N-Heterocyclic Carbene Catalysis in Organic Synthesis

N-Heterocyclic carbenes (NHCs) have emerged as versatile organocatalysts that enable the construction and functionalisation of complex molecules under mild, metal-free conditions. By forming a transient carbene–carbonyl adduct, NHCs reverse the natural polarity of aldehydes and related electrophiles, generating nucleophilic acyl anion or enolate equivalents. This “umpolung” activation underpins classical benzoin, Stetter and Claisen condensations, and has been extended to annulations, cycloadditions and C–H bond functionalisation. Recent decades have witnessed the integration of NHC catalysis with radical and photochemical strategies, unlocking radical–radical couplings, decarboxylative processes and site-selective C–H acylations. Such cooperative protocols often pair NHC activation with photoredox or hydrogen-atom-transfer catalysis to deliver ketones, lactones, heterocycles and other valuable scaffolds from simple, readily sourced precursors. The broad substrate tolerance, operational simplicity and potential for late-stage modification have rendered NHC catalysis a pillar of sustainable synthesis, with applications spanning natural-product derivatisation, pharmaceutical assembly and materials science.

Research from Nature Portfolio

A multicatalytic strategy has been disclosed for the direct synthesis of β,γ-unsaturated ketones through allylic acylation of alkenes. This method unites NHC catalysis, photoredox and hydrogen-atom-transfer activation to couple carboxylic acids with olefins, achieving high site-selectivity without pre-activation of substrates and enabling appendage of acyl groups onto highly functionalised molecules. In parallel, the combination of an NHC and a photocatalyst has been harnessed to effect decarboxylative radical coupling between carboxylic acids and acyl imidazoles. Here, carboxylate-derived radicals engage in three-component processes including alkene relay, affording complex ketones under mild, operationally simple conditions. These advances highlight the power of carbene-mediated radical generation and cross-coupling for diversified ketone synthesis and late-stage modification of bioactive frameworks.

N-Heterocyclic Carbene Catalysis in Organic Synthesis publication trend

The graph below shows the total number of articles in n-heterocyclic carbene catalysis in organic synthesis across all publications each year (not limited to Nature Index journals).

Technical terms

N-Heterocyclic carbene (NHC): A stable, nucleophilic carbene derived from an azolium salt, used to activate carbonyls by polarity inversion.

Breslow intermediate: The nucleophilic enaminol species formed by addition of an NHC to a carbonyl, serving as an acyl anion equivalent.

Photoredox catalysis: A mode of activation wherein light-excited catalysts mediate single-electron transfers to generate radical species.

Radical relay: A sequential radical process in which initial radical generation propagates through multiple bond-forming steps.

References

1. Direct allylic acylation via cross-coupling involving cooperative N‑heterocyclic carbene, hydrogen atom transfer, and photoredox catalysis. Nature Communications (2023).
2. Recent advances in N-heterocyclic carbene-based radical catalysis. Chemical Science (2020).
3. N-Heterocyclic carbene-catalyzed deaminative cross-coupling of aldehydes with Katritzky pyridinium salts. Chemical Science (2020).
4. N‐Heterocyclic Carbene Catalyzed Photoenolization/Diels–Alder Reaction of Acid Fluorides. Angewandte Chemie International Edition (2020).
5. Carbene and photocatalyst-catalyzed decarboxylative radical coupling of carboxylic acids and acyl imidazoles to form ketones. Nature Communications (2022).
6. Benzylic C−H acylation by cooperative NHC and photoredox catalysis. Nature Communications (2021).