Mono-selective N-Methylation of Amides, Indoles, and related Structures using Quaternary Ammonium Salts as Solid Methylating Agents

Abstract

In our latest publication, we described using of phenyl trimethylammonium iodide as an α-selective methylating agent for different aryl compounds. We now expanded this novel method to N-methylation using solid quaternary ammonium salts as safe, non-toxic, and easy-to-handle reagents. Herein, we found phenyl trimethyl ammonium iodide (PhMe3NI) having an outstanding mono-selectivity in the methylation of primary amides under mild basic conditions. Further, we demonstrate the broad applicability of this new method by expanding the scope towards N-heterocycles, e.g., indoles, and prove its potential use in the late-stage functionalization of bioactive compounds. We also implemented ethylation on the nitrogen using related quaternary ammonium salts.