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

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.

Ni- and Ni/Pd-Catalyzed Reductive Coupling of Lignin-Derived Aromatics to Access Biobased Plasticizers

“…The Ni-only catalyst systems noted above were evaluated in the cross-coupling of H , G , and S sulfonates; however, these reactions led to poor selectivity and yields of the desired products (Table S10). These complications prompted us to evaluate the recently disclosed dual Ni/Pd cocatalyst systems. − For example, the method of Weix and co-workers, which employs Ni/Pd chloride salts in combination with 4,4′-diphenyl-bpy (4,4′-dPhbpy) and 1,4-bis­(diphenylphosphino)­butane (dppb) and Zn as a chemical reductant, supports cross-coupling of aryl triflates and tosylates . Efforts to translate this catalyst system to electrochemical cross-coupling of G and S sulfonates were unsuccessful, regardless of the sulfonate activating groups: biaryl products formed in ≤15% yield and favored the homocoupling products (Figure S5).…”

“…Shortly thereafter, Jutand and co-workers achieved homocoupling of aryl triflates with phosphine-ligated Pd or Ni catalysts. This study included a single example of electrochemical Ni-catalyzed homocoupling, using 1-naphthyl triflate as the substrate (Scheme A). ,, In recent years, Weix and co-workers have developed methods for selective cross-coupling of aryl electrophiles with a cocatalyst system containing both Ni and Pd in the presence of Zn as the reductant. − The groups of Weix and Kramer/Lian independently reported reductive cross-coupling of two different aryl sulfonates by pairing Pd/bisphosphine and Ni/diimine cocatalysts [diimine = substituted 2,2′-bipyridine (bpy) or 1,10-phenanthroline (phen) derivatives] with Zn (Scheme B). To date, no electrochemical methods to our knowledge have been reported for reductive cross-coupling of phenol derivatives (Scheme C). − …”

Mechanistic views and computational studies on transition-metal-catalyzed reductive coupling reactions

“…The different chemoselectivity can be effectively tuned by appropriate transition metal catalysts, which are capable of identifying the subtle steric and electronic differences between two intrinsically similar coupling partners. 53,105,[142][143][144] Through a series of DFT investigations, Guan and Su's group investigated the selective reductive coupling of bromobenzene and 4methoxyphenyltriflate via Ni/Pd dual catalysis (Fig. 20).…”

Multidimensional Screening Accelerates the Discovery of Rhodium Catalyst Systems for Selective Intra- and Intermolecular C–H Amidations

“…Recent advances in high-throughput experimentation (HTE) enabled the fast examination of multiple reactions with minimum resources in a relatively short period of time. − Thus, the HTE approach has been successfully applied to pharmaceutical synthesis − and catalyst design. − Benefitting from the HTE logic and known accessibility to both Cp X - and LX-type compounds, we envisaged generating a wide array of Cp X M­(LX) complexes in situ by simple premixing of [Cp X MCl 2 ] 2 and LX co-ligands. Moreover, we also envisioned additionally screening the metal centers and nitrenoid precursors (Scheme b, right).…”