Cu(II)-Catalyzed Cascade Cyclization and Oxidative Annulation to Access Functionalized 1 H -Furo[3,2- b ]pyrazolo[4,3- e ]pyridines

A novel Cu(II)-catalyzed [3 + 3]/oxidative cyclization strategy is developed for the construction of highly functionalized 1 H -furo[3,2- b ]pyrazolo[4,3- e ]pyridine derivatives (FPPDs). This transformation employs readily accessible 5-aminopyrazole and ( E )-6-phenylhex-3-en-5-yn-2-one as coupling partners and proceeds through a sequential [3 + 3] cyclization/oxidative C–O bond-forming cascade. In 1,4-dioxane at 100 °C, using Cu(OAc) 2 as the catalyst, Ag 2 CO 3 and O 2 as co-oxidants, and PhCO 2 H as an additive, the reaction proceeds via sequential 1,6-conjugate addition and aza-Michael addition to construct the pyridine ring. Subsequently, the ketone moiety undergoes Cu(II)-catalyzed keto–enol tautomerization, followed by site-selective oxidative cyclization to furnish the furan ring. This one-pot cascade process forms one C–C bond, one C═N bond, and one C–O bond with high chemoselectivity and excellent regioselectivity. Moreover, the reaction exhibits a broad substrate scope and good functional group tolerance, enabling the synthesis of a diverse range of FPPDs in good to high yields. This protocol provides a concise route to this unprecedented tricyclic scaffold and expands the scope of copper-catalyzed cascade cyclization reactions, offering opportunities for further biological evaluation and drug discovery.