C–H Functionalization Strategies in Isoquinolone Synthesis

Isoquinolone frameworks are integral to numerous bioactive compounds and materials, driving ongoing interest in direct C–H functionalization approaches for their construction. Strategies centre on the activation of unactivated C–H bonds to forge C–C or C–N linkages without prefunctionalisation, enhancing atom- and step-economy. Transition‐metal catalysis, notably rhodium, ruthenium and palladium complexes, has enabled regioselective activation under mild conditions by employing bidentate directing groups such as amidates or N‐oxides. These directing moieties coordinate to the metal centre, orientating the catalyst to adjacent C–H sites and guiding subsequent annulation with alkynes or alkenes. Recent cascade and tandem processes have further improved efficiency by integrating multiple bond‐forming events in one pot, including sequential C(sp2)–H/C(sp3)–H activations, Lossen rearrangements and cyclocondensations. Emerging protocols leverage hypervalent iodine reagents to induce chemoselective cyclisations, while dual C–H/N–H activation routes offer late‐stage functionalisation of complex scaffolds. Collectively, these advancements extend the scope of isoquinolone synthesis, offering streamlined access to densely functionalised cores relevant to medicinal chemistry, material sciences and natural product synthesis.

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C–H Functionalization Strategies in Isoquinolone Synthesis publication trend

The graph below shows the total number of articles in c–h functionalization strategies in isoquinolone synthesis across all publications each year (not limited to Nature Index journals).

Technical terms

C–H functionalization: Direct transformation of unactivated carbon–hydrogen bonds into carbon–carbon or carbon–heteroatom bonds without prior installation of a leaving group.

Annulation: A cyclisation process that forms a new ring by connecting two components, often involving C–H activation and coupling with unsaturated partners such as alkynes.

Directing group: A functional moiety covalently attached to a substrate that coordinates to a metal catalyst, guiding site-selective C–H activation.

Hypervalent iodine(III): Iodine reagents in oxidation state +3 used to mediate chemoselective oxidative cyclisations.

Cascade (tandem) reaction: A sequence of bond-forming transformations that occur in a single reaction vessel without isolating intermediates, enhancing efficiency.

References

1. Novel Approach to the Construction of Fused Indolizine Scaffolds: Synthesis of Rosettacin and the Aromathecin Family of Compounds. Molecules (2023).
2. Isoquinolone Syntheses by Annulation Protocols. Catalysts (2021).
3. π‐Extended Polyaromatic Hydrocarbons by Sustainable Alkyne Annulations through Double C−H/N−H Activation. Chemistry - A European Journal (2019).
4. Intramolecular cascade annulation triggered by rhodium(III)-catalyzed sequential C(sp2)–H activation and C(sp3)–H amination. Beilstein Journal of Organic Chemistry (2019).
5. Synthesis of Functionalized Isoquinolone Derivatives via Rh(III)-Catalyzed [4+2]-Annulation of Benzamides with Internal Acetylene-Containing α-CF3-α-Amino Carboxylates. Molecules (2022).
6. Solvent-dependent chemoselective synthesis of different isoquinolinones mediated by the hypervalent iodine(III) reagent PISA. Beilstein Journal of Organic Chemistry (2024).