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Critical assessment of two classical synthetic methods for preparation of thiophene-substituted isoxazoles

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Abstract

Formation of thiophene-substituted isoxazoles by reaction of chalcone dibromides and 1,3-diketones with hydroxylamine hydrochloride has been examined under different conditions. Use of KOH as base in the reaction of dibromide chalcone analogs with hydroxylamine hydrochloride yields mixtures of isomeric isoxazoles in modest yields. Replacement of KOH with pyridine affords negligible amounts of isoxazoles only, the intermediate 2-bromoprop-2-en-1-one being isolated from the reaction as the major product. Substitution of the β-bromine atom from a chalcone dibromides with a methoxy group by solvolysis occurred when no base was used. Mixtures of isomeric isoxazoles in which the isoxazole that had a 2-thienyl group at position 5 were always major components, were obtained in good yields from reaction of thiophene-containing 1,3-diketones with hydroxylamine hydrochloride, irrespective of reaction pH. At low pH, regioselectivity was poorer than that observed for reaction of chalcone dibromides with hydroxylamine hydrochloride, but yields were substantially better. At high pH, yields were comparable with those at low pH and regioselectivity for 3-aryl-5-(2-thiophenyl)isoxazole was slightly enhanced, but the dioxime corresponding to the initial 1,3-diketone was also produced in low yields as a mixture of stereoisomers.

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Acknowledgments

The research leading to these results has received funding from the European Union’s Seventh Framework Programme (FP7/2007-2013) under grant agreement no. 264115—STREAM. The assistance of Miss Mihaela Bălan with the 2D NMR experiments is gratefully acknowledged. The author thanks Dr Mihaela Silion for her valuable help with the mass spectrometry experiments.

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  1. Petru Poni Institute of Macromolecular Chemistry, 41A Aleea Gr. Ghica Vodă, 700487, Iaşi, Romania

    Gheorghe Roman

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Roman, G. Critical assessment of two classical synthetic methods for preparation of thiophene-substituted isoxazoles. Res Chem Intermed 40, 2039–2057 (2014). https://doi.org/10.1007/s11164-013-1101-8

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