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

Abstract

We propose a new strategy for benzyl radical generation through a consecutive deprotonation and single-electron oxidation mechanism. The use of an HMDS base generates a low concentration of a benzyl carbanionic intermediate that is oxidized and subsequently captured using two equivalents of the persistent aminoxyl radical reagent TEMPO. Compared to oxidation reactions of stoichiometrically prepared carbanionic species, endergonic deprotonation 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 distinct scope and selectivity over hydrogen atom abstraction and direct single-electron oxidation-based methods that are instead guided by alkylarene C–H bond strengths or oxidation potentials, respectively. As such, this protocol is applicable to alkylarenes with high oxidation potentials and tolerates the presence of weak C–H bonds and oxidatively sensitive functional groups. These features enable TEMPO installation on densely functionalized compounds, including pharmaceutical and N-heteroaryl substrates. This approach also introduces the prospect of exploiting the inverse correlation between C–H acidity and the oxidation potential of its deprotonated intermediate such that either property could 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.