Expanding the Medicinal Chemist Toolbox: Comparing Seven C(sp2)–C(sp3) Cross-Coupling Methods by Library Synthesis

Despite recent advances in the field of C(sp2)–C(sp3) cross-couplings and the accompanying increase in publications, it can be hard to determine which method is appropriate for a given reaction when using the highly functionalized intermediates prevalent in medicinal chemistry. Thus a study was done comparing the ability of seven methods to directly install a diverse set of alkyl groups on “drug-like” aryl structures via parallel library synthesis. Each method showed substrates that it excelled at coupling compared with the other methods. When analyzing the reactions run across all of the methods, a reaction success rate of 50% was achieved. Whereas this is promising, there are still gaps in the scope of direct C(sp2)–C(sp3) coupling methods, like tertiary group installation. The results reported herein should be used to inform future syntheses, assess reaction scope, and encourage medicinal chemists to expand their synthetic toolbox.