Copper-Catalyzed Asymmetric Addition Of N-Sulfonyl Ketimines With Grignard Reagents

Chiral amines,as an important molecular structure,widely exist in many pharmaceuticals,alkaloids,agrochemical,functional materials and organic catalysts.In the past few decades,the synthesis techniques of chiral molecules have been developed rapidly,and the synthesis methods of chiral α-secondary amines have been well developed.In contrast,the development of synthetic strategies for chiral α-tertiary amines is relatively slow due to their more steric hindrance,which makes chiral control more difficult.Transition-metal-catalyzed asymmetric addition of organometallic reagents to ketimines represents a straightforward and highly efficient method for constructing chiral α-tertiary amines,which has attracted persistent interest from synthetic chemists.As a classical nucleophile,highly reactive Grignard reagents has been commonly used in industry and academia.It has the characteristics of high reactivity,easy availability,cheap raw materials and low toxicity.It is a powerful tool for the construction of C-C bond.The introduction of Grignard reagent into the asymmetric addition of ketimines may pave the way for the synthesis of chiral α-tertiary amines.However,the intrinsic challenges must be addressed:(1)the lower reactivity of ketimines relative to ketones and aldimines,(2)the C=N bond of the ketimines can be easily reduced directly and hydrogenated through Meerwein-Ponndorf-Verley reduction reaction,(3)the high reactivity of Grignard reagents may cause uncatalyzed additions to dominate,and(4)the basicity of Grignard reagents that leads to enolization.In this paper,we developed a new type of Cu(Ⅰ)/W-Phos as catalyst,ether as solvent,asymmetric addition of alkyl Grignard reagents to N-sulfonyl ketimines at-78 ℃,obtaining a series of chiral α-tertiary amines with up to 99% ee values and up to97% yields.This catalytic system shows a wide range of substrate scope,not only compatible with benzo five-and six-membered cyclic N-sulfonyl ketimines,but also suitable for acyclic N-sulfonyl ketimines.Substituted ketimines with different electronic effects and steric hindrance as well as linear Grignard reagents are well tolerated.Gram scale preparation and further derivation of the product show the practicability of the method.