TY - JOUR
T1 - From p-Xylene to Ibuprofen in Flow
T2 - Three-Step Synthesis by a Unified Sequence of Chemoselective C−H Metalations
AU - Lee, Hyune Jea
AU - Kim, Heejin
AU - Kim, Dong Pyo
N1 - Funding Information:
We gratefully acknowledge the support from the National Research Foundation (NRF) of Korea grant funded by the Korean government (NRF-2017R1A3B1023598).
PY - 2019/9/6
Y1 - 2019/9/6
N2 - 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.
AB - 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.
KW - C−H metalation
KW - flow chemistry
KW - ibuprofen
KW - reaction optimization
KW - superbase
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U2 - 10.1002/chem.201903267
DO - 10.1002/chem.201903267
M3 - Article
C2 - 31338883
AN - SCOPUS:85071264884
VL - 25
SP - 11641
EP - 11645
JO - Chemistry - A European Journal
JF - Chemistry - A European Journal
SN - 0947-6539
IS - 50
ER -