19.19: Preparation of 1° Amines: Hofmann and Curtius Rearrangement Overview

Primary amides can be converted into primary amines by Hofmann rearrangement using a halogen and an aqueous base.

The rearrangement involves an alkyl shift from the carbonyl carbon to the amine nitrogen. The reaction loses the carbonyl group in the form of CO₂.

An example of Hofmann rearrangement is the synthesis of an appetite-suppressant drug—phentermine—from an aryl amide.                                                     

Analogous to Hofmann rearrangement, Curtius rearrangement also gives primary amines, although with a different substrate—acyl azide, and under thermal conditions.

An alkyl migration to the closest nitrogen, followed by the loss of N₂ and carbon dioxide, drives the reaction forward to generate the amine.

Curtius rearrangement is used to make the antidepressant drug, Tranylcypromine.      

Both rearrangements produce primary amines with the loss of one carbon, and the migrating group completely retains its configuration.