Growth vector elaboration of fragments: regioselective functionalization of 5-hydroxy-6-azaindazole and
Paulo Eliandro da Silva Júnior1, Shaiani Maria Gil de Melo1, Murilo Helder de Paula1
1Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Departmento de Ciências Farmacêuticas, Universidade de São Paulo, Ribeirão Preto 14040-903, Brazil. flavioemery@usp.br.
Abstract:
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 α-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.
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