Transition Metal-Catalyzed Carbon-Sulfur Bond Formation and Functionalization

Transition metal catalysis has revolutionised the synthesis of organosulfur compounds by enabling efficient formation and manipulation of carbon–sulfur (C–S) bonds under mild conditions and with broad functional-group tolerance. Key metals such as nickel, palladium, copper and rhodium have been harnessed to promote cross-coupling reactions between thiols or disulfides and aryl or alkyl halides, to facilitate desulfonylative processes of sulfone and thiosulfonate substrates, and to enable dual photoredox-metal strategies for site-selective functionalisation. Advances in reductive coupling have obviated the need for stoichiometric organometallic reagents, while electrochemical methods have introduced sustainable, reagent-free electron sources. These developments have delivered diverse thioethers, sulfones and sulfoxides that serve as building blocks in pharmaceuticals, agrochemicals and materials science. Moreover, the late-stage C–S bond installation in complex molecules—including peptides and bioactive natural products—underscores the global importance of these methodologies. Current challenges include minimising catalyst deactivation by thiolate coordination, expanding asymmetric variants, and achieving broader substrate scopes in C–S bond functionalisation. Collectively, the field continues to push the boundaries of selectivity, sustainability and scalability in organosulfur chemistry.

Research from Nature Portfolio

Recent studies have demonstrated a nickel-catalysed reductive thiolation of unactivated primary and secondary alkyl bromides with bench-stable thiosulfonates under mild conditions. This protocol affords unsymmetrical alkyl–aryl and alkyl–alkyl thioethers with excellent functional-group compatibility and can be extended to selenide synthesis using selenosulfonates. The method avoids sensitive organometallic reagents and proceeds with high efficiency, offering a practical route to diverse aliphatic and aromatic sulfides. This work exemplifies the trend towards cross-electrophile coupling in C–S bond formation and highlights nickel’s versatility in reductive processes.

Transition Metal-Catalyzed Carbon-Sulfur Bond Formation and Functionalization publication trend

The graph below shows the total number of articles in transition metal-catalyzed carbon-sulfur bond formation and functionalization across all publications each year (not limited to Nature Index journals).

Technical terms

Cross-electrophile coupling: A catalytic process in which two electrophilic partners (for example, an alkyl halide and a thiosulfonate) are joined by simultaneous reduction and bond-forming steps without preformed nucleophiles.

Reductive thiolation: A reaction in which a thiolation reagent (such as a thiosulfonate) and an electrophile are coupled under reducing conditions, typically mediated by a transition metal catalyst and a reductant or an electrochemical cell.

Photoredox catalysis: A mode of catalysis that uses visible light to promote single-electron transfer events via a photoexcitable catalyst, enabling novel bond-forming pathways in conjunction with transition metals.

Thiosulfonate: A sulfonyl derivative (R–SO₂–SR′) that serves as a stable, bench-accessible source of thiyl radicals or thiolate equivalents in coupling reactions.

Thioether (sulfide): An organosulfur compound of the type R–S–R′, valued for its prevalence in pharmaceuticals, agrochemicals and advanced materials due to its chemical stability and electronic properties.

References

1. Nickel-catalyzed reductive thiolation and selenylation of unactivated alkyl bromides. Nature Communications (2018).
2. Electroreductive Nickel‐Catalyzed Thiolation: Efficient Cross‐Electrophile Coupling for C−S Formation. Chemistry - A European Journal (2021).
3. Scalable thioarylation of unprotected peptides and biomolecules under Ni/photoredox catalysis. Chemical Science (2018).
4. Rhodium-catalyzed odorless synthesis of diaryl sulfides from borylarenes and S -aryl thiosulfonates. Chemical Communications (2017).