Recent Advances of Transition-Metal Catalyzed Radical Oxidative Cross-Couplings

Abstract

CONSPECTUS: Oxidative cross-coupling reactions between two nucleophiles are a powerful synthetic strategy to synthesize various kinds of functional molecules. Along with the development of transition-metal-catalyzed oxidative cross-coupling reactions, chemists are applying more and more first-row transition metal salts (Fe, Co, etc.) as catalysts. Since first-row transition metals often can go through multiple chemical valence changes, those oxidative cross-couplings can involve single electron transfer processes. In the meantime, chemists have developed diverse mechanistic hypotheses of these types of reactions. However, none of these hypotheses have led to conclusive reaction pathways until now. From studying both our own work and that of others in this field, we believe that radical oxidative cross-coupling reactions can be classified into four models based on the final bond formations. In this Account, we categorize and summarize these models. In model I, one of the starting nucleophiles initially loses one electron to generate its corresponding radical under oxidative conditions. Then, bond formations between this radical and another nucleophile create a new radical, [Nu(1)-Nu(2)](•), followed by a further radical oxidation step to generate the cross-coupling product. The radical oxidative alkenylation with olefin, radical oxidative arylative-annulation, and radical oxidative amidation are examples of this model. In model II, one of the starting nucleophiles loses its two electrons via two steps of single-electron-transfer to generate an electrophilic intermediate, followed by a direct bond formation with the other nucleophile. For example, the oxidative C-O coupling of benzylic sp(3) C-H bonds with carboxylic acids and oxidative C-N coupling of aldehydes with amides are members of this model group. For model III, both nucleophiles are oxidized to their corresponding radicals. Then, the radicals combine to form the final coupling product. The dioxygen-involved radical oxidative cross-couplings between sulfinic acids and olefins or alkynes belong to this bond formation model. Lastly, in model IV, one nucleophile loses two electrons to generate an electrophilic intermediate, while the other nucleophile loses one electron to generate a radical. Then, a bond forms between the cation and the radical to generate a cationic radical, followed by a one-electron reduction to afford the final coupling product. The oxidative coupling between arylboronic acids and simple ethers was classified in this model. At the current stage, there are only a few examples presented for models III and IV, but they represent two types of potentially important transformations. More and more examples of these two models will be developed in the future.