Light-enabled scalable synthesis of bicyclo[1.1.1]pentane halides and their functionalizations

In 2012, bicyclo[1.1.1]pentanes were demonstrated to be bioisosteres of the benzene ring. Here, we report a general scalable reaction between alkyl iodides and propellane that provides bicyclo[1.1.1]pentane iodides in milligram, gram and even kilogram quantities. The reaction is performed in flow and requires just light; no catalysts, initiators or additives are needed. The reaction is clean enough that, in many cases, evaporation of the reaction mixture provides products in around 90% purity that can be directly used in further transformations without any purification. Combined with the subsequent functionalization, >300 bicyclo[1.1.1]pentanes for medicinal chemistry have been prepared. So far, this is the most general and scalable approach towards functionalized bicyclo[1.1.1]pentanes. A general and scalable approach to prepare functionalized bicyclo[1.1.1]pentanes is reported. The key reaction between alkyl iodides and propellane is performed in flow and requires just light; no catalysts, initiators or additives are needed. Combined with the subsequent functionalization, >300 bicyclo[1.1.1]pentanes for medicinal chemistry have been prepared.