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 mu mol 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.

Automated summary

A new, general approach to biheteroaryls through Ni- and Pd-catalyzed multimetallic cross-Ullmann coupling has been developed, demonstrating successful synthesis of a variety of heteroaryl halides and triflates. This method showed high generality and >90% hit rate in a 96-well plate format.