# A Riboflavin‐Derived Flavinium Salt Mediates Chemoselective Methylation Reactions

## TL;DR

A new methylation method using a flavin mediator allows selective and safe methyl group addition to complex molecules.

## Contribution

A recyclable flavin-mediated methylation strategy with high chemoselectivity and applicability to biologically relevant substrates.

## Key findings

- Flavin mediator is easily recovered and reused after methylation reactions.
- The method enables chemoselective methylation of complex molecules like venetoclax and nevirapine.
- Trideuteromethylation and nucleobase modification are promising applications of the method.

## Abstract

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.

A two‐component methylation protocol was developed, where the active flavin mediator can be recycled in a single step. Crystallographic data and NMR spectroscopy support the mechanistic proposal, while chemoselective methylation was observed for a broad range of biologically relevant substrates.