C–N Bond Activation in Organic Synthesis

The activation of carbon–nitrogen bonds has emerged as a versatile strategy for the construction of complex molecules, enabling direct conversion of abundant amine feedstocks into diverse architectures. Traditional approaches often require pre-activation of amines as diazonium salts or quaternary ammonium species, but recent advances have harnessed transition-metal catalysis, photoredox methods, electrosynthesis and mechanochemical protocols to achieve efficient C–N bond cleavage under mild conditions. These innovations facilitate deaminative coupling to forge C–C and C–heteroatom bonds while minimising waste and broadening substrate scope. Late-stage functionalisation of pharmaceuticals and natural products has become feasible through selective C–N activation, offering streamlined access to analogue libraries and enhancing sustainability. By integrating novel activation modes with well-tuned ligands, catalysts and energy inputs, contemporary research is redefining the role of amines as traceless linchpins in modern synthesis.

Research from Nature Portfolio

Recent studies have demonstrated a catalyst- and electrolyte-free electrosynthetic platform that converts alkyl pyridinium salts into radicals via direct reduction at a sacrificial metal anode, enabling deaminative reductive coupling for fluoroalkenylation, alkynylation and thiolation under continuous-flow conditions. Another approach introduced a nickel-catalysed deaminative Sonogashira coupling of alkylpyridinium salts, leveraging an amide-type pincer ligand to unite abundant amines with terminal alkynes in excellent yield and broad functional-group tolerance. Complementing these advances, pyrylium-mediated deaminative chlorination selectively transforms aminoheterocycles into aryl chlorides under mild conditions, offering a safe and efficient route to masked handles for further cross-coupling and electrophilic substitution without the need for diazonium intermediates.

C–N Bond Activation in Organic Synthesis publication trend

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

Technical terms

C–N bond activation: cleavage or transformation of a carbon–nitrogen bond to enable subsequent functionalisation.

Deaminative functionalization: removal of an amino group to generate reactive intermediates for new bond-forming reactions.

Photoredox catalysis: use of light-driven single-electron processes mediated by photocatalysts to form radical species.

SuFEx click chemistry: modular bond-forming reactions based on sulfur(VI)–fluoride exchange enabling high efficiency and atom economy.

Mechanochemical activation: use of mechanical energy, such as grinding or milling, to promote chemical transformations without bulk solvents.

Katritzky pyridinium salts: redox-active pyridinium derivatives of amines employed to generate alkyl radicals under mild conditions.

References

1. Electrochemical C–N bond activation for deaminative reductive coupling of Katritzky salts. Nature Communications (2021).
2. Nickel-catalyzed deaminative Sonogashira coupling of alkylpyridinium salts enabled by NN2 pincer ligand. Nature Communications (2021).
3. Deaminative chlorination of aminoheterocycles. Nature Chemistry (2021).
4. Harnessing Sulfur(VI) Fluoride Exchange Click Chemistry and Photocatalysis for Deaminative Benzylic Arylation. ACS Catalysis (2023).
5. Mechanochemical synthesis of aromatic ketones: pyrylium tetrafluoroborate mediated deaminative arylation of amides. Chemical Science (2024).
6. From aniline to phenol: carbon-nitrogen bond activation via uranyl photoredox catalysis. National Science Review (2021).