NHC‐Catalyzed Aldimine Umpolung/6π‐Electrocyclization Cascade to Access Tetracyclic Dihydrochromeno Indoles

Abstract The umpolung of aldimines using N‐heterocyclic carbenes (NHCs) is less explored compared to the established polarity reversal of aldehydes. Described herein is an NHC‐catalyzed imine umpolung /6π‐electrocyclization cascade, which leads to the atom‐ and pot‐economic synthesis of biologically important dihydrochromeno indoles. For the first time, the nucleophilic aza‐Breslow intermediates have been intercepted with unactivated alkynes. Preliminary mechanistic and DFT studies shed light on the role of the phenolic −OH moiety in promoting the addition of the aza‐Breslow intermediate to the unactivated alkyne via an intramolecular proton transfer in a stepwise manner. DFT studies also support the regioselectivity preference for the 5‐ exo‐dig cyclization pathway, leading to the exclusive formation of the indole products. Moreover, a comparison of Gibbs free energies provides insight into a thermodynamically preferred 6π‐electrocyclization over a competing oxa‐Michael pathway. Further, this strategy is applied to the formal synthesis of a Hepatitis C Virus (HCV) NS5A inhibitor in a step‐economical method.