Late-stage methylation reactions can be useful in organic synthesis, especially in pharmaceutical chemistry. However, many commonly used methylating reagents are hard to handle, toxic, and/or volatile. Alternative, solid, easy-to-handle methylating agents are, thus, interesting research targets.

Johanna Templ and Michael Schnürch, TU Wien, Vienna, Austria, have found that the quaternary ammonium salt phenyl trimethylammonium iodide (PhMe₃NI) can be used as a methylating agent for the selective α-methylation of aryl ketones. The team screened different ammonium salts as methyl sources. Phenyl trimethylammonium iodide provided good selectivities for the α-methylation and yields of up to 85 %.

The researchers used this reagent to methylate a variety of aryl ketones in moderate to good yields. Sterically hindered substrates and substrates that are not prone to enolization proved most challenging. N,N-Dimethylaniline is formed as a byproduct from PhMe₃NI, but can easily be removed as its HCl salt via an aqueous workup. In contrast to many conventional methylating agents, quaternary ammonium salts such PhMe₃NI are nonvolatile, safer, and easy to handle.

• Selective α-Methylation of Aryl Ketones Using Quaternary Ammonium Salts as Solid Methylating Agents,
  Johanna Templ, Michael Schnürch,
  J. Org. Chem. 2022.
  https://doi.org/10.1021/acs.joc.1c03158