Axial Chirality Control Through Palladium‐Catalyzed Alkenylation Reactions for the Atroposelective Synthesis of 4‐Arylquinolin‐2‐ones

Axially chiral biaryl scaffolds are privileged structures used in organic synthesis as ligands or chiral catalysts, but also present in natural and synthetic compounds with relevant biological properties. However, the enantioselective synthesis of atropoisomers through C-H activation reactions remains a challenge, with few approaches described that rely on de novo construction of an (hetero)arene with the chirality being installed by simultaneous ring formation. We herein disclose a Pd(II)-catalysed intramolecular C-H alkenylation of cinnamides for the atroposelective synthesis 4-arylquinolones by the chiral ligand controlled generation of a chiral axis. A chiral quinoline-oxazoline (Quinox) ligand was identified as a superior ligand for this transformation. The key for achievement of excellent enantioselectivity (up to 94% ee) was substitution on the N atom of the cinnamide (metoxycarbonyl group) and the solvent (HFIP). DFT studies have provided insight on the mechanism, showing that the reaction proceeds via prior activation of the alkene, and the enantioselectivity is determined during the beta-hydride elimination step.