used for both processes. 

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. 

More recently, Santoyo Gonzalez and co-workers [43] reported the Hofmann rearrangement of amide 84 into cyclic carbamate 85 (40% yield. Scheme 24). This was achieved with a mixture of mercuric acetate, M-bromosuccinimide and M,JV-dimethylformamide. 

Reagent for effecting the Hofmann rearrangement of amides under mildly acidic conditions used esp. for peptides. Used in the spectrophotometric and densitometric anal, of amines and hydrazines. Mp 124-126°. 

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. 

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

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. 

A number of methods involve the rearrangement of carboxylic acid derivatives via nitrenes. The best known of these is the Hofmann degradation of amides. This involves treating an amide with bromine and alkali. The A-bromo compound undergoes an a-elimination in the presence... 

Oxidative rearrangement. A reaction related to the Hofmann rearrangement of N-hromoamides occurs on oxidation of an aromatic amide with lead tetraacetate lo give the isocyanate or a derived product in moderate to excellent yield. Simple aliphatic amides react rapidly in dimethylformamide containing triethylamine. 

The synthesis of cyclopropylamines is also conveniently realized through the Hofmann rearrangement of carboxylic amides. Hofmann degradation of cyclopropanecarboxamide gives access to the parent cyclopropylamine (17) in an excellent yield of 82%. ... 

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 ... 

This means the synthesis must employ a reaction that generates an amine of 1 less carbon from succinic anhydride. Such a reaction is the Hofmann degradation of amides. As seen below, the reaction involves the migration of a group from carbonyl carbon to the adjacent nitrogen atom. It is therefore an example of a molecular rearrangement. ... 

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)... 

Studies of the Hofmann rearrangement of optically active amides in which the chirality center is directly attached to the carbonyl group have shown that these reactions occur with retention of configuration. Thus, the R group migrates to nitrogen with its electrons, but without inversion. 

In the first steps, ester condensation to diketo acid, preparadon of oxime and cyclization are completed under standard conditions. Ester ammonolysis is followed by Hofmann rearrangement of amide to heterocyclic amine. Sulfonation of amine under Schotten-Baumann conditions, in a water-organic solvent mixmre, is based on an interesting trick hydroxide is added at a controlled rate to scavenge the hydrochloric acid formed in sulfonation and to maintain the neutral pH of the aqueous solution of heterocyclic amine as a stronger nucleophile than water, avoiding the hydrolysis of sulfonyl chloride ... 

Further pport for this conclusion is found in the results of studies on the Hofmann reaction of amides such as /3,/3,jS-triphenylpropionamide and j3,jS-dimethylbutyramide. Here the migrating groups R3(XH2, if free, are extremely susceptible of rearrangement. From these amides, however, only the expected amines, i.e., /3,/3,/3-triphenylethylamine and neopentylamine, are obtained. 

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. 

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

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