A Continuous‐Flow Route to Enantioenriched 3‐Substituted‐3‐Hydroxyoxindoles: Organocatalytic Aldol Reactions of Isatin with Acetone
Kavnen Tseke, Claire M. Lennon, Joseph O'Mahony, Michael Kinsella
Abstract
Abstract An efficient L‐leucinol catalysed asymmetric synthesis of 3‐substitued‐3‐hydroxyoxindoles was for the first time completed under continuous flow, providing a safer route for accelerating the reaction at higher temperatures without adversely affecting enantioselectivity. Initial batch solvent screening of the isatin‐acetone aldol reaction revealed neat acetone as the media best suited in flow as it dissolved isatin and afforded ( S )‐enantiomer of the adduct in 84 % ee . Solvents with Kamlet‐Taft basicity (β)>0.6 and proticity (α)≈0 had a higher solubility of isatin but poor reaction performance while solvents with β<0.2 and α<0.6 performed excellently in the reaction albeit with poor isatin solubility. The addition of 10 equivalents of water improved the neat reaction to afford 94 % yield in 93 % ee at 20 °C after 48 h. When transferred to continuous flow, complete conversion was observed in 12 h residence time at 40 °C without loss in enantioselectivity. Further substrate studies in flow were undertaken with a 4‐fold dilution and a 60 °C reaction temperature required for some derivatives. Excellent yields and enantioselectivities were obtained in most cases.