Multicomponent reactions (MCRs) are one-pot processes in which three or more starting materials form a product that incorporates the structural features of each reagent. These reactions date back to the mid-19th century, when Strecker first prepared α-aminonitriles through the condensation of aldehydes with ammonia and hydrogen cyanide. In addition to affording products with structural complexity and diversity, MCRs offer the advantages of simplicity, synthetic efficiency, synthetic convergence, and atom economy. Therefore, they have played an important role in modern synthetic organic chemistry and drug-discovery research. The irreversible trapping of an active intermediate generated from two components by a third one offers an effective way to discover novel MCRs. In cases where the intermediate from the first two components is reactive enough to generate a two-component byproduct, it becomes challenging to control of the chemoselectivity of these MCRs over the side reaction. For example, researchers had expected that ammonium/oxonium ylides, high energy intermediates that have acidic protons and basic carbanions attached to adjacent carbons, would be too reactive to be intercepted by external electrophiles. Instead, a very fast 1,2-proton transfer would neutralize the charge separation, resulting in a stable N-H/O-H insertion product. In this Account, we present our efforts toward the development of novel MCRs via trapping of the active ammonium/oxonium ylide intermediates with a number of electrophiles. In these reactions, a "delayed proton transfer" that occurs after the trapping process produces novel multicomponent coupling products. Thus, transition-metal-catalyzed MCRs of diazocarbonyl compounds, anilines/alcohols, and electrophiles efficiently afford polyfunctional molecules such as α-amino-β-hydroxy acids, α-hydroxy-β-amino acids, α,β-diamino acids, and α,β-dihydroxy acid derivatives. We have also applied a cooperative catalysis strategy to some of these MCRs leading to reactions with high chemo-, diastereo-, and enantioselectivity. These MCRs also provide solid experimental evidence for the existence of the active protic onium ylides.
