Metal-Catalyzed Organic Reactions by Resonant Acoustic Mixing

We demonstrate catalytic organic synthesis by Resonant Acoustic Mixing (RAM): a mechanochemical methodology that does not require bulk solvent or milling media. Using as model reactions ruthenium-catalyzed ring-closing metathesis and copper-catalyzed sulfonamide-isocyanate coupling, RAM mechanosynthesis is shown to be faster, operationally simpler than conventional ball-milling, while also providing the first example of a mechanochemical strategy for ruthenium-catalyzed ene-yne metathesis. Reactions by RAM are readily and directly scaled-up without any significant changes in reaction conditions, as shown by the straightforward 200-fold scaling-up of the synthesis of the antidiabetic drug Tolbutamide, from hundreds of milligrams directly to 30 grams.