Ball‐Milling‐Enabled Solvent‐ and Ligand‐Free Tsuji–Trost Reaction of C ‐, N ‐, O ‐, S ‐, and Se ‐Nucleophiles in Air: Synthesis and Late‐Stage Modification of Drugs

We report a novel ball‐milling‐enabled, ligand‐free Tsuji–Trost reaction involving C ‐, N ‐, O ‐, S ‐, and Se ‐nucleophiles with allyl and cinnamyl acetates, as well as allyl phosphate. Thiophenols and benzeneselenol have been demonstrated for the first time as nucleophiles in a ball‐milling‐assisted Tsuji–Trost reaction. The reaction proceeds at room temperature under air without the need for a solvent, and exhibits a broad substrate scope (41 examples). In addition, this study successfully establishes the unexplored mechanochemical synthesis of a series of commercially available drugs containing allyl functional groups, as well as the late‐stage modification of several marketed drugs, highlighting the potential of this method in pharmaceutical applications and drug discovery. The practical utility of this methodology is further demonstrated through a gram‐scale reaction of the Cinnarizine drug, followed by downstream derivatization and reusability of the catalyst. Additionally, several spectroscopic experiments have been conducted for the first time to gain mechanistic insight and elucidate the proposed catalytic cycle of the Tsuji–Trost reaction under ball‐milling conditions.