Microreactor Synthesis of 1,2,4-Oxadiazoles

Significance

Rapid synthesis of bis-substituted 1,2,4-oxadiazoles from arylnitriles and activated carbonyls in a single, uninterrupted microreactor sequence is reported. A multiday and multistep procedure was shortened to less than an hour in this procedure. The yields are moderate to good, and substrate scope was reasonably well studied. The sequence required extensive optimization, due to problems regarding the formation of solids in the microreactor. This involved a careful monitoring of concentrations and temperatures in the reactor for the optimization. The products were isolated by preparative HPLC, making the method ideal for small-library syntheses but difficult and expensive for larger-scale syntheses. Although limited in examples, aryl, heteroaryl and aliphatic acid chlorides were successfully incorporated into the final oxadiazole product.