A General, Multimetallic Cross-Ullmann Biheteroaryl Synthesis from Heteroaryl Halides and Heteroaryl Triflates.

Despite their importance to medicine and materials science, the synthesis of biheteroaryls by cross-coupling remains challenging. We describe here a new, general approach to biheteroaryls: the Ni- and Pd-catalyzed multimetallic cross-Ullmann coupling of heteroaryl halides with triflates. An array of 5-membered, 6-membered, and fused heteroaryl bromides and chlorides, as well as aryl triflates derived from heterocyclic phenols, proved to be viable substrates in this reaction (62 examples, 63 ± 17% average yield). The generality of this approach to biheteroaryls was further demonstrated in 96-well plate format at 10 µmol scale. An array of 96 possible products provided >90% hit rate under a single set of conditions. Further, low-yielding combinations could be rapidly optimized with a single "Toolbox Plate" of ligands, additives, and reductants.

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.