ChemBead Enabled High-Throughput Cross-Electrophile Coupling Reveals a New Complementary Ligand

High-throughput experimentation (HTE) methods are central to modern medicinal chemistry. While many HTE approaches to C-N and Csp² -Csp² bonds are available, options for Csp² -Csp³ bonds are limited. We report here how the adaptation of nickel-catalyzed cross-electrophile coupling of aryl bromides with alkyl halides to HTE is enabled by AbbVie ChemBeads technology. By using this approach, we were able to quickly map out the reactivity space at a global level with a challenging array of 3×222 micromolar reactions. The observed hit rate (56 %) is competitive with other often-used HTE reactions and the results are scalable. A key to this level of success was the finding that bipyridine 6-carboxamidine (BpyCam), a ligand that had not previously been shown to be optimal in any reaction, is as general as the best-known ligands with complementary reactivity. Such "cryptic" catalysts may be common and modern HTE methods should facilitate the process of finding these catalysts.