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Expedient Synthesis of a 72-Membered Isoxazolino-β-ketoamide Library by a 2·3-Component Reaction

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journal contribution
posted on 22.02.2016, 06:25 by John M. Knapp, Jie S. Zhu, Alex B. Wood, Mark J. Kurth
An efficient 2·3-component reaction (2·3CR; a 2-component reaction followed, in one pot, by a 3-component reaction) is presented for the synthesis of isoxazolino-β-ketoamides. This 2·3CR proceeds by (i) a Meldrum’s acid-generated acyl ketene, which is trapped by an amine to form a β-ketoamide intermediate in a 2CR followed, in one pot, by (ii) a Mannich reaction followed by elimination of dimethyl amine·HCl to generate an α,β-unsaturated β-ketoamide dipolarophile that reacts in a nitrile oxide 1,3-dipolar cycloaddition reaction. This one-pot 2·3CR process delivers the targeted isoxazolino-β-ketoamide product. A total of 72 compounds are presented, all of which have been submitted to the NIH Molecular Libraries Small Molecule Repository for high-throughput biological screening.