Van Leusen Imidazole Synthesis for One-Bead-One-Compound DNA-Encoded Libraries

One-bead-one-compound (OBOC) DNA-encoded library (DEL) enables high-throughput activity-based screening to find novel hits against pharmaceutical targets. Herein, we developed solid-phase and DNA-compatible conditions to implement the three-component Van Leusen reaction (imidazole formation) for OBOC DELs. High-throughput validation was conducted (employing every potential building block) to simultaneously provide the groundwork for potential library synthesis and demonstrate the reagent scope. A total of 251 aldehydes, 380 amines, and 19 tosylmethyl isocyanides (TosMICs) were validated, with 65 aldehydes, 194 amines, and 15 TosMICs meeting the 50% yield cutoff. We take particular interest in aliphatic TosMICs because they yield more drug-like products. Encouragingly, aliphatic TosMICs perform well in solid-phase, but not solution-phase.