Electrochemical Three-Component Domino Access to Isoxazoles and Isoxazolines

Abstract Among the synthetic routes to isoxazole derivatives, since the 1960s, [3+2] cycloadditions of nitrile oxides have played a leading role, despite the need to prepare and use toxic and environmentally hazardous intermediates. The work reported here improves the sustainability of the process through the development of a three-component domino protocol involving the in situ formation of oximes, combined with the advantages inherent in the use of electricity. The electrochemical step occurs with cheap electrodes, avoids hazardous additives or electrolytes, and benefits from the use of equimolar amounts of aldehyde and alkene (or alkyne), as well as the possibility of recycling the solvent (acetonitrile/H2O 3:1) with improvements in atom economy and E-factor parameters with respect to previous approaches. Interestingly, the desired oximes could be efficiently generated by simply reacting the aldehyde and hydroxylamine hydrochloride in the presence of water.