From p-Xylene to Ibuprofen in Flow: Three-Step Synthesis by a Unified Sequence of Chemoselective C−H Metalations

Hyune Jea Lee, Heejin Kim, Dong Pyo Kim

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Ibuprofen was prepared from an inactive and inexpensive p-xylene by three-step flow functionalizations through chemoselective metalations of benzyl positions in sequence using an in situ generated LICKOR-type superbase. The flow approach in the microreactor facilitated the comprehensive exploration of over 100 conditions in the first-step reaction by varying concentrations, temperatures, solvents, and equivalents of reagents, enabling optimal conditions to be found with 95 % yield by significantly suppressing the formation of byproducts, followed by the second C−H metalation step in 95 % yield. Moreover, gram-scale synthesis of ibuprofen in the final step was achieved by biphasic flow reaction of solution-phase intermediate with CO2, isolating 2.3 g for 10 min of operation time.

Original languageEnglish
Pages (from-to)11641-11645
Number of pages5
JournalChemistry - A European Journal
Volume25
Issue number50
DOIs
Publication statusPublished - 2019 Sep 6

Keywords

  • C−H metalation
  • flow chemistry
  • ibuprofen
  • reaction optimization
  • superbase

ASJC Scopus subject areas

  • Catalysis
  • Organic Chemistry

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