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.