A Continuous-Flow Route to Enantioenriched 3-Substituted-3-Hydroxyoxindoles: Organocatalytic Aldol Reactions of Isatin with Acetone

Kavnen Tseke, Claire Lennon, Joseph O'Mahony, Michael Kinsella

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)5767-5774
Number of pages8
JournalEuropean Journal of Organic Chemistry
Volume2021
Issue number42
DOIs
Publication statusPublished - 15 Nov 2021

Keywords

  • Amino alcohol
  • Asymmetric synthesis
  • Continuous flow
  • Kamlet-Taft parameters
  • Organocatalysis

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