Generation and Use of Bicyclo[1.1.0]butyllithium under Continuous Flow Conditions

The bicyclo[1.1.0]butyl scaffold has emerged as a valuable
bioisostere
in drug discovery programs. Here, we present a streamlined approach
for the generation of bicyclo[1.1.0]butyllithium and its functionalization
with various classes of electrophiles in a one-flow process, eliminating
the need for intermediate isolation. In comparison to traditional
batch processes, the flow method allows the use of a single organolithium
reagent instead of two and operates at significantly higher temperatures
(0 °C versus −78 °C), enhancing both practicality
and scalability.