Photoredox C_sp³−C_sp² Reductive Cross‐Couplings of Cereblon Ligands for PROTAC Linker Exploration in Batch and Flow

Abstract Proteolysis‐targeting chimeras (PROTACs) have recently emerged as powerful molecules for targeted protein degradation. As such, synthetic methods their modular synthesis are of prime importance in medicinal chemistry. We report the development both batch and flow photoredox methodologies C sp 3 −C 2 cross‐electrophile couplings alkyl bromides with E3 ligase‐binding aryl (thalidomide lenalidomide derivatives). Despite challenging reaction system, containing several insoluble species, conditions were discovered to facilitate stable processing an oscillatory photochemical reactor. The approach can enable larger material quantities a shorter time period. A range saturated linker molecules, various functional handles, successfully combined four ligand variants using developed conditions. Finally, scalability use organic photocatalyst explored.