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.