Dearomatization-Rearomatization Reaction of Metal-Polarized Aza-ortho-Quinone Methides.

Metal-polarized aza-ortho-quinone methides (aza-o-QMs) are a unique and efficient handle for azaheterocycle synthesis. Despite great achievements, the potential of these reactive intermediates has not yet been fully exploited, especially the new reaction modes. Herein, we disclosed an unprecedented dearomatization process of metal-polarized aza-o-QMs, affording transient dearomatized spiroaziridine intermediates. Based on this serendipity, we accomplished three sequential dearomatization-rearomatization reactions of benzimidazolines with aza-sulfur ylides, enabling the divergent synthesis of bis-nitrogen heterocycles with high efficiency and flexibility. Moreover, experimental and theoretical studies were performed to explain the proposed mechanisms and observed selectivity. Further cellular evaluation of the dibenzodiazepine products identified a hit compound for new antitumor drugs.

De Novo Construction of Chiral Aminoindolines by Cu-Catalyzed Asymmetric Cyclization and Subsequent Discovery of an Unexpected Sulfonyl Migration.

Searching for efficient strategies to access structurally novel aminoindolines is of great significance for drug discovery. However, catalytic asymmetric de novo construction of aminoindoline scaffolds with functionality primed for diversification still remains elusive. Here, we report a Cu-catalyzed asymmetric cyclization of ethynyl benzoxazinones with amines, producing chiral 3-aminoindolines in good yield and with high enantioselectivity (up to 97% yield and 98:2 er). Moreover, a radical-mediated sulfonyl migration of these products was unexpectedly found, further affording new chiral 3-aminoindolines bearing alkenyl sulfonyl groups with retained enantiopurity (up to 84% yield and 98:2 er). Bioactivity evaluations indicate that these 3-aminoindolines show notable antitumor activities and chirality is proven to have a significant impact on their antitumor activity.