Palladium-catalysed C(sp 2 )-N cross-coupling (that is, Buchwald-Hartwig amination) is employed widely in synthetic chemistry, including in the pharmaceutical industry, for the synthesis of (hetero)aniline derivatives. However, the cost and relative scarcity of palladium provides motivation for the development of alternative, more Earth-abundant catalysts for such transformations. Here we disclose an operationally simple and air-stable ligand/nickel(II) pre-catalyst that accommodates the broadest combination of C(sp 2 )-N coupling partners reported to date for any single nickel catalyst, without the need for a precious-metal co-catalyst. Key to the unprecedented performance of this pre-catalyst is the application of the new, sterically demanding yet electron-poor bisphosphine PAd-DalPhos. Featured are the first reports of nickel-catalysed room temperature reactions involving challenging primary alkylamine and ammonia reaction partners employing an unprecedented scope of electrophiles, including transformations involving sought-after (hetero)aryl mesylates for which no capable catalyst system is known.

The utility of RockPhos, Ad‐BippyPhos, JosiPhos (CyPF‐tBu), and Mor‐DalPhos in palladium‐catalyzed C–O cross‐coupling reactions involving aliphatic alcohols and (hetero)aryl halides under analogous conditions was examined, both at room temperature and at elevated temperature (90 °C). In general, the RockPhos‐based catalyst system proved superior, especially at room temperature, but catalysts based on the other ligands examined also proved effective across a range of C–O cross‐couplings, in some cases providing better catalytic performance than RockPhos. New reactivity was established in terms of the scope of room temperature reactions. Proof‐of‐principle examples of such cross‐couplings involving aryl mesylates were also demonstrated.

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The successful application of (DPEPhos)Ni(mesityl)Br (C1) as a pre-catalyst in the Suzuki-Miyaura cross-coupling of heteroaryl chlorides or bromides and heteroaryl boronic acids is reported. The use of C1 in this context allows for such reactions to be conducted under mild conditions (2 mol% Ni, 25 °C), including cross-couplings leading to unsymmetrical biheteroaryls. Successful transformations of this type involving problematic pyridinyl boronic acid substrates (10 mol% Ni, 60°C) are also described.Key words Suzuki-Miyaura, nickel, biheteroaryls, heteroaryl boronic acids, heteroaryl halidesThe broad utility of the palladium-catalyzed cross-coupling of arylboron and aryl (pseudo)halide reagents (i.e., the Suzuki-Miyaura reaction, SM) in the assembly of biarylcontaining pharmaceuticals, natural products, conjugated materials, and fine chemicals was recognized in the awarding of the 2010 Nobel Prize in Chemistry.1,2 Notwithstanding the now well-established nature of such transformations, important challenges remain with regard to new catalyst development and reaction scope. In an effort to circumvent the use of precious metals and to access new reactivity manifolds, there is significant interest in the establishment of SM catalysts featuring more abundant 3d transition metals. Base-metal catalysts of this type that are capable of effecting cross-couplings of heteroaryl electrophiles and heteroarylboron substrates (Scheme 1) represent particularly attractive targets, given the prevalence of the unsymmetrical biheteroaryl motif in biologically active compounds.3 However, the synthesis of biheteroaryl compounds by use of SM cross-coupling protocols represents a potential challenge, owing in part to the possibility of catalyst inhibition by the substrate and/or product. Additionally, it has been shown that heteroaryl boronic acids are particularly prone to unwanted protodeborylation at elevated temperatures.

Synthesis and characterization of the new air-stable pre-catalyst (DPEPhos)Ni(2-mesityl)Br (C1) is reported, along with the application of this pre-catalyst in the cross-coupling of secondary amines/azoles with activated (hetero)aryl chlorides to afford tertiary (hetero)anilines. The performance of C1 in these cross-couplings is competitive with some of the best and/or most widely employed nickel catalysts for such transformations.