Development of a Continuous‐Flow Curtius Rearrangement for the Scalable Preparation of a Protected 3‐Aminobicyclo[1.1.1]Pentane‐1‐carboxylate

ABSTRACT Bicyclo[1.1.1]pentane (BCP) derivatives are important motifs in medicinal chemistry as they are three‐dimensional bioisosteres of para‐substituted arenes. Herein, we describe the development of a safer and more scalable Curtius rearrangement of a BCP monoacid mono‐methyl ester under continuous‐flow conditions. Optimization of the reaction parameters and a chromatography‐free purification protocol enabled isolation of the target protected amino acid in high yield and excellent purity. On extended operation, the process delivered a projected daily productivity of 978 g/day.