C–N Bond Formation via Transition Metal Catalysis

Transition metal catalysis has revolutionised the construction of carbon–nitrogen bonds by enabling direct functionalisation of C–H and C–H-type bonds with amine and amide partners. Key advances encompass palladium-, copper-, iron-, nickel- and ruthenium-based systems that promote C(sp2)–H amination, amidation and arylation under ever-milder conditions. Photoredox approaches harness visible light to trigger redox cycles in tandem with metal catalysts, often eliminating the need for stoichiometric oxidants. Directing groups coordinated to the metal centre impart site-selectivity, while chelating or transient auxiliaries expand substrate scope. These methodologies deliver step- and atom-economical routes to anilines, heteroarylamines and complex N-heterocycles, with broad applicability in pharmaceuticals, agrochemicals and materials science. Current challenges centre on enhancing enantioselectivity, reducing catalyst loadings, improving catalyst recyclability and achieving late-stage C–N bond installation in densely functionalised molecules.

Research from Nature Portfolio

Recent studies have demonstrated a photo-induced, oxidant-free oxidative C(sp2)–H/N–H cross-coupling between simple arenes and heterocyclic azoles. Under visible-light irradiation, a transition metal complex mediates selective C–H amination with concomitant hydrogen evolution, dispensing with sacrificial oxidants. Kinetic isotope experiments reveal that C–H cleavage is not rate-limiting, and mechanistic investigations indicate a first-order dependence on the arene substrate. This protocol affords N-arylazoles under exceptionally mild conditions, offering a sustainable avenue for the late-stage functionalisation of oxidation-sensitive arenes.

C–N Bond Formation via Transition Metal Catalysis publication trend

The graph below shows the total number of articles in c–n bond formation via transition metal catalysis across all publications each year (not limited to Nature Index journals).

Technical terms

Transition metal catalysis: Use of a metal centre to facilitate bond formation by cycling through oxidation states.
C–H activation: Direct cleavage of a carbon–hydrogen bond via coordination to a metal, enabling subsequent functionalisation.
Directing group: A coordinating moiety on the substrate that guides the metal catalyst to a specific C–H site.
Photoredox catalysis: Strategy that employs light absorption to drive redox transformations, often in concert with metal catalysts.
Regioselectivity: Preference for reaction at one position in a molecule over others, critical for precise synthetic outcomes.

References

1. Photo-induced oxidant-free oxidative C–H/N–H cross-coupling between arenes and azoles. Nature Communications (2017).
2. A directing group switch in copper-catalyzed electrophilic C–H amination/migratory annulation cascade: divergent access to benzimidazolone/benzimidazole. Chemical Science (2022).
3. Practical and sustainable preparation of pyrrolo[2,3- b ]indoles by Cu/Fe catalyzed intramolecular C(sp 2 )–H amination. Green Chemistry (2022).
4. Precise control of the site selectivity in ruthenium-catalyzed C–H bond amidations using cyclic amides as powerful directing groups. Organic Chemistry Frontiers (2022).