Reductive amination (also known as reductive alkylation) is a form of amination that converts a carbonyl group to an amine via an intermediate imine. The carbonyl group is most commonly a ketone or an aldehyde. It is a common method to make amines and is widely used in green chemistry since it can be done catalytically in one-pot under mild conditions. In biochemistry, dehydrogenase enzymes use reductive amination to produce the amino acid glutamate. Additionally, there is ongoing research on alternative synthesis mechanisms with various metal catalysts which allow the reaction to be less energy taxing, and require milder reaction conditions. Investigation into biocatalysts, such as imine reductases, have allowed for higher selectivity in the reduction of chiral amines which is an important factor in pharmaceutical synthesis.
Reaction process Reductive amination occurs between a carbonyl such as an aldehyde or ketone and an amine in the presence of a reducing agent. The reaction conditions are neutral or weakly acidic.
Reaction steps The nucleophilic amine reacts at the carbon of the carbonyl group to form a hemiaminal species reversible loss of one molecule of water from the hemiaminal species by alkylimino-de-oxo-bisubstitution to form the imine intermediate. The equilibrium between aldehyde/ketone and imine is shifted toward imine formation by dehydration. The intermediate imine can be isolated or reacted in-situ with a suitable reducing agent (e.g., sodium borohydride) to produce the amine product. Intramolecular reductive amination can also occur to afford a cyclic amine product if the amine and carbonyl are on the same molecule of starting material. There are two ways to conduct a reductive amination reaction: direct and indirect.
Direct reductive amination In a direct reaction, the carbonyl and amine starting materials and the reducing agent are combined and the reductions are done sequentially. These are often one-pot reactions since the imine intermediate is not isolated before the final reduction to the product. Instead, as the reaction proceeds, the imine becomes favoured for reduction over the carbonyl starting material. The two most common methods for direct reductive amination are hydrogenation with catalytic platinum, palladium, or nickel catalysts and the use of hydride reducing agents like cyanoborohydride (NaBH3CN).
Indirect reductive amination Indirect reductive amination, also called a stepwise reduction, isolates the imine intermediate. In a separate step, the isolated imine intermediate is reduced to form the amine product.
Designing a reductive amination reaction There are many considerations to be made when designing a reductive amination reaction.
Chemoselectivity issues may arise since the carbonyl group can also be reduced. The reaction between the carbonyl and amine are in equilibrium, favouring the carbonyl unless water is removed from the system. reduction-sensitive intermediates may form in the reaction which can affect chemoselectivity. The amine substrate, imine intermediate, or amine product might deactivate the catalyst. Acyclic imines have E/Z isomers. This makes it difficult to create enantiopure chiral compounds through stereoselective reductions. To solve the last issue, asymmetric reductive amination reactions can be used to synthesize an enantiopure product of chiral amines. In asymmetric reductive amination, a carbonyl that can be converted from achiral to chiral is used. The carbonyl undergoes condensation with an amine in the presence of H2 and a chiral catalyst to form the imine intermediate, which is then reduced to form the amine. However, this method is still limiting to synthesize primary amines which are non-selective and prone to overalkylation.
Common reducing agents
Sodium borohydride Sodium borohydride (NaBH4) reduces both imines and carbonyl groups. However, it is not very selective and can reduce other reducible functional groups present in the reaction. To ensure that this does not occur, reagents with weak electrophilic carbonyl groups, poor nucleophilic amines and sterically hindered reactive centres should not be used, as these properties do not favour the reduction of the carbonyl to form an imine and increases the chance that other functional groups will be reduced instead.
Sodium cyanoborohydride Sodium cyanoborohydride (NaBH3CN) is soluble in hydroxylic solvents, stable in acidic solutions, and has different selectivities depending on the pH. At low pH values, it efficiently reduces aldehydes and ketones. As the pH increases, the reduction rate slows and instead, the imine intermediate becomes preferential for reduction. For this reason, NaBH3CN is an ideal reducing agent for one-pot direct reductive amination reactions that don't isolate the intermediate imine. When used as a reducing agent, NaBH3CN can release toxic by-products like HCN and NaCN during work up.
Sodium triacetoxyborohydride Sodium triacetoxyborohydride (STAB, NaBH(OAc)3) is a common reducing agent for reductive aminations. STAB selectively reduces the imine intermediate formed through dehydration of the molecule. STAB is a weaker reductant than NaBH4, and can preferentially reduce the imine group in the presence of other reduction-sensitive functional groups. While STAB has also been reported as a selective reducing agent for aldehydes in the presence of keto groups, standard reductive amination reaction conditions greatly favour imine reduction to form an amine.
Variations and related reactions The reductive amination reaction is related to the Eschweiler–Clarke reaction, in which amines are methylated to tertiary amines, the Leuckart–Wallach reaction, and other amine alkylation methods such as the Mannich reaction and Petasis reaction. A classic named reaction is the Mignonac reaction (1921) involving reaction of a ketone with ammonia over a nickel catalyst. An example of this reaction is the synthesis of 1-phenylethylamine from acetophenone:
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