A simpler way to perform C–H methylation

Magic shows fascinate us because they defy our expectations in exciting ways. Of course, no supernatural powers are really involved; a skilled magician can use the standard tools of their trade to produce astonishing outcomes.

Medicinal chemists have an impressive trick of their own. In drug molecules, replacing a hydrogen atom with a methyl group often results in higher potency, reduced toxicity and increased stability – an effect so dramatic that it is termed the magic methyl effect. But it is only recently that researchers have started to master the art of this transformation.

Over the years, chemists have striven to make methylation reactions simpler and robust, but direct C(sp³)–H methylation methods remained somewhat underdeveloped. A big step forward came last year, when Christina White’s group at the university of Illinois Urbana-Champaign, US disclosed a two-step protocol that oxidises amines to their corresponding iminium ions, followed by nucleophilic methylation with AlMe₃.¹ While the scope of the reaction seems appealing, it must be performed at temperatures as low as –78 ºC to prevent its pyrophoric reagents from spontaneously igniting. Higher-temperature alternatives needed to be developed.