Replacing aryl rings with bicyclo[1.1.1]pentanes (BCPs) can be useful, e.g., to tune the properties of drug candidates. 1,3-disubstituted BCPs, for example can be used as replacements for para-substituted aryl rings. The synthesis of 2-substituted BCPs is less well studied. New methods for the general and rapid synthesis of this type of compound would be useful.
David W. C. MacMillan, Merck Center for Catalysis at Princeton University, NJ, USA, and colleagues have developed a generalizable synthetic strategy for accessing 2-substituted BCPs (example structure pictured) that is based on a radical C–H abstraction at the BCP core. The team first prepared carboxylated 2-brominated BCPs starting from, e.g., commercially available 1,3-dicarboxylic acid BCP using N-chlorosuccinimide (NCS) under visible-light in the presence of bromotrichloromethane as a brominating agent. This reaction proceeds via a radical C–H abstraction, followed by a reaction with the brominating agent.
The resulting BCP bromides were then arylated with a variety of (hetero)aryl bromide coupling partners using a metallaphotoredox protocol with an iridium-based catalyst, a nickel-based catalyst, and photocatalytically generated silyl radicals. The desired products were obtained in moderate to high yields, depending on the substrates. Under modified conditions with a copper source instead of a nickel-based catalyst, the team achieved BCP 2-amination using, e.g., indazoles, pyrazoles, or azaindazoles. According to the researchers, these methods can be used in the synthesis of complex drug substrates.
- Rapid Access to 2-Substituted Bicyclo[1.1.1]pentanes,
Olivia L. Garry, Michael Heilmann, Jingjia Chen, Yufan Liang, Xiaheng Zhang, Xiaoshen Ma, Charles S. Yeung, David Jonathan Bennett, David W. C. MacMillan,
J. Am. Chem. Soc. 2023.