Synthesis of 3,5-Disubstituted-1,2,4-oxadiazole Sulfonamides in the Superbasic t-BuONa/DMAA System

Abstract— An improved synthesis of 3,5-disubstituted-1,2,4-oxadiazoles with a sulfonamide fragment is proposed. Our previously developed synthesis of the target 1,2,4-oxadiazoles, which involves reaction in the superbasic NaOH/DMSO medium, has a number of disadvantages. The improved synthesis involves the reaction of amidoximes with carboxylic acid esters in a t-BuON/DMAA medium. The reaction proceeds at room temperature for 8– 18 h. The advantages of the proposed method consist in the broader temperature range of the reaction (due to the change of solvent from DMSO to DMAA), as well as the absence of side hydrolysis processes, which is important for moisture sensitive substrates. The potential of the method was demonstrated by the synthesis of 9 novel 1,2,4-oxadiazole derivatives containing various substituents in the 3 position (R = 2-ClPh, 3-C₂H₅C(O)NH-Ph, i-Pr, Ph, thiophene, 4-Me-thiophene, 4-OMe-Ph, Py, 2-tolyl) and at the 5-position of the 1,2,4-oxadiazole ring (R = 4-SO₂NH₂-Ph, 2-OMe-4-SO₂NH₂-phenyl). The 3,5-disubstituted-1,2,4-oxadiazole derivatives synthesized in good yields (35–89%) are of interest for medicinal chemistry as potential drugs for the treatment of neurodegenerative diseases (such as Parkinson's syndrome and Alzheimer's disease) by inhibiting monoamine oxidase B. The synthesized compounds can be useful as antiglaucoma and anticancer agents, because they inhibit carbonic anhydrase I, II, IX, and XII isoforms. The structure and purity of the novel heterocyclic derivatives were confirmed by ¹H and ¹³C NMR spectroscopy and mass spectrometry. Biological ac testing of the synthesized compounds on cell and animal glaucoma models is planned.