Mild Sustainable Amide Alkylation Protocol Enables a Broad Orthogonal Scope

Abstract

Herein, the development of a mild sustainable protocol to couple primary alkyl chlorides and bromides with amides is described. In contrast to current methodologies, our system does not require the use of strongly basic conditions, high temperatures, or the addition of an organometallic catalyst, thereby enabling access to a remarkably orthogonal scope. K₃PO₄ is used to facilitate the formation of secondary and tertiary amides, which are ubiquitous scaffolds in bioactive molecules and natural products. Alkylated amide products are obtained in good to excellent yields, with no substantial limitations observed based on the steric and electronic properties of either coupling partner.