19.18:
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.
19.18:
Preparation of 1° Amines: Hofmann and Curtius Rearrangement Overview
In the presence of an aqueous base and a halogen, primary amides can lose the carbonyl (as carbon dioxide) and undergo rearrangement to form primary amines. This reaction, called the Hofmann rearrangement, can produce primary amines (aryl and alkyl) in high yields without contamination by secondary and tertiary amines.
In the Curtius rearrangement, acyl azides are converted into primary amines under thermal conditions, accompanied by the loss of gaseous N2 and CO2. The loss of nitrogen acts as a driving force to complete the reaction.
The Hofmann and Curtius rearrangement reactions are applied in the synthesis of phentermine (an appetite-suppressant drug) and tranylcypromine (an antidepressant drug), respectively.
If the substrates are optically active, both rearrangement reactions occur with retention of configuration.
