Radical Cyclization Techniques in Nitrogen Heterocycle Synthesis

Radical cyclization has emerged as a versatile and powerful strategy for the construction of nitrogen‐containing heterocycles, which are ubiquitous in pharmaceuticals, agrochemicals and functional materials. By generating reactive radical intermediates—either carbon‐centred or nitrogen‐centred—under thermal, photochemical or catalytic conditions, intramolecular bond formation can proceed rapidly to forge five‐, six‐ and larger rings with high atom economy. Key radical precursors include oxime derivatives, isocyanides, carboxylic acid esters and benzothiazoline derivatives, enabling access to scaffolds such as phenanthridines, quinolines, indoles, pyrroles, triazoloquinoxalines and benzotriazolodiazepines. Advances in photoredox catalysis have allowed visible‐light activation of organic dyes or simple reagents to induce single‐electron transfer, while decarboxylative approaches exploit readily available carboxylates to generate alkyl radicals. Cascade and tandem radical cyclizations further streamline complex molecule assembly by combining multiple bond‐forming events in one operation. These methods are characterised by mild reaction conditions, broad functional‐group tolerance and modularity of substrate design. Mechanistic control over regioselectivity—between ortho-cyclization, spiro-cyclization or cascade ring closures—has been elucidated through kinetic, spectroscopic and computational studies. Collectively, radical cyclization techniques continue to expand the chemist’s toolkit for rapid, sustainable and selective synthesis of nitrogen heterocycles with applications ranging from drug discovery to advanced materials.

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Radical Cyclization Techniques in Nitrogen Heterocycle Synthesis publication trend

The graph below shows the total number of articles in radical cyclization techniques in nitrogen heterocycle synthesis across all publications each year (not limited to Nature Index journals).

Technical terms

Radical cyclization: Intramolecular ring‐closing reaction mediated by neutral radical species.

Iminyl radical: Nitrogen‐centred radical generated from oxime or oxime ester precursors.

Photoredox catalysis: Light‐induced single‐electron transfer process catalysed by dyes or photocatalysts.

Decarboxylative cyclization: Radical formation via loss of carbon dioxide from a carboxylate precursor, followed by ring closure.

Homolytic aromatic substitution (HAS): Radical addition to an aromatic ring followed by rearomatisation.

References

1. PPh 3 /NaI driven photocatalytic decarboxylative radical cascade alkylarylation reaction of 2-isocyanobiaryls. RSC Advances (2020).
2. Synthetic Strategies for 5- and 6-Membered Ring Azaheterocycles Facilitated by Iminyl Radicals. Molecules (2016).
3. Direct Photoexcitation of Benzothiazolines: Acyl Radical Generation and Application to Access Heterocycles. Molecules (2021).