Programmed Multiple C-H Bond Functionalization of the Privileged 4-hydroxyquinoline Template |
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Authors: | Quentin Ronzon Dr Wei Zhang Dr Nicolas Casaretto Dr Elisabeth Mouray Prof?Dr Isabelle Florent Dr Bastien Nay |
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Institution: | 1. Laboratoire de Synthèse Organique, Ecole Polytechnique, ENSTA, CNRS, Institut Polytechnique de Paris, 91128 Palaiseau Cedex, France;2. Laboratoire de Chimie Moléculaire, Ecole Polytechnique, CNRS, Institut Polytechnique de Paris, 91128 Palaiseau Cedex, France;3. Unité Molécules de Communication et Adaptation des Microorganismes (MCAM, UMR7245) Muséum national d'Histoire naturelle, CNRS, CP 52, 57 rue Cuvier, 75005 Paris, France |
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Abstract: | 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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Keywords: | Antimalarial drugs C?H bond functionalization Compound library Directing groups Divergent synthesis |
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