Metal-catalyzed organic reactions by Resonant Acoustic Mixing

We introduce 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, ene-yne metathesis and copper-catalyzed sulfonamide-isocyanate coupling, we demonstrate RAM-based mechanochemical synthesis that is faster and operationally simpler than conventional ball milling. Moreover, the method can be readily scaled-up, as demonstrated by straightforward catalytic synthesis of the antidiabetic drug Tolbutamide from hundreds of milligrams to at least 10 grams, without any significant changes in reaction conditions.