Mizoroki-Heck Macrocyclization Reactions at 1 M Concentration Catalyzed by Sub-nanometric Palladium Clusters

The synthesis of cyclized organic compounds with more than ten atoms (macrocycles) is traditionally based on reversible reactions under highly diluted conditions, typically <0.05 M, in order to circumvent the formation of intermolecular products. These reaction conditions severely hamper industrial productivity and the use of solid catalysts. Herein, it is shown that the intramolecular Mizoroki-Heck reaction of ω-iodide cinnamates proceeds at 1 M concentration when catalyzed by few-atom Pd clusters, either in solution or supported on a solid, to give different macrocycles in good yields. This paradigmatic increase in reaction concentration not only opens the door for macrocycle production with high throughputs but also enables the use of solid catalysts for a macrocyclization reaction in flow.