Efficient Diastereoselective Three-Component Synthesis of Pipecolic Amides

Gydo van der Heijden, Timo B. van Schaik, Valentinos Mouarrawis, Martin J.M. de Wit, Christophe M.L.Vande Velde, Eelco Ruijter*, Romano V.A. Orru

*Corresponding author for this work

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Abstract

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.

Original languageEnglish
Pages (from-to)5313-5325
Number of pages13
JournalEuropean Journal of Organic Chemistry
Volume2019
Issue number31-32
Early online date25 Apr 2019
DOIs
Publication statusPublished - 1 Sep 2019

Bibliographical note

Special Issue: Heterocyclic Chemistry

Keywords

  • Argatroban
  • Multicomponent reactions
  • Pharmaceuticals
  • Pipecolic amides
  • Stereoselectivity

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    van der Heijden, G., van Schaik, T. B., Mouarrawis, V., de Wit, M. J. M., Velde, C. M. L. V., Ruijter, E., & Orru, R. V. A. (2019). Efficient Diastereoselective Three-Component Synthesis of Pipecolic Amides. European Journal of Organic Chemistry, 2019(31-32), 5313-5325. https://doi.org/10.1002/ejoc.201900399