Electrochemical Site-Selective Aromatic C–H Amination via Bicyclic N-Radical Cations

Conspectus Aromatic amination has long been a reaction of interest in organic synthesis, and aromatic amines themselves are prized for their bioactivity and their usefulness in the synthesis of organic materials. However, traditional syntheses have struggled to directly access aryl amines, going through sequences of aromatic prefunctionalization followed by reduction or cross-coupling. Modern advances in the control of radical chemistry have reopened the avenue of aromatic C–H functionalization based on electrophilic radical(s) (cations). However, radical C–H amination methods have struggled with generality in aromatic substrate, being unable to access electron poor arenes in a selective manner. Further challenges present themselves in the fundamental reactivities of amino radical(s) (cations), due to their tendency to undergo alpha elimination in oxidizing conditions, forcing the field to access such radicals reductively through activated, electrophilic precursors. Bicyclic amino radical cations, however, have proven more robust, due to their constrained geometry. In this Account, we present our efforts to broaden the utility of radical aromatic C–H amination using bicyclic amino radical cations generated via electrochemistry. We first recount the synthetic results of accessing these radicals reductively, showing selective radical amination. Computational studies help to illuminate the chemoselectivity of the amination reaction compared to other known reactivities of N-radical cations, such as hydrogen atom transfer (HAT). Next, we flipped the polarity of N-radical cation generation to oxidative, utilizing the bicyclic amine itself as an oxidizable radical cation precursor. By leveraging both electrophilicity-enhancing conditions and the inherent recyclability of bicyclic amines in anodic electrochemical systems, we were successfully able to broaden the scope of aromatic C–H amination to highly electron deficient arenes. The broader scope of the reaction was able to shed more light on the regioselectivity, showing that positional electron density is not the only determining factor in radical C–H amination. Photoelectrochemical studies revealed that arene oxidation mechanisms were operative for electron-rich arenes, explaining their preservation and efficient amination in a system otherwise expected to be too oxidizing. Lastly, we showcased that the resulting aryl-ammonium salts can (1) be transformed into an array of aryl piperazine derivatives through substitution/elimination and (2) act as synthetically useful aryl radical precursors in C–C, C–B, and C–P bond formations. We anticipate that the direct comparison between our two systems can help future synthetic efforts parse between reductive or oxidative strategies when targeting new electrophilic radicals, recognizing inherent advantages of each approach.