Programmed Multiple C‐H Bond Functionalization of the Privileged 4‐hydroxyquinoline Template

The introduction of substituents on bare heterocyclic scaffolds can selectively be achieved by directed C−H functionalization. However, such methods have only occasionally been used, in an iterative manner, to decorate various positions of a medicinal scaffold to build chemical libraries. We herein report the multiple, site selective, metal‐catalyzed C−H functionalization of a “programmed” 4‐hydroxyquinoline. This medicinally privileged template indeed possesses multiple reactive sites for diversity‐oriented functionalization, of which four were targeted. The C‐2 and C‐8 decorations were directed by an N ‐oxide, before taking benefit of an O ‐carbamoyl protection at C‐4 to perform a Fries rearrangement and install a carboxamide at C‐3. This also released the carbonyl group of 4‐quinolones, the ultimate directing group to functionalize position 5. Our study highlights the power of multiple C−H functionalization to generate diversity in a biologically relevant library, after showing its strong antimalarial potential.