Dynamic Kinetic Resolution Approach to C–O Axially Chiral Benzonitriles via N-Heterocyclic Carbene-Catalyzed Atroposelective Imine Umpolung
Sayan Shee, Darshini Ramachandran, Romin Gogoi, Akkattu T. Biju
Abstract
Despite the potential applications of axially chiral benzonitriles and dual C–O axis containing diaryl ethers, the synthesis of C–O axially chiral benzonitriles remains a significant challenge. Herein, we report a metal- and cyanide-free strategy for atroposelective access to C–O axially chiral benzonitriles via a desymmetrization/dynamic kinetic resolution sequence. The strategy utilized the N-heterocyclic carbene (NHC)-catalyzed polarity reversal of imines generated in situ from the symmetric isophthalaldehydes and sulfonamides to afford atropoisomeric benzonitriles proceeding via aza-Breslow intermediates. Density functional theory studies toward the mechanism revealed that the rate-determining step involves the addition of NHC to the in situ generated imines. The racemization barrier studies reveal robust configurational stability of the C–O axis allowing for diverse downstream functionalizations.