Alkylation of ammonia or primary and secondary amines often loses its synthetic value because the degree of alkylation is difficult to control. Reductive alkylation with aldehydes and ketones (which can also be regarded as reductive amination of aldehydes and ketones) is one of the solutions.
Leuckart-Wallach Reaction
Reductive alkylation of ammonia/amines with formic acid as a reducing agent is called Wallach reaction. If formate or formamide of ammonia (or amine) is used to react under Wallach conditions, it is called Leuckart reaction. The product obtained at this time is often an N-formylated derivative rather than a free amine. Sometimes it is collectively referred to as the Leuckart-Wallach reaction. The alkylation product of ammonia or primary amine reduction may further undergo alkylation to form secondary or tertiary amines, so an excess of ammonia or primary amine is generally required.
The Leuckart-Wallach reaction is simple and easy to perform, but it also has defects, such as the need to react at high temperature (>180 °C), the generation of N-formylated byproducts, and the difficulty in synthesizing primary amines from ammonia.
- Reagents: Formic acid, ammonium formate.
- Reactants: Aldehyde or ketone, amine (often ammonia or a primary amine).
- Products: Secondary or tertiary amines.
- Reaction type: Formation of C-N bonds (reductive amination).
- Related reactions: Wolff-Kishner reduction, Eschweiler-Clarke reaction.
Fig 1. Leuckart-Wallach reaction and its mechanism. [1]
Mechanism of Leuckart-Wallach Reaction
The reaction first generates an iminium ion intermediate, which is then reduced by formate anions as a negative hydrogen source, and the reaction finally stops at the tertiary amine step.
Eschweiler-Clarke Reaction
When aldehydes are used instead of ketones, it is an Eschweiler-Clarke reduction amination reaction. Primary and secondary amines are reduced and methylated using a formaldehyde/formic acid system. Since N-methyl is a structural feature of many cyclic alkaloids, this reaction is often used in the synthesis of alkaloids.
Fig 2. Eschweiler-Clarke reaction. [1]
Application Examples of Leuckart-Wallach Reaction or Eschweiler-Clarke Reaction
- Example 1: Michael O. Frederick et al. used the Leuckart–Wallach reaction to synthesize the CDK 4/6 inhibitor abemaciclib. Specifically, the synthesis used Suzuki coupling, followed by Hartwig-Buchwald amination to connect three of the four subunits. The last step was reductive amination using Leuckart-Wallach conditions. The key to the Leuckart-Wallach reaction is the addition of trimethyl orthoformate to remove the water formed during the reaction and allow the reaction to go to completion. [2]
- Example 2: Oxygenated components for isocyanide generation via Leuckart-Wallach are often much cheaper than the corresponding primary amines used in the classical synthetic pathway. In addition, the structural diversity and accessibility of oxygenated components are greater than those of primary amines. The work of Constantinos G. Neochoritis et al. demonstrates a modified Leuckart-Wallach formamide procedure and representative examples with yields. [3]
- Example 3: Adam T. Gillmore et al. report a synthetic route to prepare novel PARP inhibitors by multikilogram-scale scale-up of a reductive alkylation pathway. The Eschweiler–Clarke reaction can be used to synthesize the poly(ADP-ribosyl) polymerase (PARP) inhibitor rucaparib (Rubraca). [4]
Fig 3. Synthetic examples via Leuckart-Wallach reaction or Eschweiler-Clarke reaction.
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References
- Jie Jack Li. Name Reactions-A Collection of Detailed Mechanisms and Synthetic Applications, Sixth Edition, 2021.
- Frederick, Michael O., et al. Tetrahedron Letters, 2015, 56(7), 949-951.
- Neochoritis, Constantinos G., et al. Organic letters, 2015, 17(8), 2002-2005.
- Gillmore, Adam T., et al. Organic Process Research & Development, 2012, 16(12), 1897-1904.
