Installation of d3-methyl group to drugs by continuous-flow solid-phase synthesis

The d3-methyl group, which combines the “magic methyl effect” and the deuterium effect, is highly sought after by medicinal chemists, resulting in the development of various d3-methyl reagents derived from low-cost, readily available CD₃OD. However, a universally applicable, cost-effective, easily accessible and handleable, highly active, and recyclable d3-methyl reagent remains elusive. Herein, we design a thianthrene-based organic polymer (TT-OP) that shows the ability of capturing and releasing the d3-methyl reagent. This polymer demonstrates excellent loading capacity, scalability, and stability. Utilizing this developed heterogeneous d3-methyl reagent (TT-OP-CD₃), we achieve selective d3-methylation of over 35 biologically active molecules d3-at oxygen, nitrogen, sulfur, and carbon sites—transformations that are very challenging to be realized by other methods. Finally, we establish an automated platform for high-throughput, scalable d3-methylation of pharmaceutical molecules by integrating solid-phase synthesis with continuous-flow, demonstrating its sustainability and practicality for drug synthesis. © The Author(s) 2025.