Hofmann rearrangement
Abstract
The Hofmann rearrangement converts a primary amide into its corresponding primary amine, one carbon shorter, using bromine and a base. Carbon dioxide and water are released as by-products in the process.
Keywords
Amide, Rearrangement, Amine
Category
Amide, Rearrangement
Mechanism
Under basic conditions, the amide is deprotonated to generate the amidate ion, which then reacts with bromine to form the N-bromoamide intermediate. Subsequent deprotonation of this intermediate yields the N-bromoamidate species. A 1,2-shift then occurs concomitantly with the departure of the bromide, generating a highly reactive isocyanate. This unstable compound is rapidly intercepted by the aqueous base to form a carbamic acid, which undergoes decomposition into carbon dioxide, hydroxide anion and ultimately affords the primary amine product.
Recent review
Debnath, P. Recent advances in the Hofmann rearrangement and its application to natural product synthesis. Curr. Org. Synth. 2019, 23, 2402-2435