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. 2012 Feb 13;14(2):85-8.
doi: 10.1021/co200199h. Epub 2012 Jan 3.

Expedient synthesis of a 72-membered isoxazolino-β-ketoamide library by a 2·3-component reaction

John M Knapp, Jie S Zhu, Alex B Wood, Mark J Kurth

Expedient synthesis of a 72-membered isoxazolino-β-ketoamide library by a 2·3-component reaction

John M Knapp et al. ACS Comb Sci. .

Abstract

An efficient 2·3-component reaction (2·3CR; a 2-component reaction followed, in one pot, by a3-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.

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Figures

Figure 1
Figure 1
2•3CR diversity inputs.
Scheme 1
Scheme 1
4CR route to isoxazolino-β-ketoamides.
Scheme 2
Scheme 2
Isoxazolino-β-ketoamides by a multicomponent (2•3CR) process.
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