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

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.