Enantioselective catalytic Strecker reaction on cyclic (Z)-aldimines in flow: reaction optimization and sustainability aspects

Abstract

Catalytic enantioselective Strecker reactions on an achiral substrate using sub-stoichiometric amounts of a chiral catalyst represent an evolving key strategy for the effective synthesis of α-amino nitriles. We herein disclosed the set-up of a flow-based methodology for enantioselective Strecker, employing ethyl cyanoformate as a relatively safe cyanide source, a cinchona-based catalyst, and methanol as additive. A thorough exploration of key parameters allowed the identification of the most efficient reagent mixing mode, the optimum solvent for the flow synthesis, minimum catalyst loading, additive, temperature, and residence time. The newly developed method allows straightforward reaction channeling towards the fast and complete formation of the α-amino nitrile products, thus reducing the yield drop due to indolenine degradation during long-lasting batch-wise reactions. Moreover, we herein provide preliminary hints for sustainability, by proposing a simple procedure for catalyst recycling, thus opening the way for further optimization of the proposed methodology.

Graphical Abstract