Environmentally Friendly Synthesis of Indoline Derivatives using Flow-Chemistry Techniques

Róbert Örkényi, Gyula Beke, Eszter Riethmüller, Zoltán Szakács, János Kóti, F. Faigl, János Éles, István Greiner

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1 Citation (Scopus)

Abstract

Flow chemistry proved to be a valuable technique to improve the synthesis route to melanin-concentrating hormone receptor 1 (MCHr1) antagonists with the 1H,2H,3H,4H,5H-[1,4]diazepino[1,7-a]indole scaffold. A one-step route for the heterogeneous catalytic hydrogenation of ethyl 4-(2-nitrophenyl)-3-oxobutanoate for the synthesis of ethyl 2-(2,3-dihydro-1H-indol-2-yl)acetate was developed, and the use of common reducing chemicals was avoided. N-Alkylation of the indoline nitrogen atom was also optimized by using a purpose-built flow reactor and by design of experiment (DoE). Applying an optimal set of parameters allowed us to decrease the amount of carcinogenic 1,2-dibromoethane used by a factor of 10. Additionally, nearly complete conversion was achieved in a fraction of the original reaction time (30 min vs. 4 d); therefore, the productivity (space-time yield) of the flow-reactor system was proven to be ca. 200 times higher than that of the batch process.

Original languageEnglish
Pages (from-to)6525-6532
Number of pages8
JournalEuropean Journal of Organic Chemistry
Volume2017
Issue number44
DOIs
Publication statusPublished - Dec 1 2017

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Keywords

  • Alkylation
  • Continuous flow
  • Heterogeneous catalysis
  • Hydrogenation
  • Nitrogen heterocycles

ASJC Scopus subject areas

  • Physical and Theoretical Chemistry
  • Organic Chemistry

Cite this

Örkényi, R., Beke, G., Riethmüller, E., Szakács, Z., Kóti, J., Faigl, F., Éles, J., & Greiner, I. (2017). Environmentally Friendly Synthesis of Indoline Derivatives using Flow-Chemistry Techniques. European Journal of Organic Chemistry, 2017(44), 6525-6532. https://doi.org/10.1002/ejoc.201700849