Sustainable Synthesis of Isoxazoles and Isoxazolines Directly from Aldehydes via One‐Pot Metal‐Free Approach Using a Reusable Ionic Liquid [C8DABCO][OH] at Room Temperature

This study presents a one-pot and a multistep approach for the regioselective formation of 3,5-disubstituted isoxazoles, isoxazolines, and bis-isoxazoles at room temperature. The metal-free method enhances product yield, allowing lower catalyst loading, reduced reaction time, and broad substrate tolerance . Gram-scale synthesis and reusability of the ionic-liquid underscore its sustainable advantages, reinforcing the efficiency and eco-friendliness of the protocol.

Isoxazole and isoxazoline derivatives demonstrate versatile therapeutic properties, captivating widespread global attention. Despite the potential benefits of these scaffolds, hurdles such as reliance on cytotoxic and expensive metal catalysts, low productivity, and limited substrate scope impede their effective synthesis. In this work, a 1,4-Diazabicyclo[2.2.2]octane, based ionic liquid has been developed for the sustainable and eco-friendly synthesis of isoxazole and isoxazoline derivatives under metal and solvent-free conditions from chloroaldoximes. The room temperature mediated protocol framed the desired 3,5-disubstituted and 3,4,5-trisubstituted compounds, tolerating an array of functionalized and substituted chloroaldoximes, alkynes, and olefins. Moreover, this basic catalytic system even formulates the generation of bis-isoxazole derivatives and fabricates a one-pot telescopic strategy for forming the 3,5-isomer directly from aldehydes. Single-crystal X-ray diffraction done on three of the synthesized compounds confirms the formation of the 3,5-disubstituted isoxazole and bis-isoxazole derivatives. In addition, formation of some interesting, unusual products other than the desired isoxazole derivatives provides a new insight into this cycloaddition reaction. The reusability of the catalytic system for up to four consecutive runs and the successful outcome of the gram-scale reactions illustrate the synthetic efficiency of the protocol.

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