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

Tseke, Kavnen and Lennon, Claire and O'Mahony, Joseph and Kinsella, Michael (2021) A Continuous-Flow Route to Enantioenriched 3-Substituted-3-Hydroxyoxindoles : Organocatalytic Aldol Reactions of Isatin with Acetone. European Journal of Organic Chemistry, 2021 (42). pp. 5767-5774. ISSN 1434-193X

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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.

Item Type: Article
Additional Information: Funding Information: The authors are thankful for the financial support received from the Waterford Institute of Technology Postgraduate Scholarship Scheme (WD?2017?PhD?026w) for this research. Funding Information: The authors are thankful for the financial support received from the Waterford Institute of Technology Postgraduate Scholarship Scheme (WD 2017 PhD 026w) for this research. Publisher Copyright: © 2021 Wiley-VCH GmbH
Uncontrolled Keywords: /dk/atira/pure/subjectarea/asjc/1600/1606
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Depositing User: Admin SSL
Date Deposited: 19 Oct 2022 23:06
Last Modified: 03 Aug 2023 16:05
URI: http://repository-testing.wit.ie/id/eprint/4115

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