Substrate-Dependent Selectivity in Sc(OTf)₃-Catalyzed Cyclization of Alkenoic Acids and <i>N</i>-Protected Alkenamides

Abstract

Five- and six-membered ring lactones and lactams are ubiquitous frameworks in various natural and synthetic molecules and are key building blocks in organic synthesis. Catalytic addition of an O-H or N-H bond across an unactivated C–C double bond is an appealing approach to rapidly access such highly valuable N- and O-containing skeletons in a waste-free and 100% atom efficient process. Herein, we report, for the first time, the efficient and high-yield cyclization of δ/ε-alkenoic acids and N-protected δ-alkenamides catalyzedby practical and easily accessible Lewis acid scandium(III) triflate under thermal and microwave conditions. The selectivity outcome of the reaction of δ/ε-alkenoic acids was dependent on the substitution patterns of the backbone chain and alkene moiety, leading to the exclusive formation of either the corresponding γ/δ-lactones via an O-selective cyclization or the Friedel–Crafts-type product by C-selective cyclization. An uncommon and rarely disclosed O-selective cyclization occurred preferentially or exclusively when N-protected δ-alkenamides were engaged in the reaction. The atom selectivity of the cyclization was unambiguously confirmed by single crystal X-ray crystallography.

Keywords

• alkene hydrofunctionalization
• scandium triflate
• lactones
• lactames
• Friedel–Crafts
• alkenoic acids