Harnessing the "Methyl Effect" in the Development of Novel meta-Directing Template for C-H Cyanation

The significance of chelation-assisted C-H functionalization stands upon the superior site-selectivity, easy synthesis, and diverse product utility. In this work, we design a meta-directing scaffold by tuning the side chain of a pyrimidine-based template to attain unconventional site-selectivity in anilines. A simple methyl substitution at the side chain enhances the directing group (DG) efficacy significantly, leading to an almost exclusive meta-selectivity. The current DG further enables a meta-selective cyanation of aniline and its higher homologues irrespective of the substrate electronic bias. The synthetic impact of the methodology is further highlighted with late-stage functionalizations of two very popular local anesthetics butamben and benzocaine. A thorough experimental and in silico study further unfolds the importance of the substitution effect in attaining superior site-selectivity and the role of silver carbonate in the mechanistic cycle.