Nonpolar C-H Bond Activation by Multi-Site Concerted Electron-Proton Transfer for Electrochemical Dimerization of β-Ketoester

Dimerized β-ketoesters are crucial intermediate organic molecules for the synthesis of natural products and pharmaceutically essential molecules. Herein, we present a direct electro-oxidation of α-C-H bond of β-ketoesters on graphite electrode surface in acetonitrile solvent with NH4PF6 electrolyte and sodium hydride base employing a constant potential (1.8 V) methodology in a two-electrodes setup for the synthesis of dimerized β-ketoesters eliminating the need for toxic oxidants or metal-based expensive catalysts. Cyclic voltammetry, UV-Vis spectroscopy, kinetic isotopic effects, and other control experiments suggested multi-site concerted electron-proton transfer (MS-CEPT) was operational for the α-C-H bond activation towards the generation of a neutral radical intermediate on α-carbon, which enabled C(sp³)−C(sp³) bond formation. This study is the first example of activation of a nonpolar C-H bond employing MS-CEPT in a direct electro-oxidative methodology. Twenty-one examples of dimerization of β-ketoesters having diverse substituents have been provided with excellent yields (average yield of 73%). The methodology has been further utilized for the total syntheses of naturally occurring dimeric aromatic propanoids, such as dihydrocubebin and epi-dihydrocubebin.