4.5 Article

Maleic Acid/Thiourea-Catalyzed Dearomative ipso-Friedel-Crafts Reaction of Indoles to Produce Functionalized Spiroindolenines

Journal

EUROPEAN JOURNAL OF ORGANIC CHEMISTRY
Volume 2021, Issue 29, Pages 3999-4006

Publisher

WILEY-V C H VERLAG GMBH
DOI: 10.1002/ejoc.202100215

Keywords

Brø nsted acid; Cyclization; Heterocycles; Organocatalysis; Spiro compound

Funding

  1. Toray Science Foundation
  2. Futaba Electronics Memorial Foundation
  3. Takeda Science Foundation
  4. JSPS KAKENHI [JP18K05098, 18H02550, 19J21528]
  5. Grants-in-Aid for Scientific Research [18H02550, 19J21528] Funding Source: KAKEN

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A dual catalyst system consisting of maleic acid and Schreiner's thiourea was used to successfully synthesize a spiroindolenine core, providing a new approach for synthetic strategies that were previously difficult to achieve. Computational studies revealed a unique macrocyclic transition state that lowered the activation energy of the spirocyclization reaction.
A dearomative spirocyclization of diazo-functionalized indoles was developed under metal-free conditions. Although the spiroindolenine architecture with a tertiary alkyl substituent at the 2-position is a privileged scaffold of bioactive molecules, a general synthetic strategy has remained elusive. In this study, a dual catalyst system comprising maleic acid and Schreiner's thiourea was used to construct a spiroindolenine core that was inaccessible by rhodium or silver catalysis. Computational studies revealed a unique macrocyclic transition state consisting of the substrate, maleic acid, and thiourea cocatalyst, which lowered the activation energy of spirocyclization through multipoint mutual interactions.

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