Reductive amination

Reductive amination (also known as reductive alkylation) is a form of amination that involves the conversion of a carbonyl group to an amine via an intermediate imine. The carbonyl group is most commonly a ketone or an aldehyde. It is considered the most important way to make amines, and a majority of amines made in the pharmaceutical industry are made this way.

In this organic reaction, the amine first reacts with the carbonyl group to form a hemiaminal species, which subsequently loses one molecule of water in a reversible manner by alkylimino-de-oxo-bisubstitution, to form the imine. The equilibrium between aldehyde/ketone and imine can be shifted toward imine formation by removal of the formed water through physical or chemical means. This intermediate imine can then be isolated and reduced with a suitable reducing agent (e.g., sodium borohydride). This method is sometimes called indirect reductive amination.

Imine formation and reduction occur sequentially in one pot. This approach, known as direct reductive amination, employs reducing agents that are more reactive toward protonated imines than towards the ketone/aldehyde precursors. These hydride reagents also must tolerate moderately acidic conditions. Typical reagents that meet these criteria include sodium cyanoborohydride (NaBH₃CN) and sodium triacetoxyborohydride (NaBH(OCOCH₃)₃). This reaction can be performed in an aqueous environment, which casts doubt on the necessity of forming the imine. Possibly the reaction proceeds via reduction of the hemiaminal species.

This reaction is related to the Eschweiler–Clarke reaction, in which amines are methylated to tertiary amines, the Leuckart–Wallach reaction, or by other amine alkylation methods such as the Mannich reaction and Petasis reaction.

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