Brønsted Acid Organocatalyzed Three-Component Hydroamidation Reactions of Vinyl Ethers.

Hydroamidation of carbon-carbon double bonds is an attractive strategy for installing nitrogen functionality into molecular scaffolds and, with it, increasing molecular complexity. To date, metal-based approaches have dominated this area of chemical synthesis, despite the drawbacks of air and moisture sensitivity, limited functional group tolerance, toxicity, and/or high cost often associated with using metals. Here, in offering an alternative solution, we disclose an operationally simple, metal-free, one-pot, regioselective, multicomponent synthetic procedure for the hydroamidation of carbon-carbon double bonds. This method features mild reaction conditions and utilizes isocyanides and vinyl ethers for the rapid and modular synthesis of privileged α-oxygenated amide scaffolds. In unraveling the mechanistic underpinning of this non-metal-based reactivity, we present kinetic solvent isotope effect studies, variable time normalization analysis, and density functional theory computations offering insight into the mechanism of this multistep catalytic hydroamidation process.