Aryne Chemistry in Organic Synthesis

Arynes are reactive intermediates derived from aromatic compounds by formal removal of adjacent substituents, creating a highly strained triple bond. Since their initial characterisation, the strategic generation and trapping of arynes has transformed synthetic routes to complex molecules. Modern methods typically employ ortho-silylaryl triflates activated by fluoride or base-induced elimination of ortho-halogenated precursors. Once formed, arynes engage in a spectrum of processes including nucleophilic additions, cycloadditions and pericyclic rearrangements. Control over chemoselectivity and regioselectivity has advanced through tailored substituents and reaction conditions, enabling access to biaryls, heterocycles and polysubstituted arenes under metal-free or catalysed regimes. Applications span natural-product synthesis, pharmaceutical lead generation and functional materials, underscoring the global utility of aryne chemistry.

Research from Nature Portfolio

Recent studies have established orthogonal control of aryne reactivity by tuning the electronic nature of the triple bond. By employing distinct benzyne variants—one bearing an electron-donating 3-methoxy substituent and another with a 3-silyl moiety—researchers have demonstrated selective pathways between nucleophilic addition and pericyclic cycloadditions. This protocol orchestrates chemoselective engagement of arynes with a variety of nucleophiles, such as imidazoles, phenols and anilines, and diverse pericyclic partners including furans and cycloalkenes. Beyond simple arylations, the approach enables C–N bond insertion, azacycle formation via Truce–Smiles rearrangement and nucleophilic annulation, broadening the scope for constructing complex aromatic architectures without recourse to transition metals.

Aryne Chemistry in Organic Synthesis publication trend

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

Technical terms

Aryne: A highly reactive intermediate derived from an aromatic ring by removing two adjacent substituents, featuring a strained carbon–carbon triple bond.

Nucleophile: A species rich in electrons that donates an electron pair to form a chemical bond with an electrophilic centre.

Pericyclic reaction: A concerted transformation in which bonding electrons shift in a cyclic array, encompassing cycloadditions and rearrangements.

Silylaryl triflate: An aryne precursor bearing a trimethylsilyl group and a triflate leaving group, activated by fluoride to generate arynes.

Truce–Smiles rearrangement: An intramolecular aryl migration following nucleophilic addition to an aryne, producing rearranged biaryl systems.

References

1. Switchable chemoselective aryne reactions between nucleophiles and pericyclic reaction partners using either 3-methoxybenzyne or 3-silylbenzyne. Nature Communications (2024).
2. Aryne‐Enabled C−N Arylation of Anilines. Angewandte Chemie International Edition (2023).
3. Metal Free Bi(hetero)aryl Synthesis: A Benzyne Truce–Smiles Rearrangement. Angewandte Chemie International Edition (2016).
4. One-step synthesis of benzo[ b ]thiophenes by aryne reaction with alkynyl sulfides. Chemical Science (2020).