Catalytic Rearrangement Reactions in Organic Synthesis

Catalytic rearrangement reactions encompass a diverse class of transformations in which the connectivity of atoms within a molecule is reorganised under the guidance of a catalyst. These processes, which include sigmatropic shifts, Stevens and Wittig rearrangements, ring expansions and migrations of acyl or heteroatom substituents, are powerful tools for the rapid assembly of complex carbon and heteroatom frameworks. Advances in catalyst design—ranging from transition-metal carbenoid systems to small-molecule organocatalysts—have enabled mild reaction conditions, broad functional-group tolerance and high levels of stereocontrol. Key developments include the use of reactive ylides and carbenes to effect bond reorganisation in a single step, as well as the integration of enantioselective strategies to furnish chiral centres with high fidelity. These methods have found widespread application in the synthesis of natural products, pharmaceuticals and functional materials, allowing late-stage modification of advanced intermediates and a reduction in step count. Ongoing research focuses on sustainable catalyst platforms, mechanistic elucidation by computation and the expansion of substrate scope to include complex nitrogen and sulphur-containing scaffolds.

Research from Nature Portfolio

Recent studies have demonstrated a general difluorocarbene-induced strategy for tertiary amine rearrangements. In situ generation of difluoromethyl ammonium ylides enables both [1,2]- and [2,3]-Stevens rearrangements under uniform, mild conditions, accommodating allyl, benzyl and propargyl substituents and facilitating late-stage modifications of bioactive molecules. Another report has introduced a rhodium(II)-catalysed [1,4]-acyl shift between α-diazo carbonyl compounds and thioesters to assemble tetrasubstituted vinyl sulfides with high chemo- and stereoselectivity; this modular approach yields a diverse library of photoactive and biological probes. A further advance exploits bicyclic aziridines and rhodium-bound vinyl carbenes in an intermolecular [3+3] ring expansion. The process proceeds via an aziridinium ylide intermediate and a pseudo-[1,4]-sigmatropic rearrangement to deliver dehydropiperidines with complete stereospecificity, offering efficient access to enantioenriched N-heterocycles.

Catalytic Rearrangement Reactions in Organic Synthesis publication trend

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

Technical terms

Ylide: A neutral molecule featuring adjacent oppositely charged atoms, typically a carbanion and a positively charged heteroatom, that serves as a key rearrangement intermediate.

Sigmatropic rearrangement: A pericyclic process in which a σ-bond migrates across a conjugated π-system in a concerted fashion, classified by the number of atoms involved in bond breaking and forming.

Carbene: A divalent carbon species with two nonbonded electrons, often generated catalytically to induce insertions or rearrangements.

Stevens rearrangement: A rearrangement of quaternary ammonium or sulfonium ylides leading to migration of a substituent and formation of new C–C bonds.

Ion-binding catalysis: A strategy employing catalysts that simultaneously bind both an anionic intermediate and its countercation to control reactivity and stereoselectivity.

References

1. Difluorocarbene-induced [1,2]- and [2,3]-Stevens rearrangement of tertiary amines. Nature Communications (2024).
2. Modular and stereoselective synthesis of tetrasubstituted vinyl sulfides leading to a library of AIEgens. Nature Communications (2021).
3. Intermolecular [3+3] ring expansion of aziridines to dehydropiperi-dines through the intermediacy of aziridinium ylides. Nature Communications (2020).
4. Synergistic Ion-Binding Catalysis Demonstrated via an Enantioselective, Catalytic [2,3]-Wittig Rearrangement. ACS Central Science (2016).
5. Sigmatropic [1,5] Carbon Shift of Transient C3 Ammonium Enolates. Angewandte Chemie International Edition (2022).