Silane-mediated, facile C–H and N–H methylation using formaldehyde

Abstract

The use of (para)-formaldehyde for the methylation/alkylation 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 indole substrates, the process utilizes a Friedel–Crafts alkylation, followed by silane as a hydride donor, under a mild acidic medium. The method has been employed for the synthesis of the antifungal drug butenafine and a derivative of the non-steroidal anti-inflammatory drug (NSAID) flurbiprofen.