COMU: A Safer and More Effective Replacement for Benzotriazole-Based Uronium Coupling Reagents

We describe a new family of uronium‐type coupling reagents that differ in their iminium moieties and leaving groups. The presence of the morpholino group in conjunction with an oxime derivative—especially ethyl 2‐cyano‐2‐(hydroxyimino)acetate (Oxyma)—had a marked influence on the solubilities, stabilities, and reactivities of the reagents. Finally, the new uronium salt derived from Oxyma (COMU) performed extremely well in the presence of only 1 equiv of base, thereby confirming the effect of the hydrogen bond acceptor in the reaction. COMU also showed a less hazardous safety profile than the benzotriazole‐based HDMA and HDMB, which exhibited unpredictable autocatalytic decompositions. Furthermore, the Oxyma moiety contained in COMU suggests a lower risk of explosion than in the case of the benzotriazole derivatives. Uronium coupling reagents: A new family of uronium‐type coupling reagents differing in their iminium moieties and leaving groups (see figure) is described. The presence of the morpholino group in combination with an oxime derivative, especially ethyl 2‐cyano‐2‐(hydroxyimino)acetate (Oxyma), had a marked influence on the solubilities, stabilities, and reactivities of the reagents. Furthermore, the Oxyma moiety offers a lower explosion risk than benzotriazole derivatives.