Journal
CHEMISTRY-A EUROPEAN JOURNAL
Volume 27, Issue 28, Pages 7764-7772Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/chem.202100929
Keywords
Antimalarial drugs; C− H bond functionalization; Compound library; Directing groups; Divergent synthesis
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Funding
- Labex CHARM3AT
- graduate school of Institut Polytechnique de Paris
- CNRS
- Ecole Polytechnique
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Our study reports the multiple, site-selective, metal-catalyzed C-H functionalization of a programmed 4-hydroxyquinoline, demonstrating its ability to introduce diversity into a biologically relevant chemical library.
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.
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