Synthesis of 1-(Halo)alkyl-3-heteroaryl Bicyclo[1.1.1]pentanes Enabled by a Photocatalytic Minisci-type Multicomponent Reaction

Aryl-substituted bicyclo[1.1.1]pentane (BCP-aryl) derivatives represent the most important bioisosteres of biaryl scaffolds and widely exist in numerous complex pharmaceutical molecules. The current synthetic method limitations of using only tertiary radical precursors, prefunctionalized heteroarenes, toxic transition metals, and expensive photocatalysts make it urgent to develop a more simple and practical protocol. To confront the limitations and enrich Minisci-type chemistry, herein, we disclose a photocatalytic Minisci-type multicomponent reaction for the synthesis of various (halo)alkyl BCP-aryls using [1.1.1]propellane, alkyl halides, and unfunctionalized heteroarenes as starting materials. Diverse kinds of unfunctionalized heteroarenes and alkyl radicals (primary, secondary, and tertiary carbons) derived from various alkyl chlorides, alkyl bromides, and fluoroalkyl iodides are very compatible in this transformation. The practicability of this method is additionally boosted by product derivatizations and the late-stage functionalization of pharmaceutically relevant molecules. The mechanistic studies demonstrate that a radical relay mechanism initiated by a consecutive photoinduced electron transfer (ConPET) process is in operation. We anticipate that this methodology would act as a useful tool for the synthesis of (halo)alkyl BCP-aryls as the bioisosteres of biaryl-type drug derivatives, ultimately resulting in great utility in the drug discovery program.