Aqueous Amine-Tolerant [2+2] Photocycloadditions of Unactivated Olefins

The Kochi-Salomon reaction is the only photochemical [2+2] cycloaddition capable of combining two electronically unactivated olefins into a cyclobutane. Yet, the reaction has remained largely unexplored and suffers many drawbacks, most notably an intolerance to Lewis/Bronsted basic amines and amides. Since these groups are ubiquitous in biologically active pharmaceuticals, an amine-tolerant Kochi-Salomon reaction would greatly facilitate rapid exploration of novel drug scaffolds. Herein, we disclose a transformation that is run in water with the most widely available Cu(II) salts and mineral acids. Furthermore, we apply this methodology to synthesize a variety of amine-containing cyclobutanes, including known and novel pharmacological analogues.

Automated summary

The Kochi-Salomon reaction is a photochemical [2+2] cycloaddition that can combine two electronically unactivated olefins into a cyclobutane. However, this reaction remains largely unexplored and is known for its intolerance to Lewis/Bronsted basic amines and amides. In this study, we disclose a transformation that can be carried out in water using readily available Cu(II) salts and mineral acids. Additionally, we demonstrate the application of this methodology in synthesizing a variety of amine-containing cyclobutanes, including known and novel pharmacological analogues.