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Catalytic Hydrogenation

Mechanism + Description

Can be via hetero or homogeneous metal catalysis and H2 Typically a reduction to the hemi-aminal occurs followed by elimination of water to an imine or iminium species which is then hydrogenated to the amine product. A side reaction is the alcohol formed by elimination of the amine from the hemi-aminal. Heterogeneous catalysts can reduce aromatic rings.

General comments

Potentially the greenest route to amines from amides, but traditionally not widely used in the pharmaceutical industry due to harsh conditions and specialist equipment – high temp, high H2 pressures. Poor selectivity and side reactions can also lower yields. Recently a number of groups have developed much more active catalysts (mainly homogeneous) that show high selectivity for the amine under milder conditions. Primary and secondary amides are preferred substrates, tertiary amides are possible, but problematic. Key academic groups working in this area are listed below. The advances in identifying more active and selective catalysts will make this route to amines more attractive for pharma synthesis.

David Cole-Hamilton
Robert Crabtree
David Milstein
Matthias Beller

Key references

Angew. Chem. Int. Ed. 2013, 52, 2231-2234 Catalytic Hydrogenation of Amides to Amines under Mild Conditions

J.Am. Chem. Soc. 1934, 56, 2419–2424 Catalytic Hydrogenation of Amides to Amines

J.Am. Chem. Soc. 2010, 132, 16756–16758  Direct Hydrogenation of Amides to Alcohols and Amines under Mild Conditions

Org. Process Res. Dev. 2014, 18, 289−302 Catalytic Hydrogenation of Carboxylic Acid Esters, Amides, and Nitriles with Homogeneous Catalysts

Doods and Cole HamlitonCatalytical Reduction of Amides Using LiAlH4 OR B2H6 in Sustainable Catalysis: Challenges and Practices for the Pharmaceutical and Fine Chemical Industries, Wiley

Relevant scale up example

None found.