Preparation of Amines: Reductive Amination of Aldehydes and Ketones

Reductive amination is a one-pot reaction where carbonyl compounds and primary amines form imines, which are then reduced to secondary amines without isolation. The reaction introduces C–H and C–N bonds in place of the C=O bond. This process uses selective reducing agents like sodium cyanoborohydride to selectively reduce the imine intermediate rather than the original carbonyl group.

Sodium cyanoborohydride is selective because its electron-withdrawing cyano group stabilizes the negative charge on the hydride, making it reduce the protonated imine preferentially. Sodium borohydride, lacking this cyano group, reduces the carbonyl precursor directly, preventing imine formation and inhibiting the reductive amination reaction.

Reductive amination can produce primary, secondary, and tertiary amines depending on the amine precursor used. The degree of amine substitution is controlled by selecting the appropriate starting amine substrate. This versatility makes reductive amination valuable for synthesizing amines with varying levels of alkyl substitution.

The Borch reaction is reductive amination using sodium cyanoborohydride as the reducing agent. Sodium cyanoborohydride is a mild reductant that operates under mildly acidic conditions, making it ideal for selectively reducing imines to amines while preserving other functional groups in the molecule.

The imine forms when a carbonyl compound condenses with a primary amine. The imine nitrogen is then protonated, and sodium cyanoborohydride transfers a hydride ion to the imine carbon, reducing it to an amine. This two-step process occurs in the same reaction vessel without isolating the reactive imine intermediate.

Reductive amination has significant pharmaceutical applications. The antidepressant drug Fluoxetine is synthesized from an aldehyde and a primary amine using this method. Additionally, reductive amination is used to synthesize the central nervous system stimulant amphetamine and in the biosynthesis of the amino acid proline.

Suitable reducing agents for reductive amination include catalytic hydrogenation and selective hydride reducing agents like sodium cyanoborohydride and sodium triacetoxyborohydride. These agents selectively reduce the imine intermediate while avoiding unwanted reduction of other functional groups present in the molecule during synthesis.