Allylation of C-, N-, and O-Nucleophiles via a Mechanochemically-Driven Tsuji–Trost Reaction Suitable for Late-Stage Modification of Bioactive Molecules

Abstract

We present the first solvent-free, mechanochemical protocol for a palladium-catalyzed Tsuji–Trost allylation. This approach features exceptionally low catalyst loadings (0.5 mol %), short reaction times (<90 min), and a simple setup, eliminating the need for air or moisture precautions, making the process highly efficient and environmentally benign. We introduce solid, nontoxic, and easy-to-handle allyl trimethylammonium salts as valuable alternative to volatile or hazardous reagents. Our approach enables the allylation of various O-, N-, and C-nucleophiles in yields up to 99 % even for structurally complex bioactive compounds, owing to its mild conditions and exceptional functional group tolerance.