Cross–coupling reactions are at the heart of modern organic synthesis, enabling selective formation of carbon–carbon and carbon–heteroatom bonds. Despite the great progress made in method developments – including the recent advancement of combining transition metal cross–coupling reactions with photochemistry – a large variety of required ligands and reaction conditions imposes a challenge to non-experts in selecting the right parameters and predicting the reaction outcome for a specific (hetero)arene - nucleophile combination. Commercial sets of ligands or pre-catalysts, advancement of fast screening methods, and the recent use of machine learning predictions can facilitate the choice of suitable cross–coupling reaction conditions. Instead of following the common notion of ligand design and additive screening for a specific cross–coupling reaction, we demonstrate a general premise for cross–coupling reactions that gravitates towards predicting right reaction conditions for successful outcome. Keeping the necessary parameters – i.e., halogenated (het)arene, respective nucleophile coupling partner, a bench-stable nickel salt (NiBr2 ● glyme), an all organic photocatalyst, 455 nm LED irradiation – constant, the only variable is a low molecular weight nitrogenous base (here, tertiary, primary, or an imine). The synthetic examples cover (het)arene cross–coupling reactions with a range of aryl and (het)aryl halides (in this case, bromides, iodides, chlorides) in C(sp2)–S, C(sp2)–Se, C(sp2)–N(sp3/sp2), C(sp2)–P, C(sp2)–B, C(sp2)–O, C(sp2)–C(sp3/sp2/sp) bond forming reactions covering forty different classes of nucleophiles and exemplifying more than three hundred cross–coupling products. Examples comprise late–stage functionalization of pharmaceuticals or natural products under predictable reaction conditions. We believe that the simple yet very predictable nickel–photocatalytic reaction conditions will accelerate the adoption of (hetero)arene halide/nucleophile cross–coupling reactions to many disciplines.

Simplifying (het)arene cross–coupling reactions with nickel and visible light

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ACS Fall 2022

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