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

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.

Automated summary

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.