Sulfur-Mediated Rearrangement Reactions in Organic Synthesis

Sulfur-mediated rearrangement reactions represent a versatile class of transformations in which bond reorganisation at a sulphur centre enables efficient carbon–carbon and carbon–heteroatom bond formation under mild, often metal-free, conditions. Central to this chemistry are Pummerer and interrupted Pummerer sequences, sigmatropic shifts of sulfonium intermediates and rearrangements of sulfur ylides. By harnessing the unique electrophilic character of oxidised sulfur species—sulfoxides, sulfonium salts and sulfinate esters—synthetic chemists have achieved regio- and stereoselective functionalisation of heterocycles, late-stage arylation and alkylation, and the construction of complex scaffolds such as γ-lactones, γ-lactams and fused polycyclic frameworks. Mechanistic studies, often coupled with quantum chemical analysis, have unveiled charge-accelerated pathways and clarified the influence of electronic and steric factors on migration selectivity. Recent innovations include catalytic asymmetric variants, cascade sequences that merge multiple bond-forming events in a single operation, and the application of mechanochemical methods to eliminate solvents and metal catalysts. These advances have broad implications for the streamlined synthesis of pharmaceuticals, agrochemicals and functional materials, emphasising both sustainability and operational simplicity.

Research from Nature Portfolio

Building on classical sulfoxide chemistry, one seminal report demonstrated that benzothiophene S-oxides serve as precursors for direct C3 functionalisation. An interrupted Pummerer coupling with phenols or silanes forms transient sulfonium intermediates that rearrange selectively to deliver C3-alkylated and arylated benzothiophenes under entirely metal-free and mild conditions. This directing-group-free strategy achieves complete regioselectivity and broad substrate scope, offering a sustainable route to heteroaromatic motifs with applications in medicinal and materials chemistry.

Sulfur-Mediated Rearrangement Reactions in Organic Synthesis publication trend

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

Technical terms

Pummerer rearrangement: Transformation of a sulfoxide into a sulfonium intermediate via activation (often by an electrophile), followed by migration of an α-substituent to produce an α-functionalised product.

Interrupted Pummerer reaction: Variant in which an external nucleophile intercepts the sulfonium intermediate prior to full rearrangement, enabling diverse C–X bond formations.

[3,3]-Sigmatropic rearrangement: Concerted pericyclic shift of substituents across a six-membered transition state, common in transformations of sulfur ylides and sulfonium salts.

Sulfonium salt: A positively charged sulphur species bearing three substituents; key intermediate in many rearrangement pathways and electrophilic transfer processes.

Sulfur ylide: A zwitterionic species containing a positively charged sulfur centre adjacent to a carbanion, capable of undergoing [2,3]- and [1,2]-rearrangements to install carbon substituents.

References

1. Bond-Forming and -Breaking Reactions at Sulfur(IV): Sulfoxides, Sulfonium Salts, Sulfur Ylides, and Sulfinate Salts. Chemical Reviews (2019).
2. Regioselective synthesis of C3 alkylated and arylated benzothiophenes. Nature Communications (2017).
3. Stereodivergent Synthesis of 1,4-Dicarbonyl Compounds through Sulfonium Rearrangement: Mechanistic Investigation, Stereocontrolled Access to γ‑Lactones and γ‑Lactams, and Total Synthesis of Paraconic Acids. Journal of the American Chemical Society (2024).
4. Metal‐Free Arylation of Benzothiophenes at C4 by Activation as their Benzothiophene S‐Oxides. Angewandte Chemie International Edition (2023).
5. Reshuffle Bonds by Ball Milling: A Mechanochemical Protocol for Charge-Accelerated Aza-Claisen Rearrangements. Molecules (2023).
6. Dual vicinal functionalisation of heterocycles via an interrupted Pummerer coupling/[3,3]-sigmatropic rearrangement cascade. Chemical Science (2018).