Copper(I)-Catalyzed Asymmetric Alkylation of α-Sulfanyl Acetamides

Abstract

α-Sulfanyl carbonyl moieties are common structural features in bioactive molecules. Herein, a copper(I)-catalyzed enantioselective alkylation of α-sulfanyl acetamides is disclosed, affording a broad array of chiral α,α-disubstituted amides in high yields with high enantioselectivity. Benzyl bromides, allyl bromides, propargyl bromide, and non-activated alkyl iodides serve as suitable alkylation electrophiles. Furthermore, structurally diversified amides are well tolerated. Control experiments and NMR studies indicate that α-phenylthioacetamide coordinates to the copper(I) catalyst through chelation, leading to activation of the α-protons, facile deprotonation, and subsequent formation of stabilized copper(I)-enolate. Finally, various transformations based on the amide moiety, especially the Weinreb amide, demonstrate synthetic utilities of the present method, together with the formal synthesis of a presynaptic cholinergic modulator (11).