C-H Methylation of Iminoamido Heterocycles with Sulfur Ylides*

Abstract

The direct methylation of N-heterocycles is an important transformation for the advancement of pharmaceuticals, agrochemicals, functional materials, and other chemical entities. Herein, the unprecedented C(sp² )-H methylation of iminoamido heterocycles as nucleoside base analogues is described. Notably, trimethylsulfoxonium salt was employed as a methylating agent under aqueous conditions. A wide substrate scope and excellent level of functional-group tolerance were attained. Moreover, this method can be readily applied to the site-selective methylation of azauracil nucleosides. The feasibility of gram-scale reactions and various transformations of the products highlight the synthetic potential of the developed method. Combined deuterium-labeling experiments aided the elucidation of a plausible reaction mechanism.

Keywords: C−H functionalization; N-heterocycles; alkylation; methylation; sulfur ylides.