Silane-mediated, Facile and Selective C(sp²)−H and N−Methylation using Formaldehyde

The use of (para)-formaldehyde for the selective reductive methylation of C(sp²)−H and N−H bonds, utilizing a combination of silane and hexafluoroisopropanol (HFIP) as activators, is reported. Overcoming the complexity of C(sp²)−H methylation on aryl and heteroaryl substrates, the process utilizes Friedel–Crafts alkylation, followed by silane as a hydride donor under mild acidic medium. The developed protocol offers a promising avenue for converting amines into their monomethylated counterparts with excellent yields. Mechanistic insights into the reductive methylation process are provided, highlighting the role of silane and HFIP in achieving good selectivity. This scalable transformation is well-suited for general alkylation using various non-activated aliphatic aldehydes under mild conditions in a shorter reaction time and is also adaptable for the late-stage methylation of pharmaceuticals and natural products. Notably, the method has been successfully employed for the efficient synthesis of the antifungal drug Butenafine and non-steroidal anti-inflammatory drug (NSAID) Flurbiprofen derivative.