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.

Comment

The 1,2,4-oxadiazole scaffold is commonly found in biologically active molecules and drugs, such as the potent S1P1 agonist (Z. Li et al. J. Med. Chem. 2005, 48, 6169). It is also often used as an amide or ester bioisostere (G. D. Diana et al. J. Med. Chem. 1994, 37, 2421). The synthesis of the oxadiazole core has been traditionally achieved by the reaction of arylnitriles with hydroxyl­amine, followed by subsequent cyclization with an acyl chloride. Especially the last step requires harsh conditions and long reaction times (J. Roppe et al. J. Med. Chem. 2004, 47, 4645). The reported methodology considerably shortens reaction times compared to the traditional synthesis and elegantly demonstrates the usefulness of micro­reactors, especially in the synthesis of small libraries.