An efficient Ugi-type three-component reaction (U-3CR) for the synthesis of pipecolic amides is reported. The U-3CR between electronically diverse isocyanides, carboxylic acids and 4-substituted Δ1-piperideines proceeds in a highly diastereoselective fashion. The Δ1-piperideines are obtained by NCS-mediated oxidation of the corresponding 4-substituted piperidines, which in turn are generated by an efficient two-step procedure involving the alkylation of 4-picoline and subsequent catalytic hydrogenation of the pyridine ring. We demonstrate the utility of this U-3CR, in combination with the convertible isocyanide 2-bromo-6-isocyanopyridine, in the synthesis of the anticoagulant argatroban.
Bibliographical noteSpecial Issue: Heterocyclic Chemistry
- Multicomponent reactions
- Pipecolic amides
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van der Heijden, G. (Contributor), van Schaik, T. (Contributor), Mouarrawis, V. (Contributor), de Wit, M. (Contributor), Velde, C. V. (Contributor), Ruijter, E. (Contributor) & Orru, R. (Contributor), Unknown Publisher, 1 Jan 2019