Enantioconvergent Alkylations of Amines by Alkyl Electrophiles: Copper-Catalyzed Nucleophilic Substitutions of Racemic α-Halolactams by Indoles

Abstract

Transition-metal catalysis has the potential to address shortcomings in the classic S_N2 reaction of an amine with an alkyl electrophile, both with respect to reactivity and to enantioselectivity. In this study, we describe the development of a user-friendly method (reaction at room temperature, with commercially available catalyst components) for the enantioconvergent nucleophilic substitution of racemic secondary alkyl halides (α-iodolactams) by indoles. Mechanistic studies are consistent with the formation of a copper(I)–indolyl complex that reacts at different rates with the two enantiomers of the electrophile, which interconvert under the reaction conditions (dynamic kinetic resolution). This investigation complements earlier work on photoinduced enantioconvergent N-alkylation, supporting the premise that this important challenge can be addressed by a range of strategies.