Reusable Brønsted Acidic Ionic Liquid Catalyzed Reductive Alkylation of Quinolines to Functionalized Tetrahydroquinolines

Abstract

A Brønsted acidic ionic liquid (BAIL)-catalyzed one-pot tandem reduction of quinoline to tetrahydroquinoline (THQ) followed by reductive alkylation by the aldehyde has been demonstrated under mild reaction conditions with a shorter reaction time. This step-economical synthetic approach is suitable for late-stage functionalization of complex bioactive molecules. The reaction is highly chemoselective and tolerates a wide range of reducible-sensitive functional groups. The current reductive N-alkylation approach was also successfully utilized to synthesize novel tricyclic oxazino-fused-tetrahydroquinoline/benzoxazine compounds via tandem reductive cyclization of 1-aryl-2-(8-quinolinyloxy) ethanones. Further reductive protocol has been applied for the synthesis of antiarrhythmic drug nicainoprol and tubulin polymerization inhibitor efficiently. Notably, BAIL was easily recovered and reused multiple times without a considerable loss in catalytic activity. The elucidation of the underlying mechanism was achieved through a combination of several control experiments, kinetic studies, and isotopic labelling experiments. This study offers a new reaction pathway for the reduction of quinoline, in which BAIL facilitates proton transfer through a distinctive hydrogen bonding ion-pair mechanism.

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