Nickel-Catalyzed Functionalization of Alkynes

Alkynes, characterised by a carbon–carbon triple bond, serve as versatile platforms for the construction of complex molecular architectures. Nickel catalysts have emerged as powerful tools for transforming alkynes into a broad spectrum of functionalised alkenes, dienes and cyclic frameworks. The unique electronic properties of nickel—its ability to access multiple oxidation states and engage in both two-electron and single-electron pathways—enable diverse reaction manifolds, including migratory insertions, cross-electrophile couplings and radical-mediated processes. These approaches deliver high levels of regio-, stereo- and enantioselectivity while operating under relatively mild conditions and using earth-abundant metal precursors.

Contemporary strategies harness ligand control, photoredox activation and electrochemical stimuli to modulate the reactivity and selectivity of nickel centres. This has led to stereodivergent syntheses of E- and Z-alkenes, syn-selective dialkylations and multicomponent cascades that install two or more new bonds in a single operation. Applications extend from the rapid assembly of densely substituted dienes and cyclopentanes to the enantioselective construction of heterocycles bearing chiral tertiary alcohols. Such methods find utility in the synthesis of pharmaceuticals, agrochemicals and natural product frameworks, underscoring the global significance of nickel-catalysed alkyne functionalisation in sustainable synthesis.

Research from Nature Portfolio

Recent studies have demonstrated a ligand-controlled dual photoredox and nickel catalytic system for stereodivergent sulfonylalkenylation of terminal alkynes. By selecting simple nickel salts and tunable phosphine ligands, both Z- and E-sulfonyl-1,3-dienes are obtained from identical substrates under mild visible-light conditions, with excellent chemo-, regio- and stereoselectivity. Mechanistic investigations, including computational analysis, reveal ligand-dependent pathways for controlling the alkene geometry.

A complementary advance reports a three-component electrochemical and photochemical cascade for arylalkylation of alkynes. This protocol switches between purely electrochemical conditions to deliver E-tri substituted alkenes and photo-electrochemical conditions for Z-isomers, without the need for separate photocatalysts in the latter. The method enables facile access to both stereoisomers of pharmaceutically relevant olefins in high yield and selectivity.

Another contribution describes a nickel-catalysed cross-electrophile dialkylation of unactivated alkynes, effected at room temperature. By combining two-electron oxidative cyclometallation with single-electron cross-electrophile coupling, two different alkyl groups are installed across the triple bond in a syn fashion. This reductive protocol circumvents the use of preformed organometallic reagents and affords multi-substituted alkenes amenable to further transformations.

Nickel-Catalyzed Functionalization of Alkynes publication trend

The graph below shows the total number of articles in nickel-catalyzed functionalization of alkynes across all publications each year (not limited to Nature Index journals).

Technical terms

Alkyne: An organic moiety containing a carbon–carbon triple bond, serving as a reactive platform for bond-forming reactions.

Photoredox catalysis: Activation mode in which light-absorbing catalysts mediate single-electron transfer to generate reactive intermediates.

Cross-electrophile coupling: A process in which two electrophilic partners are reductively coupled under metal catalysis, without preformed nucleophiles.

Regioselectivity: Preference for bond formation at one position over another in unsymmetrical substrates.

Stereoselectivity: Control over the spatial arrangement of substituents in the product (e.g., E vs. Z geometry).

Enantioselectivity: Preference for formation of one enantiomer over its mirror image in chiral products.

References

1. Ligand-controlled stereodivergent alkenylation of alkynes to access functionalized trans- and cis-1,3-dienes. Nature Communications (2023).
2. Nickel catalyzed multicomponent stereodivergent synthesis of olefins enabled by electrochemistry, photocatalysis and photo-electrochemistry. Nature Communications (2022).
3. Ni-catalyzed regio- and stereo-defined intermolecular cross-electrophile dialkylation of alkynes without directing group. Nature Communications (2021).
4. Practical synthesis of allylic amines via nickel-catalysed multicomponent coupling of alkenes, aldehydes, and amides. Chemical Science (2023).
5. Transition-Metal-Catalyzed Functionalization of Alkynes with Organoboron Reagents: New Trends, Mechanistic Insights, and Applications. ACS Catalysis (2021).
6. Nickel‐Catalyzed Arylative Cyclizations of Alkyne‐ and Allene‐Tethered Electrophiles using Arylboron Reagents. Chemistry - A European Journal (2022).