Chemistry: A European Journal 2015-08-17

Dehydrogenative TEMPO-Mediated Formation of Unstable Nitrones: Easy Access to N-Carbamoyl Isoxazolines.

Andrea Gini, Marwin Segler, Dominik Kellner, Olga García Mancheño

Index: Chemistry 21 , 12053-60, (2015)

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Abstract

N-carbamoyl nitrones represent an important class of reagents for the synthesis of a variety of natural and biologically active compounds. These compounds are generally converted into valuable 4-isoxazolines upon cyclization reaction with dipolarophiles. However, these types of N-protected nitrones are highly unstable, which limits their synthesis, storage and practical use, enforcing alternative lengthy or elaborated synthetic routes. In this work, a 2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPO)-mediated formal "dehydrogenation" of N-protected benzyl-, allyl- and alkyl-substituted hydroxylamines followed by in situ trapping of the generated unstable nitrones into N-carbamoyl 4-isoxazolines is presented. A plausible mechanism is also proposed, in which the dipolarophile shows an important assistant role in the generation of the active nitrone intermediate. This simple protocol avoids the problematic isolation of N-carbamoyl protected nitrones, providing new synthetic possibilities in isoxazoline chemistry. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.