19.17 : Preparation of Amines: Reductive Amination of Aldehydes and Ketones

Recall that carbonyl compounds and primary amines react to form imines, which can be further reduced to secondary amines without isolation.

This one-pot conversion of carbonyl compounds to amines using another amine and a reducing agent is called reductive amination.

The reaction introduces a C–H and a C–N bond in place of a C=O bond.

Reductive amination uses catalytic hydrogenation or a selective hydride reducing agent like NaBH₃CN.

The imine formed from condensing a carbonyl compound and a primary amine is protonated at the nitrogen center.

Next, NaBH₃CN transfers the hydride ion to the imine carbon, reducing the imine to an amine.

NaBH₃CN is a NaBH₄ derivative, but unlike the cyano compound, NaBH₄ is not suitable for reductive amination as it reduces the carbonyl precursor, inhibiting imine formation.

The electron-withdrawing cyano group stabilizes the negative charge, making the hydride more selective in reducing the protonated imine instead of the carbonyl group.

Depending on the amine precursor, reductive amination can give primary, secondary and tertiary amines.

Using reductive amination, an antidepressant drug, Fluoxetine, is synthesized from an aldehyde and a primary amine.