Manganese-Catalyzed C–H Activation in Organic Synthesis

Manganese-catalyzed C–H activation has emerged as a versatile and sustainable approach for direct functionalisation of unactivated C–H bonds in organic molecules. Leveraging manganese’s abundance, low toxicity and redox flexibility, chemists have devised catalytic cycles that transform inert C–H bonds into C–C, C–N and other C–X linkages without the need for pre-functionalised substrates. Key mechanistic steps include ligand-assisted deprotonation, often via a concerted metalation–deprotonation pathway, and migratory insertion into transient manganacycles. Directing groups such as pyridyl or imine moieties guide site selectivity, enabling orthogonal activation of aromatic, alkenyl or alkyl C–H sites. Time-resolved spectroscopic methods have revealed the fate of precatalysts and intermediates on time scales spanning picoseconds to milliseconds, clarifying the roles of CO dissociation, solvent coordination and catalyst deactivation via hydroxyl-bridged clusters. Collectively, these insights underpin a growing array of applications, from late-stage functionalisation of complex bioactive molecules to stereoselective syntheses of conjugated dienes and heterocyclic scaffolds under mild conditions.

Research from Nature Portfolio

Recent studies have demonstrated the reversal of innate C–H bond reactivity in ketone substrates by manganese catalysis. Under mild conditions, aromatic C(sp²)–H bonds adjacent to an imine directing group undergo regioselective aminomethylation, yielding ortho-aminoalkylated ketones, exo-olefinic isoindolines and three-component methylated heterocycles in a single pot. This work expands the synthetic utility of simple ketones and illustrates how judicious choice of catalyst and directing group can override conventional selectivity patterns, enabling access to complex nitrogen-containing frameworks without pre-activation of the ketone.

Manganese-Catalyzed C–H Activation in Organic Synthesis publication trend

The graph below shows the total number of articles in manganese-catalyzed c–h activation in organic synthesis across all publications each year (not limited to Nature Index journals).

Technical terms

C–H activation: The direct cleavage and functionalisation of carbon–hydrogen bonds without prior installation of reactive handles.

Migratory insertion: A mechanistic step in which an unsaturated ligand (e.g. alkyne or alkene) inserts into a metal–carbon bond to form a new carbon–carbon linkage.

Concerted metalation–deprotonation (CMD): A pathway in which a base (often a carboxylate) mediates simultaneous deprotonation of a C–H bond and metal–carbon bond formation.

Directing group: A functional moiety in the substrate that coordinates to the metal centre, guiding site-selective C–H bond cleavage.

Precatalyst activation: The process by which an inactive metal complex is converted into the active catalytic species, often involving ligand dissociation.

References

1. Unveiling Mechanistic Complexity in Manganese-Catalyzed C–H Bond Functionalization Using IR Spectroscopy Over 16 Orders of Magnitude in Time. Accounts of Chemical Research (2024).
2. Regioselectivity Control in the Synthesis of Linear Conjugated Dienes Enabled by Manganese(I)-Catalyzed C–H Activation. ACS Catalysis (2023).
3. The importance of understanding (pre)catalyst activation in versatile C–H bond functionalisations catalysed by [Mn 2 (CO) 10 ]. Chemical Science (2024).
4. Aromatic C-H addition of ketones to imines enabled by manganese catalysis. Nature Communications (2017).