Cascade oxime formation, cyclization to a nitrone, and intermolecular dipolar cycloaddition
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Solid-phase Synthesis of [4.4] Spirocyclic Oximes
Published on: February 6, 2019
Rachel C Furnival1, Rungroj Saruengkhanphasit1, Heather E Holberry1
1Department of Chemistry, University of Sheffield, Brook Hill, Sheffield, S3 7HF, UK. i.coldham@sheffield.ac.uk.
Abstract:
Simple haloaldehydes, including enolisable aldehydes, were found to be suitable for the formation of cyclic products by cascade (domino) condensation, cyclisation, dipolar cycloaddition chemistry. This multi-component reaction approach to heterocyclic compounds was explored by using hydroxylamine, a selection of aldehydes, and a selection of activated dipolarophiles. Initial condensation gives intermediate oximes that undergo cyclisation with displacement of halide to give intermediate nitrones; these nitrones undergo in situ intermolecular dipolar cycloaddition reactions to give isoxazolidines. The cycloadducts from using dimethyl fumarate were treated with zinc/acetic acid to give lactam products and this provides an easy way to prepare pyrrolizinones, indolizinones, and pyrrolo[2,1-a]isoquinolinones. The chemistry is illustrated with a very short synthesis of the pyrrolizidine alkaloid macronecine and a formal synthesis of petasinecine.
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