Effect of Solvate Ionic Liquids in the Enantioselective (S)‐Proline‐Catalyzed Mechanochemical Robinson Annulation

Abstract

Herein we report our observations from the study of the classical Robinson annulation reaction under solvent‐free mechanochemical activation by means of high‐speed ball milling. In particular, the enantioselective synthesis of the Wieland‐Miescher ketone was used as model reaction. (S)‐Proline was employed as chiral organocatalyst, either alone or in the presence of additives in order to determine their influence on the reaction’s speed and stereoselectivity. Most interesting, among the additives that were examined, four solvate ionic liquids (SIL) afforded the desired product with significantly improved enantioselectivity relative to the mechanochemically‐activated reaction catalyzed by (S)‐proline alone. Furthermore, the required reaction time was reduced from 3 days to 90 min. The potential of other proline‐type organocatalysts was explored in this ball‐milling process. Initial attempts to increase the scope of the reaction to afford related annulation products were unsuccessful. HPLC‐MS experiments were carried out in order to detect some of the species that intervene in the mechanism of the (S)‐proline‐catalyzed Robinson cyclization reaction involving 2‐methyl‐1,3‐cyclohexanedione and methyl vinyl ketone.