Transition Metal-Catalyzed C–H Functionalization Techniques

Transition metal-catalysed C–H functionalization has revolutionised synthetic chemistry by enabling the direct conversion of ubiquitous C–H bonds into C–C or C–heteroatom bonds without pre-functionalisation. Central to this advance is the ability of metals such as palladium, rhodium, cobalt, nickel and iridium to orchestrate selective bond activation through tailored ligand environments and directing groups. Strategies now encompass directed and undirected approaches, employing concepts such as concerted metalation–deprotonation, single-electron transfer and ligand-to-ligand hydrogen transfer. These protocols deliver high atom economy and step efficiency, often under mild conditions, and can achieve remarkable regio- and stereocontrol. Advances in base-metal catalysis and traceless directing groups have further enhanced sustainability, while remote and enantioselective C–H functionalisations broaden the scope of target scaffolds ranging from pharmaceutically relevant heterocycles to complex natural product frameworks.

Research from Nature Portfolio

Recent studies have demonstrated a nickel(0)–N-heterocyclic carbene system capable of stereoselectively α-allylating ketones with non-conjugated dienes. This catalyst directly activates the α-C–H bond of the carbonyl and transfers the hydrogen atom to the olefin partner via a ligand-to-ligand hydrogen transfer pathway, forging adjacent quaternary and tertiary stereogenic centres with high diastereo- and enantioselectivity. In parallel, an iridium-catalysed enolization strategy exploits the native directing ability of a glycine-derived N–H unit to generate stereodefined enolates of carbonyl substrates. These intermediates undergo regio- and stereocontrolled cross-coupling with alkenes to construct β-substituted α-amino acids with complete atom economy and exceptional selectivity, illustrating a powerful approach to contiguous stereocentre assembly.

Transition Metal-Catalyzed C–H Functionalization Techniques publication trend

The graph below shows the total number of articles in transition metal-catalyzed c–h functionalization techniques across all publications each year (not limited to Nature Index journals).

Technical terms

C–H functionalization: Direct conversion of a carbon–hydrogen bond into a carbon–carbon or carbon–heteroatom bond under catalytic conditions.

Directing group: A coordinating moiety that guides a metal catalyst to activate a specific C–H bond within a molecule.

Atom economy: A measure of how many atoms of the reactants are incorporated into the final product, reflecting reaction efficiency.

Enolization: Transformation of a carbonyl compound into its enol or enolate form, enabling subsequent bond-forming events.

Stereocontrol: The ability of a reaction to favour the formation of one stereoisomer over other possible spatial arrangements.

References

1. Nickel-catalyzed direct stereoselective α-allylation of ketones with non-conjugated dienes. Nature Communications (2023).
2. A directed enolization strategy enables by-product-free construction of contiguous stereocentres en route to complex amino acids. Nature Chemistry (2024).
3. Rh( iii )-Catalyzed [5 + 1] annulation of 2-alkenylanilides and 2-alkenylphenols with allenyl acetates. Chemical Science (2022).
4. Recent Developments in Transition-Metal Catalyzed Direct C–H Alkenylation, Alkylation, and Alkynylation of Azoles. Molecules (2020).
5. Traceless Directing Groups in Sustainable Metal-Catalyzed C–H Activation. Catalysts (2021).