Dynamic Kinetic Resolution Approach to C–O Axially Chiral Benzonitriles via N‑Heterocyclic Carbene-Catalyzed Atroposelective Imine Umpolung

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.