Selective [2σ+2σ] Cycloaddition Enabled by Boronyl Radical Catalysis: Synthesis of Highly Substituted Bicyclo[3.1.1]heptanes

In contrast to the traditional and widely-used cycloaddition reactions involving at least a x bond component, a [2 sigma + 2 sigma] radical cycloaddition between bicyclo[1.1.0]butanes (BCBs) and cyclopropyl ketones has been developed to provide a modular, concise, and atom-economical synthetic route to substituted bicyclo[3.1.1]heptane (BCH) derivatives that are 3D bioisosteres of benzenes and core skeleton of a number of terpene natural products. The reaction was catalyzed by a combination of simple tetraalkoxydiboron(4) compound B(2)pin(2) and 3-pentyl isonicotinate. The broad substrate scope has been demonstrated by synthesizing a series of new highly functionalized BCHs with up to six substituents on the core with up to 99% isolated yield. Computational mechanistic investigations supported a pyridine-assisted boronyl radical catalytic cycle.

Automated summary

In this study, a novel [2 sigma + 2 sigma] radical cycloaddition reaction between bicyclo[1.1.0]butanes (BCBs) and cyclopropyl ketones was developed. This reaction provides a modular, concise, and atom-economical synthetic route to substituted bicyclo[3.1.1]heptane (BCH) derivatives, which are 3D bioisosteres of benzenes and core skeleton of terpene natural products. The reaction was catalyzed by a combination of tetraalkoxydiboron(4) compound B(2)pin(2) and 3-pentyl isonicotinate. The broad substrate scope was demonstrated by synthesizing highly functionalized BCHs with up to six substituents on the core and up to 99% isolated yield. Computational mechanistic investigations supported a pyridine-assisted boronyl radical catalytic cycle.