1,3,4-Oxadiazole-containing compounds have been applied in a broad spectrum of applications, ranging from biologically active molecules with antibacterial, anti-inflammatory and anticancer properties to electron transporting materials in organic light emitting diodes. The functionality is also employed as a bioisostere for carboxylic acids, esters and amides in medicinal chemistry. The wide array of uses for this moiety mean that it can be considered a very versatile group in numerous fields of chemistry. Current synthetic methods towards this scaffold are prevalent within the literature; however, these frequently require toxic and difficult to handle reagents, such as POCl3, and the use of bespoke intermediates. An under-utilised approach towards these compounds is the Huisgen reaction, in which a 5-substituted tetrazole and an acid chloride or acid anhydride combine under high temperatures to afford the desired heterocycle via the highly reactive nitrile imine intermediate (Figure 1a). In pursuit of more sustainable methodologies for the synthesis of desirable heterocyclic motifs, we have successfully adapted the Huisgen synthesis of 1,3,4-oxadiazoles for use in the 21st century through the utilisation of flow photochemistry. Photolysis initiated by a UV-B lamp and the integration of benign carboxylic acid starting materials represents a significant advancement in the applicability of the procedure (Figure 1b). This methodology has been exemplified with a broad susbtrate scope, exhibiting comparable efficiency to existing approaches and compatability extending to the generation of active pharmaceutical agents and highly substituted amino acids (Figure 1c).

UV-induced 1,3,4-oxadiazole formation from 5-substituted tetrazoles and carboxylic acids in flow

ACS Fall 2020 Virtual Meeting

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