Catalytic asymmetric formal nucleophilic C2-substitution of indoles via C2-umpolung toward 2,3’-bisindole atropisomers

The electrophilic substitution of indoles represents the predominant functionalization strategy. However, due to the electron-rich nature of the indole scaffold, catalytic asymmetric nucleophilic substitution remains markedly underdeveloped—presenting significant synthetic challenges and standing in stark contrast to its well-established electrophilic counterpart. To overcome these challenges, we herein report a visible-light-mediated, chiral Brønsted acid-catalyzed C2-umpolung of 3-azoindoles, enabling their catalytic asymmetric formal nucleophilic C2-substitution with 2-substituted indoles. This strategy provides efficient access to axially chiral 2,3’-bisindoles in good yields with excellent enantioselectivities, thereby overcoming key challenges in both catalytic asymmetric nucleophilic substitution of indoles and the enantioselective construction of axially chiral 5-5 ring systems. This work not only establishes the catalytic asymmetric formal nucleophilic C2-substitution of indoles and an organocatalytic asymmetric synthesis of 2,3’-bisindole atropisomers, but also introduces a photoinduced umpolung strategy to promote nucleophilic substitutions of indoles, significantly expanding the frontiers of chiral indole chemistry and atropisomeric chemistry. The authors report a visible-light-mediated, chiral Brønsted acid-catalyzed C2-umpolung of 3-azoindoles, enabling their catalytic asymmetric formal nucleophilic C2-substitution with 2-substituted indoles. This strategy provides efficient access to axially chiral 2,3’-bisindoles in good yields with excellent enantioselectivities.