Growth vector elaboration of fragments: regioselective functionalization of 5-hydroxy-6-azaindazole and 3-hydroxy-2,6-naphthyridine

Autor(es)

da Silva Junior, Paulo Eliandro ; Gil de Melo, Shaiani Maria ; de Paula, Murilo Helder ; Vessecchi, Ricardo ; Opatz, Till ; Day, James E. H. ; Ganesan, A. ; Emery, Flavio da Silva

• Tipo de documento: Artigo Científico
• Fonte: ORGANIC & BIOMOLECULAR CHEMISTRY; v. 20, n. 37, p. 8-pg., 2022-08-26.

Resumo

This article discusses the reactivity of 6-azaindazole (1) and 2,6-naphthyridine (2), proposed to be "heteroaromatic rings of the future," which would be useful for fragment-based drug discovery (FBDD) campaigns, developing growth vectors for fragment elaboration by selectively functionalizing different positions on the rings. The pyridone oxygens and pyrazole nitrogen can be functionalized selectively. Arylation at the alpha-carbon of the pyridone moiety was achieved by a transition metal-free radical cross-coupling using aryl hydrazines. This method proceeded under mild conditions without the need for protection of the hydroxypyridine. Additionally, we developed a method for the regioselective C-3 functionalization of heterocycle 1via N-sulfonamide rearrangement. This method involved a novel regioselective base-mediated N-C migration of the N-1 sulfonamide to yield the C-3 sulfone. This procedure is also applicable for indazole C-3 functionalization and mechanistic studies of the rearrangement suggest that an intermolecular process is involved. These reactions enable the fragment elaboration of heterocycles 1 and 2 in several growth vectors to facilitate their use in FBDD. (AU)

• Processo FAPESP: 16/24817-4 - Desenvolvimento de funcionalizações seletivas em novos heterociclos
• Beneficiário: Paulo Eliandro da Silva Júnior
• Modalidade de apoio: Bolsas no Exterior - Estágio de Pesquisa - Doutorado
• Processo FAPESP: 13/26485-0 - Desenvolvimento de novos ligantes de Receptor Ativado por Proliferadores de Peroxissoma por meio de uma abordagem de Descoberta de Fármacos baseada em fragmento
• Beneficiário: Paulo Eliandro da Silva Júnior
• Modalidade de apoio: Bolsas no Brasil - Doutorado