<p>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 <i>N</i>-oxide,
before taking benefit of an <i>O</i>-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.</p>