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Continuous-Flow Hydrogenation of 4-Phenylpyridine to 4-Phenylpiperidine with Integrated Product Isolation Using a CO2 Switchable System

Abstract

A process comprising a continuous-flow hydrogenation reaction integrated with selective water-organic solvent biphasic extraction using CO2 as molecular switch to control partitioning was devised for the synthesis of arylpiperidines from arylpyridines. The selective hydrogenation of 4-phenylpyridine using heterogeneous carbon-supported metal catalysts was chosen as model reaction. A design-of-experiment approach was used for the identification of suitable reaction conditions under continuous-flow operation. A maximum selectivity for 4-phenylpiperidine of 96% was achieved at 87% conversion suppressing the deep hydrogenation to 4-cyclohexylpiperidine almost completely (≤5%). The higher basicity of piperidines over pyridines was exploited for selective and reversible protonation of the product upon pressurization with CO2 separating it quantitatively from the remaining starting material in a water-EtOAc biphasic system. This concept enabled a fully integrated and a salt-free synthetic process using a standard Pd/C catalyst for the hydrogenation coupled with the CO2-triggered isolation of the desired product 4-phenylpiperidine in 81% yield and 98% purity.

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Correspondence to Giancarlo Franciò or Walter Leitner.

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Barwinski, B., Migowski, P., Gallou, F. et al. Continuous-Flow Hydrogenation of 4-Phenylpyridine to 4-Phenylpiperidine with Integrated Product Isolation Using a CO2 Switchable System. J Flow Chem 7, 41–45 (2017). https://doi.org/10.1556/1846.2017.00003

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  • DOI: https://doi.org/10.1556/1846.2017.00003

Keywords

  • Continuous flow catalysis
  • selective hydrogenation of pyridine in the presence of a phenyl substituent
  • carbon dioxide as molecular switch
  • aqueous biphasic selective isolation of amines triggered by carbon dioxide
  • reversible formation of piperidium bicarbonate