Synthesis of Quinoline Derivatives in Organic Chemistry

Quinolines, characterised by a fused benzene and pyridine ring system, occupy a central position in medicinal and materials chemistry owing to their versatile pharmacological profiles and electronic properties. Traditional approaches to constructing the quinoline core exploit classical condensations—such as Skraup, Friedländer, Doebner–von Miller and Conrad–Limpach—each offering distinctive substitution patterns but often demanding harsh conditions or hazardous reagents. Contemporary strategies have shifted towards sustainable protocols, integrating transition-metal catalysis, photocatalysis, enzyme-mediated transformations and solvent-free processes to enhance yields, reduce environmental impact and expand functional group tolerance. Advances in C–H functionalisation and tandem multicatalytic sequences have streamlined access to diverse substitution patterns, while green chemistry paradigms drive the adoption of benign solvents, reusable catalysts and energy-efficient activation methods. The capacity to tailor substituents at judicious positions on the quinoline scaffold underpins the development of novel therapeutics, agrochemicals and optoelectronic materials with precisely modulated activity and physicochemical characteristics.

Research from Nature Portfolio

Recent foundational work has demonstrated a rhodium-catalysed C–H activation and carbonylation tandem process that converts unprotected anilines and electron-deficient alkynes into quinoline derivatives under benign aqueous conditions. This multicatalytic, auto-tandem reaction proceeds with high regioselectivity and atom economy, utilises carbon monoxide surrogates and water as solvent, and generates hydrogen gas as the sole by-product. Such a strategy exemplifies the integration of C–H functionalisation with annulation steps to achieve efficient and sustainable assembly of complex heterocycles from simple precursors.

Synthesis of Quinoline Derivatives in Organic Chemistry publication trend

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

Technical terms

C–H activation: Direct functionalisation of carbon–hydrogen bonds, enabling the transformation of inert C–H sites into carbon–carbon or carbon–heteroatom bonds without pre-functionalisation.

Carbonylation: Introduction of a carbonyl group into an organic molecule, often by incorporating carbon monoxide or its surrogates, facilitating ring formation and diversification.

Annulation: Cyclisation reaction that forms a new ring by joining two non-adjacent atoms or groups within a molecule, commonly used to construct fused heterocycles.

Atom economy: A measure of synthetic efficiency, defined as the proportion of reactant atoms incorporated into the desired product, minimising waste and by-products.

Friedländer condensation: A classical method for quinoline synthesis involving the condensation of o-aminoarylketones with carbonyl compounds under acidic or basic conditions to form the heterocyclic core.

References

1. Recent advances in the synthesis of biologically and pharmaceutically active quinoline and its analogues: a review. RSC Advances (2020).
2. Reversed reactivity of anilines with alkynes in the rhodium-catalysed C–H activation/carbonylation tandem. Nature Communications (2015).
3. A review on synthetic investigation for quinoline- recent green approaches. Green Chemistry Letters and Reviews (2022).
4. Phenanthrenequinone-Sensitized Photocatalytic Synthesis of Polysubstituted Quinolines from 2‑Vinylarylimines. Organic Letters (2021).
5. Solvent-free and room temperature synthesis of 3-arylquinolines from different anilines and styrene oxide in the presence of Al2O3/MeSO3H. Beilstein Journal of Organic Chemistry (2017).
6. Ionic Liquid as an Efficient Medium for the Synthesis of Quinoline Derivatives via α-Chymotrypsin-Catalyzed Friedländer Condensation. Molecules (2017).