Direct C–H metallation of tetrahydrofuran and application in flow

The direct C–H metallation of tetrahydrofuran (THF) to generate α-anionic THF is one of the most straightforward methods for the functionalization of THF. However, the stability of THF makes it difficult to activate the α-proton and the instability of α-anionic THF leads to an uncontrollably rapid cleavage. These factors are well-known challenges for both the generation and utilization of α-anionic THF. Here we develop a reaction for the direct metallation of THF using a strong base as well as precise control of the temperature and reaction time in a microfluidic system. Various electrophiles, which include those with complex structures, were introduced to give products in high yields. Also, transmetallations to α-cuprated THF and α-borylated THF were successfully achieved and α-borylated THF was further functionalized via cross-coupling reactions, which demonstrates the value of this microfluidic approach.