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Programmed multiple C-H bond functionalization of the privileged 4hydroxyquinoline template

Abstract : The introduction of substituents on bare heterocyclic scaffolds can selectively be achieved by directed C-H functionalisation. 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 functionalisation of a "programmed" 4-hydroxyquinoline. This medicinally privileged template indeed possesses multiple reactive sites for diversity-oriented functionalisation, 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 functionalise position 5. Our study highlights the power of multiple C-H functionalisation to generate diversity in a biologically relevant library, after showing its strong antimalarial potential.
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https://hal.archives-ouvertes.fr/hal-03256641
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Submitted on : Thursday, June 10, 2021 - 1:18:43 PM
Last modification on : Saturday, June 26, 2021 - 3:39:01 AM
Long-term archiving on: : Saturday, September 11, 2021 - 6:48:09 PM

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Quentin Ronzon, Wei Zhang, Nicolas Casaretto, Elisabeth Mouray, Isabelle Florent, et al.. Programmed multiple C-H bond functionalization of the privileged 4hydroxyquinoline template. Chemistry - A European Journal, Wiley-VCH Verlag, 2021, 27 (28), pp.7764-7772. ⟨10.1002/chem.202100929⟩. ⟨hal-03256641⟩

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