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

Research output: Contribution to JournalArticleAcademicpeer-review

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

Fingerprint

Cyanides
Amides
amides
Picolines
Piperidines
anticoagulants
piperidine
alkylation
Alkylation
synthesis
Carboxylic Acids
carboxylic acids
Anticoagulants
Hydrogenation
hydrogenation
pyridines
Oxidation
oxidation
rings
pyridine

Bibliographical note

Special Issue: Heterocyclic Chemistry

Keywords

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

Cite this

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
van der Heijden, Gydo ; van Schaik, Timo B. ; Mouarrawis, Valentinos ; de Wit, Martin J.M. ; Velde, Christophe M.L.Vande ; Ruijter, Eelco ; Orru, Romano V.A. / Efficient Diastereoselective Three-Component Synthesis of Pipecolic Amides. In: European Journal of Organic Chemistry. 2019 ; Vol. 2019, No. 31-32. pp. 5313-5325.
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van der Heijden, G, van Schaik, TB, Mouarrawis, V, de Wit, MJM, Velde, CMLV, Ruijter, E & Orru, RVA 2019, 'Efficient Diastereoselective Three-Component Synthesis of Pipecolic Amides' European Journal of Organic Chemistry, vol. 2019, no. 31-32, pp. 5313-5325. https://doi.org/10.1002/ejoc.201900399

Efficient Diastereoselective Three-Component Synthesis of Pipecolic Amides. / van der Heijden, Gydo; van Schaik, Timo B.; Mouarrawis, Valentinos; de Wit, Martin J.M.; Velde, Christophe M.L.Vande; Ruijter, Eelco; Orru, Romano V.A.

In: European Journal of Organic Chemistry, Vol. 2019, No. 31-32, 01.09.2019, p. 5313-5325.

Research output: Contribution to JournalArticleAcademicpeer-review

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AU - Mouarrawis, Valentinos

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AU - Velde, Christophe M.L.Vande

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van der Heijden G, van Schaik TB, Mouarrawis V, de Wit MJM, Velde CMLV, Ruijter E et al. Efficient Diastereoselective Three-Component Synthesis of Pipecolic Amides. European Journal of Organic Chemistry. 2019 Sep 1;2019(31-32):5313-5325. https://doi.org/10.1002/ejoc.201900399