Sulfonylation Strategies in Organic Synthesis

Sulfonylation encompasses a suite of methods for installing the sulfonyl moiety (–SO₂–) into organic frameworks, a transformation of central importance across pharmaceuticals, agrochemicals and advanced materials. Traditional approaches have relied on pre-functionalised sulfonyl chlorides or direct insertion of gaseous SO₂, often under harsh conditions and with limited substrate scope. In recent years, the field has witnessed a shift towards catalytic and flow-based platforms that enable more sustainable practices. Key strategies include transition-metal-mediated coupling of boronic acids or halides with SO₂ surrogates, radical-driven hydrosulfonylation of alkenes, and hydrogen atom transfer photocatalysis for the activation of otherwise inert C–H bonds. These advances deliver high atom-economy, broad functional-group tolerance and, in some cases, enantioselective control. The development of stable SO₂ equivalents and dual-catalytic systems has further reduced safety concerns and expanded access to sulphones, sulfonamides and sulfonate esters. Collectively, these innovations promise scalable routes to complex sulfonylated molecules, underpinned by improved reaction efficiency and environmental profiles.

Research from Nature Portfolio

Recent studies have demonstrated the power of photocatalytic systems to effect direct sulfonylation of alkanes under mild, scalable conditions. One approach employs flow-based hydrogen atom transfer to convert light hydrocarbons such as methane or propane into alkyl radicals that insert SO₂, generating sulfinates which serve as versatile precursors to sulfones, sulfonamides and sulfonate esters. This methodology offers robust safety and throughput advantages for handling gaseous feedstocks. In parallel, a dual-catalytic platform combining a chiral nickel complex and an organic photoredox catalyst achieves asymmetric C(sp³)–H sulfonylation. Through a radical relay mechanism with an SO₂ surrogate, this three-component protocol furnishes enantioenriched α-chiral sulfones with excellent regio- and enantioselectivity and is amenable to late-stage functionalisation of bioactive scaffolds.

Sulfonylation Strategies in Organic Synthesis publication trend

The graph below shows the total number of articles in sulfonylation strategies in organic synthesis across all publications each year (not limited to Nature Index journals).

Technical terms

Sulfonylation: Introduction of a sulfonyl (–SO₂–) functional group into an organic substrate.

Sulfinate: Salt or ester of sulfinic acid (–SO₂M), serving as a key intermediate en route to sulfones and sulfonamides.

Sulfone: Organic compound featuring a sulfonyl group bonded to two carbon atoms (R–SO₂–R′), valued for chemical stability and bioactivity.

Sulfonamide: Derivative containing a sulfonyl group linked to a nitrogen atom (R–SO₂–NR′₂), widely used in medicinal chemistry.

Photocatalysis: Use of light-activated catalysts to generate reactive radical or electron-transfer species under mild conditions.

Cross-electrophile coupling: Catalytic union of two electrophilic partners via radical intermediates, bypassing pre-formed organometallic reagents.

Sulfur dioxide surrogate: Stable reagent that releases SO₂ in situ, avoiding the direct use of toxic gaseous sulfur dioxide.

References

1. C(sp3)–H sulfinylation of light hydrocarbons with sulfur dioxide via hydrogen atom transfer photocatalysis in flow. Nature Communications (2024).
2. Photocatalytic three-component asymmetric sulfonylation via direct C(sp3)-H functionalization. Nature Communications (2021).
3. Zinc Promoted Cross‐Electrophile Sulfonylation to Access Alkyl–Alkyl Sulfones. Advanced Science (2024).
4. Hydrosulfonylation of Alkenes with Sulfonyl Chlorides under Visible Light Activation. Angewandte Chemie International Edition (2020).
5. Nickel(II)-Catalyzed Synthesis of Sulfinates from Aryl and Heteroaryl Boronic Acids and the Sulfur Dioxide Surrogate DABSO. ACS Catalysis (2019).