NaH-promoted one-pot oxidation/aromatization and C-3H chalcogenation of indoline: atmospheric control-based selective intermediates†

A sub-stoichiometric sodium hydride promoted strategy with diselenides and disulphides has been devised for the one-pot cascade oxidation/aromatization and regioselective C-3 selenylation/sulfenylation of indolines under transition metal-free conditions. The newly introduced protocol facilitates the synthesis of C-3 chalcogenated indoles with exceptional flexibility and efficiency. The chalcogenation reaction was successfully performed under both aerobic and inert conditions leading to the formation of C-3 chalcogenated indoles via two different intermediates. Mechanistic insights were derived from various controlled experiments and trapping of reaction intermediates under both sets of conditions, with structural verification achieved via spectral analysis. The prevalence of the radical route was validated by EPR spectroscopy and radical quenching experiments. A broad range of 3-arylthioindoles and 3-arylselenylindoles containing electron donating and withdrawing substituents were obtained in high to excellent yields with this modest and environmentally benign protocol. Additionally, post-transformation of sulfenylated derivatives has further led to the generation of a diarylsulfoxide core of pharmaceutical interest. The reaction is applicable to gram scale synthesis without significant loss of product yield, indicating its application for large-scale synthesis. Interestingly, the biological evaluation of the 5-bromo-3-((4-(trifluoromethyl)phenyl)selanyl)-1H-indole and 3-((4-chlorophenyl)thio)-1H-indole revealed significant activity against rapidly growing mycobacteria (RGM).