Deprotonative Single Electron Oxidation as a General and Controllably Selective Platform for Benzylic C-H Functionalization

We propose a new strategy for benzyl radical generation through a consecutive deprotonation and single electron oxidation mechanism. The use of HMDS bases generates low concentrations of benzyl carbanionic intermediates that are oxidized and subsequently captured using two equivalents of the persistent aminoxyl radical reagent TEMPO. Compared to traditional oxidation reactions of stoichiometrically prepared carbanionic species, transient carbanion generation ensures selective radical coupling over dimerization and enables a major improvement in functional group tolerance and site-selectivity control. This approach is guided by C-H acidity and carbanion oxidation trends and therefore exhibits fundamentally distinct scope and selectivity trends over hydrogen atom abstraction and single electron oxidation-based radical protocols that are instead guided by alkylarene C-H bond strengths or oxidation potentials, respectively. As such, this method is applicable to alkylarenes with high oxidation potentials and tolerates the presence of traditionally reactive weak C-H bonds and oxidatively-sensitive functional groups. These features enable TEMPO installation on densely functionalized compounds, including a wide array of pharmaceutical and N-heteroaryl substrates. This approach also introduces the opportunity to exploit the inverse correlation between C-H acidity and carbanion oxidation potential such that either property can interchangeably dictate site-selectivity for arenes with multiple benzylic positions. Thus, simple adjustments to the base strength are proposed to initiate a Curtin-Hammett-regulated oxidation pathway that enables a switch in selectivity from the most to least acidic benzylic position. We anticipate that these collective features will enhance benzylic C-H diversification efforts given the downstream synthetic versatility of benzyl-OTMP units.