Diversity-Oriented C–H Activation Reactions of the Naphthalene Scaffold

Diversity-oriented synthesis (DOS) has emerged as an efficient strategy for constructing diverse compound libraries, facilitating hit or lead identification in the drug discovery process. In parallel, developing diverse transformations at different sites is an appealing strategy to expand the diversity of appendages on scaffolds. Owing to the availability of C-H bonds at multiple sites of pharmacophores, diversity-oriented C-H activation reactions are an ideal approach to realize this goal. Given the pharmacophoric significance of the naphthalene scaffold in clinical drugs, diversity-oriented C-H functionalization reactions on this scaffold would be useful for drug discovery. Direct C-H activation at the challenging C6 and C7 positions has remained unexplored due to electronic similarity, remote distance from the directing group, and interference from geometrically identical positions (C7 vs C3, C6 vs C4). Herein, we report two types of templates designed to differentiate the C6 and C7 positions on the naphthalene scaffold. The success is attributed to manipulation of the distance parameter in the template and the utilization of an oligopeptide ligand. Notably, the utility of this diversity-oriented C-H activation is showcased through the divergent modification of naphthalene-containing complex molecules.