General Synthesis of <i>N</i>-Alkylindoles from <i>N</i>,<i>N</i>-Dialkylanilines via [4 + 1] Annulative Double C–H Functionalization
Bowen Zhang, Frederik R. Erb, Aristidis Vasilopoulos, Eric A. Voight, Erik J. Alexanian
Abstract
Strategies enabling the construction of indoles and novel polycyclic heterocycles from simple building blocks streamline syntheses in synthetic and medicinal chemistry. Herein, we report a C–H functionalization approach to N -alkylindoles proceeding via a double, site-selective C(sp 3 )–H/C(sp 2 )–H [4 + 1] annulation of readily accessed N,N -dialkylanilines. This protocol features a site-selective hydrogen atom transfer by a tuned N - t Bu amidyl radical and addition of a sulfonyl diazo coupling partner, which promotes highly site-selective homolytic aromatic substitution of the (hetero)aromatic core. Mild decarboxylation of the annulation product enables the overall introduction of a carbyne equivalent into the N,N -dialkylaniline scaffold. Furthermore, the site-selectivity and mild conditions of the indolization facilitate direct access to N -alkyl indole scaffolds in late-stage functionalization (LSF) settings.