Cross-Electrophile Coupling Reactions in Organic Synthesis

Cross-electrophile coupling reactions have emerged as a transformative approach in organic synthesis, enabling the direct formation of carbon–carbon bonds between two electrophilic partners without pre-formed nucleophiles. By employing a stoichiometric reductant or electrochemical driving force, these methodologies bypass the need for organometallic reagents, thus reducing waste and improving functional-group tolerance. Central to these advances is the utilisation of nickel catalysts, which can engage in diverse oxidative states to mediate single-electron processes, radical generation and selective bond formation under mild conditions. Recent progress has expanded the substrate scope to include unactivated alkyl alcohols, heterocycles and sp3–sp3 coupling partners, while enantioselective variants now permit asymmetric synthesis of biologically relevant molecules. Mechanistic elucidation, aided by electroanalytical and spectroscopic studies, has clarified the roles of radical capture, oxidative addition and reductive elimination steps, guiding ligand design and reaction optimisation. The convergence of photoredox co-catalysis, mechanochemical activation and continuous flow technologies continues to drive the field towards more sustainable and scalable syntheses with broad industrial applications.

Research from Nature Portfolio

Recent studies have demonstrated an enantioconvergent deoxygenative reductive coupling of unactivated alkyl alcohols with aryl bromides, employing an N-heterocyclic carbene to activate the C–O bond and nickel catalysis to achieve high enantioselectivity and gram-scale utility in the synthesis of β-aryl ketones. Another advance combines nickel catalysis with visible-light photoredox activation to effect reductive cross-coupling of aryl iodides and α-chloroboranes, delivering chiral benzylic boronic esters under mild, redox-neutral conditions with exceptional stereocontrol. Foundational work has introduced hydrazine as a traceless mediator for the homo- and cross-coupling of aryl electrophiles, enabling the clean generation of biaryls with only nitrogen and hydrogen gas by-products, thereby minimising metal waste and expanding the functional-group tolerance of the protocol.

Cross-Electrophile Coupling Reactions in Organic Synthesis publication trend

The graph below shows the total number of articles in cross-electrophile coupling reactions in organic synthesis across all publications each year (not limited to Nature Index journals).

Technical terms

Cross-electrophile coupling: A reaction that joins two electrophilic substrates in the presence of a reductant and catalyst, forming a new carbon–carbon bond without preformed nucleophiles.

Electrophile: A chemical species that accepts electrons, often bearing a leaving group such as a halide or tosylate.

Reductive coupling: A bond-forming process driven by a reductant, which provides electrons to facilitate oxidative addition, radical formation and reductive elimination steps.

Photoredox catalysis: A strategy that employs light-absorbing catalysts to generate reactive radical species via single-electron transfer under visible-light irradiation.

Enantioconvergent reaction: A process in which both enantiomers of a racemic starting material are converted into a single enantiomer of the product, delivering high optical purity.

Mechanochemical activation: The use of mechanical force, such as ball-milling, to activate solid reagents and enhance reaction rates in the absence of bulk solvents.

Oxidative addition and reductive elimination: Fundamental steps in transition-metal catalysis whereby a metal inserts into a σ-bond (oxidative addition) and subsequently forms a new bond while regenerating the lower oxidation state (reductive elimination).

References

1. Ni-catalyzed enantioconvergent deoxygenative reductive cross-coupling of unactivated alkyl alcohols and aryl bromides. Nature Communications (2024).
2. Dual Ni/photoredox-catalyzed asymmetric cross-coupling to access chiral benzylic boronic esters. Nature Communications (2021).
3. N2H4 as traceless mediator for homo- and cross- aryl coupling. Nature Communications (2018).
4. Nickel-Catalyzed Enantioselective Electrochemical Reductive Cross-Coupling of Aryl Aziridines with Alkenyl Bromides. Journal of the American Chemical Society (2023).
5. Mechanical Activation of Zero-Valent Metal Reductants for Nickel-Catalyzed Cross-Electrophile Coupling. ACS Catalysis (2022).
6. Electrochemical Nickel-Catalyzed C(sp3)–C(sp3) Cross-Coupling of Alkyl Halides with Alkyl Tosylates. Journal of the American Chemical Society (2023).