Remote C6-Selective Ruthenium-Catalyzed C–H Alkylation of Indole Derivatives via σ-Activation

Abstract

The site-selective functionalization of an indole template offers exciting possibilities for the derivatization of molecules with useful biological properties. Herein, we report the remote C6-selective C–H alkylation of indole derivatives enabled by dual cyclometalation/redox ruthenium catalysis. Remote alkylation was achieved using N-pyrimidinyl indoles with an ancillary ester directing group at the C3 position. This ancillary directing group proved pivotal to reactivity at C6, with yields up to 92% achieved. A one-pot procedure to install this directing group followed by remote C6 functionalization has also been reported; both processes are shown to proceed via ruthenium redox catalysis. Computationally calculated Fukui indices elucidated that the C6 position was the most reactive vacant C–H site toward potential functionalization. When this investigation was coupled with deuterium incorporation studies, a C2-cyclometalation/remote σ-activation pathway was deduced.