Nickel-Catalyzed Cross-Coupling Reactions with Carbon-Oxygen Bonds

Nickel-catalysed cross-coupling reactions with carbon–oxygen bonds have emerged as versatile methodologies in organic synthesis, enabling the transformation of readily available phenolic and ester derivatives into diverse functionalised molecules. Unlike traditional cross-couplings that rely on halide electrophiles, C–O activation harnesses inert aryl ethers, esters and carbamates as coupling partners, utilising nickel’s unique oxidative addition propensity and redox flexibility. These processes typically proceed via oxidative insertion of a Ni(0) species into the C–O bond, generating Ni(II) complexes that undergo transmetalation and reductive elimination to form new C–C and C–heteroatom bonds. Advances in ligand design, such as N-heterocyclic carbenes and tailored phosphines, have enhanced reactivity, selectivity and substrate scope, while mechanistic elucidation of mono- and dinickel intermediates has deepened understanding of key steps. Nickel-catalysed C–O cross-coupling strategies offer sustainable routes to pharmaceuticals, agrochemicals and π-conjugated materials by exploiting abundant feedstocks, mild conditions and low-cost catalysts.

Research from Nature Portfolio

Recent studies have unlocked enantioselective alkylative cross-coupling of unactivated aromatic C–O electrophiles, employing a chiral N-heterocyclic carbene ligand in nickel catalysis to access axially chiral biaryl frameworks with excellent enantiocontrol. Mechanistic investigations indicate the involvement of bis-ligated nickel complexes as active species in C(sp3)–C(sp2) bond formation. Foundational research has further demonstrated nickel-mediated polycondensation of bifunctional aryl ethers to yield π-conjugated polymers, illustrating the broader applicability of C–O bond activation for constructing high-performance materials under mild conditions.

Nickel-Catalyzed Cross-Coupling Reactions with Carbon-Oxygen Bonds publication trend

The graph below shows the total number of articles in nickel-catalyzed cross-coupling reactions with carbon-oxygen bonds across all publications each year (not limited to Nature Index journals).

Technical terms

Oxidative addition: Insertion of a low-valent nickel species into a C–O bond to form a higher-valent organonickel intermediate.

Transmetalation: Transfer of an organic group from a main-group metal reagent to a nickel centre, enabling bond formation.

Reductive elimination: Coupling of two ligands on a metal centre to form a new bond and regenerate the lower-valent catalyst.

N-heterocyclic carbene (NHC): A strong σ-donor ligand used to stabilise nickel intermediates and enhance catalytic activity and selectivity.

Dinickel complex: A bimetallic nickel species involved in C–O bond activation, which can equilibrate to mononickel catalysts.

References

1. The Versatile and Strategic O‑Carbamate Directed Metalation Group in the Synthesis of Aromatic Molecules: An Update. Chemical Reviews (2024).
2. Intermediacy of Ni–Ni Species in sp2 C–O Bond Cleavage of Aryl Esters: Relevance in Catalytic C–Si Bond Formation. Journal of the American Chemical Society (2018).
3. Cross-coupling polycondensation via C–O or C–N bond cleavage. Nature Communications (2018).
4. Enantioselective alkylative cross-coupling of unactivated aromatic C–O electrophiles. Nature Communications (2022).