Method for Reductive N ‐Alkylation of a Secondary Amine With an Aldehyde at Room Temperature Through Utilization of an Imine Reductase

An organic‐synthetic method for smooth N ‐alkylation of a secondary amine with an aldehyde as reagents and glucose as a reducing agent in aqueous medium has been developed, exemplified for the N ‐benzylation of 2‐methylpyrrolidine. This transformation proceeds through enzyme catalysis with an imine reductase as a biocatalyst and a glucose dehydrogenase for in situ‐cofactor regeneration. In a one‐pot three‐step synthesis, consisting of non‐catalyzed hemiaminal formation, dehydration to the iminium ion and its subsequent enzymatic reduction, the desired N ‐benzylated pyrrolidine product was formed in 45% yield with >99% ee. In general, this synthetic methodology represents a “biocatalytic analog” of the Eschweiler‐Clarke reaction, but proceeds under much milder reaction conditions. Furthermore, this method contributes to opening a perspective for inserting non‐branched substituted alkyl moieties as N ‐substituents, thus leading to tertiary amine structures that are often found in pharmaceutical molecules.