Anticancer Molecule Discovery via C2-Subsituent Promoted Oxidative Coupling of Indole and Enolate

Summary C2, C3-disubstituted indole is one of the most frequently encountered motifs in bioactive alkaloids and medicinal chemistry. Thus, developing novel, concise, and efficient access to it is highly desired in drug discovery. Herein, we present such an approach to this scaffold by direct oxidative coupling of C2-substituted indoles and enolates. Compared with indole bearing no C2-substituent, higher yields (up to 96%) were obtained for C2-substituted indoles in most cases. Mechanistic studies showed the reaction went through a Fe-chelated radical-anion oxidative coupling procedure promoted by C2-substituent on indole by two means: (1) stabilizing C2-radical intermediate during the reaction; (2) reducing indole homocoupling. This approach serves as a synthetic useful tool to quickly build up bioactive small molecule library of C2, C3-disubstituted indoles, and several products showed promising anticancer activities. Besides, indomethacin and its analogs were conveniently prepared in three-step sequence efficiently, indicating the potential application of our approach in medicinal chemistry.