Hofmann Rearrangement

In 1881, the German chemist August Wilhelm Hofmann discovered that by treating acetamide with one equivalent of bromine and either sodium or potassium hydroxide, N-bromoacetamide was formed. Further deprotonation and heating under anhydrous conditions afforded methyl isocyanate. However, when an excess of base was used under aqueous conditions, the resulting product was methylamine. Since this discovery, the conversion of primary carboxamides to the corresponding one-carbon-shorter amines has become known as the Hofmann rearrangement.

Several modifications have been introduced since the original discovery. In the case of hydrophobic amines, the use of methanolic sodium hypobromite, made from reacting bromine with sodium methoxide in methanol, produces the corresponding methylurethanes in high yields. Where the substrate is either acid- or base-sensitive, the use of a neutral electrochemically-induced Hofmann degradation was developed. To broaden the scope of the reaction for base-sensitive substrates, an oxidative rearrangement can be induced using hypervalent iodine reagents such as (diacetoxyiodo)benzene (PIDA).

Pharmaceutical application are among the many industrial uses for the Hofmann rearrangement. The reaction is used, for example, in the manufacture of diuretics such as furosemide.

In the total synthesis of the antifungal agent (+)-preussin, a modified version of the Hofmann rearrangement was used as one of the key steps in the final stages of the synthetic route.