From p-Xylene to Ibuprofen in Flow: Three-Step Synthesis by a Unified Sequence of Chemoselective C-H Metalations
- Authors
- Lee, Hyune-Jea; Kim, Heejin; Kim, Dong-Pyo
- Issue Date
- 6-9월-2019
- Publisher
- WILEY-V C H VERLAG GMBH
- Keywords
- C-H metalation; flow chemistry; ibuprofen; reaction optimization; superbase
- Citation
- CHEMISTRY-A EUROPEAN JOURNAL, v.25, no.50, pp.11641 - 11645
- Indexed
- SCIE
SCOPUS
- Journal Title
- CHEMISTRY-A EUROPEAN JOURNAL
- Volume
- 25
- Number
- 50
- Start Page
- 11641
- End Page
- 11645
- URI
- https://scholar.korea.ac.kr/handle/2021.sw.korea/62899
- DOI
- 10.1002/chem.201903267
- ISSN
- 0947-6539
- 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.
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