Pyridine-Boryl Radical-Catalyzed [2?+2?] Cycloaddition of with Alkenes

Bicyclo[2.1.1]hexanes (BCHs) represent an intriguing class of structurally rigid hydrocarbons that can serve as the bioisosteres of benzenoids in medicinal chemistry. Methods for the synthesis of BCHs are, however, limiting. Reported herein is a facile synthesis of BCHs via a strain-release-driven [27r + 2o-] cycloaddition of bicyclo[1.1.0]butanes (BCBs) with alkenes facilitated by a pyridine-boryl radical catalyst. The mild reaction conditions, broad substrate scope, and decent functional group tolerance of this protocol render it appealing in relevant fields of drug design and synthesis. Theoretical mechanistic studies reveal that a radical relay mechanism is involved. Synthetic applications of the products are performed.

Automated summary

This article reports a facile synthesis strategy for bicyclo[2.1.1]hexanes (BCHs) as bioisosteres of benzenoids in medicinal chemistry. The synthesis is achieved through a strain-release-driven [27r + 2o-] cycloaddition of bicyclo[1.1.0]butanes (BCBs) with alkenes using a pyridine-boryl radical catalyst. The mild reaction conditions, wide substrate scope, and good functional group tolerance make this protocol appealing for drug design and synthesis. Theoretical mechanistic studies suggest a radical relay mechanism, and synthetic applications of the products are demonstrated.