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From p ‐Xylene to Ibuprofen in Flow: Three‐Step Synthesis by a Unified Sequence of Chemoselective C−H Metalations
Author(s) -
Lee HyuneJea,
Kim Heejin,
Kim DongPyo
Publication year - 2019
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201903267
Subject(s) - yield (engineering) , reagent , ibuprofen , flow chemistry , chemistry , microreactor , metalation , combinatorial chemistry , xylene , reaction conditions , sequence (biology) , organic chemistry , toluene , catalysis , materials science , medicine , biochemistry , metallurgy , pharmacology
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 CO 2 , isolating 2.3 g for 10 min of operation time.