Changing a hydrogen for a methyl can have profound effects on both the biological stability and the binding affinity of a lead compound. As a consequence, medicinal chemists are on a constant lookout for that “magic methyl” which will, for example, rigidify their molecule to provide a boost in potency, at a very low cost in terms of lipophilicity and molecular weight.<br/>The medicinal chemistry interest in changing a C-H for a C-Me is in sharp contrast to the available synthetic method that enables this transformation, especially if one wants to modify an advanced intermediate or complex lead compound. Most current chemistry for late stage C-H methylation either rely on activated C-H bonds and/or require multiple synthetic steps, making this small molecular change far from trivial.<br/>In our efforts to address this synthetic challenge, we have developed and cobalt catalyzed C-H methylation protocol that uses a benign transmetallating reagent, which renders this chemistry mild and tolerant to a wide variety of functional groups. To facilitate C-H activation, the reaction relies on a broad selection of directing groups commonly found in biologically active compounds. All these features enable this chemistry to perform late stage C-H methylation on a diverse selection of unprotected biologically active compounds under a mild and uniform set of conditions.

Versatile C-H methylation reaction for late-stage functionalization

2019 Spring National Meeting

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.