Continuous Flow Photochemical Synthesis of 3-Methyl-4-arylmethylene Isoxazole-5(4H)-ones through Organic Photoredox Catalysis and Investigation of Their Larvicidal Activity

Abstract

Isoxazole-5(4H)-ones are heteropentacycle compounds found in several bioactive molecules with pharmaceutical and agrochemical properties. A well-known multicomponent reaction between β-ketoester, hydroxylamine, and aromatic aldehydes leads to 3-methyl-4-arylmethylene isoxazole-5(4H)-ones, in mild conditions. The initial purpose of this work was to investigate whether the reaction might be induced by light, as described in previous works. Remarkable results were obtained using a high-power lamp, reducing reaction times compared to methodologies that used heating or catalysis. Since there are many examples of successful continuous flow heterocycle synthesis, including photochemical reactions, the study evolved to run the reaction in flow conditions and scale up the synthesis of isoxazolones using a photochemical reactor set-up. Eight different compounds were obtained, and among them, three showed larvicidal activity on immature forms of Aedes aegypti in tests that investigated its growth inhibitory character. Mechanistic investigations indicate that the reactions occur through organic photoredox catalysis.

Keywords

• isoxazolone
• photochemistry
• continuous flow
• larvicidal activity