Copper-Catalyzed Cascade Cyclization of Indolyl Homopropargyl Amides: Stereospecific Construction of Bridged Aza-[n.2.1] Skeletons.Angew Chem Int Ed Engl. 2019 07 08; 58(28):9632-9639.AC
Catalytic cycloisomerization-initiated cascade cyclizations of terminal alkynes have received tremendous interest, and been widely used in the facile synthesis of a diverse array of valuable complex heterocycles. However, these tandem reactions have been mostly limited to noble-metal catalysis, and are initiated by an exo-cyclization pathway. Reported herein is an unprecedented copper-catalyzed endo-cyclization-initiated tandem reaction of indolyl homopropargyl amides, where copper catalyzes both the hydroamination and Friedel-Crafts alkylation process. This method allows the practical and atom-economical synthesis of valuable bridged aza-[n.2.1] skeletons (n=3-6) with wide substrate scope, and excellent diastereoselectivity and enantioselectivity by a chirality-transfer strategy. Moreover, the mechanistic rationale for this novel cascade cyclization is also strongly supported by control experiments, and is distinctively different from the related gold catalysis.