Preparation and Synthetic Manipulation of Four-Membered Aza-Heterocycles: New Strategies and Enabling Flow Technologies in Action

Aliphatic four-membered rings including cyclobutanes, oxetanes, thietanes, and bicyclo[1.1.1]pentanes are receiving increasing attention in medicinal chemistry due to their beneficial physicochemical properties and applications as functional group bioisosteres. In this scenario, the nitrogenated specimens, i.e. azetidines and 1-azabicyclo[1.1.0]butanes (ABBs), play a leading role. In this contribution, our efforts in preparing and decorating these strained motifs using flow chemistry as enabling technology will be presented. In particular, we could generate three different lithiated four-membered aza-heterocycles under continuous flow conditions obtaining C3-functionalized azetidines, C3-ABBs, and C2-functionalized azetines after electrophilic trapping. The microfluidic technology allows for exquisite control of the reaction parameters and the processes operate at higher temperatures and safer conditions if compared to batch mode. Furthermore, we developed various strategies to synthetically manipulate the obtained four-membered aza-heterocycles accessing unexplored chemical space in heterocyclic chemistry.