A Riboflavin-Derived Flavinium Salt Mediates Chemoselective Methylation Reactions

Selective methylation is among the most relevant transformations in synthetic chemistry and the discovery of new drug molecules. A methyl group is typically installed using strong electrophiles such as methyl iodide or dimethyl sulfate, which are associated with safety hazards and limited chemoselectivity. A promising strategy for circumventing these limitations relies on splitting the methylation into a two-step procedure under mediator control. However, such reactions, including the Mukaiyama redox condensation, currently lack applicability since the mediator is lost as organic waste, resulting in a low atom economy. We have developed a flavin-mediated methylation strategy with easily accessible methyl diphenylphosphinite (Ph₂POMe) as the source of the methyl group. The flavin mediator is easily recovered by a simple acidic treatment followed by oxidation with air. Detailed NMR spectroscopic studies and structural information by X-ray crystallography paint a clear mechanistic picture, while we show the chemoselective modification of a variety of organic substrates and also demonstrate trideuteromethylation. Methylation is accomplished with complex molecules, including venetoclax and nevirapine. We envision the flavin-mediated methodology to be adaptable to other alkylation reactions besides methylation. Within the realm of the latter, chemoselective modification of nucleobases stands out as a promising target.