Palladium-Catalyzed Enantioselective C(sp3)-H/C(sp3)-H Umpolung Coupling of N-Allylimine and α-Aryl Ketones.

Abstract

Asymmetric functionalization of the C(sp3)-H bond is an attractive yet challenging strategy to achieve versatile bond-forming events, enabling the precise assembly of molecular complexity with minimal manipulation of functional groups. Here, we report an asymmetric C(sp3)-H/C(sp3)-H umpolung coupling of N-allylimine and coordinating α-aryl carbonyls by using chiral phosphoramidite-palladium catalysis. A wide variety of α-heteroaryl ketones and 2-acylimidazoles are nicely tolerated to open a convenient and tunable avenue for efficient synthesis of enantioenriched β-amino-γ,δ-unsaturated carbonyl derivatives with high levels of regio- and stereoselectivities, capable of providing a key intermediate for asymmetric synthesis of Focalin. This protocol showcases an umpolung reactivity of the N-allylimines through a concerted proton and two-electron transfer process to cleave the allylic C-H bond, effectively complementing established methodology for allylic C-H functionalization. An inner-sphere allylation pathway for both α-heteroaryl carbonyls and 2-acylimidazoles to attack the π-allylpalladium species is suggested by computational studies and experimental facts, wherein the nitrogen coordination to the palladium center enables the preference of branched regioselectivity.