Cu(II)-Catalyzed Cascade Cyclization and Oxidative Annulation to Access Functionalized 1H-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 1H-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, Ag2CO3 and O2 as co-oxidants, and PhCO2H 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.