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

Overview

Journal J Am Chem Soc

Publisher American Chemical Society

Specialty Chemistry

Date 2021 Dec 17

PMID 34918908

Citations 12

Authors

Kai Kang

Nathan L Loud

Tarah A DiBenedetto

Daniel J Weix

Affiliations

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Abstract

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.

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