Synthetic Chemistry of Nitrogen Heterocycles

The synthesis of nitrogen-containing ring systems underpins the development of many pharmaceuticals, agrochemicals and advanced materials. Nitrogen heterocycles span simple five-membered rings such as pyrroles and imidazoles to six- and seven-membered systems like pyridines and azepines, each offering distinct electronic properties and synthetic challenges. Classical methods have typically relied on stepwise cyclisation of linear precursors or peripheral functionalisation of existing rings. However, the demand for more efficient and versatile routes has driven the emergence of strategies that manipulate the core framework directly. Skeletal editing approaches now enable insertion, deletion or exchange of atoms within a heterocycle, while direct carbon–nitrogen bond activation and novel ring-expansion tactics increase molecular diversity in fewer steps. Photochemical and electrochemical protocols have further improved atom economy and selectivity, furnishing streamlined access to structurally complex, bioactive heterocycles and facilitating rapid exploration of chemical space for drug discovery and materials science.

Research from Nature Portfolio

Recent studies have introduced a modular atom-pair swap strategy to convert pyridines into benzenes and naphthalenes by replacing a CN bond with a CC unit through a one-pot sequence of dearomatisation, cycloaddition and rearomatisation. This skeletal editing route enables late-stage modification of drug cores with precise substitution patterns. In parallel, a skeletal metalation method has been developed to transform lactams into organonickel intermediates by selective activation of unstrained amide C–N bonds. This formal carbonyl-to-nickel exchange under mild conditions allows direct carbon framework modification and subsequent synthetic elaboration. Another advance employs an electrochemical dehydrogenative insertion of ammonia into alkenes, delivering substituted pyridines and quinolines in a single step with near-quantitative atom economy and hydrogen gas as the only by-product. These breakthroughs collectively exemplify new paradigms for constructing and remodelling nitrogen heterocycles with high efficiency and functional group tolerance.

Synthetic Chemistry of Nitrogen Heterocycles publication trend

The graph below shows the total number of articles in synthetic chemistry of nitrogen heterocycles across all publications each year (not limited to Nature Index journals).

Technical terms

Nitrogen heterocycle: An organic ring structure that incorporates one or more nitrogen atoms into its cyclic framework.

Skeletal editing: A synthetic tactic involving targeted insertion, deletion or exchange of atoms within the core of a molecule to modify its ring structure.

Organonickel reagent: An intermediate featuring nickel–carbon bonds, enabling controlled formation of new C–C or C–N bonds in synthesis.

Chlorodiazirine: A three-membered ring precursor that, upon photolysis, generates a reactive carbene capable of one-carbon insertion into heterocycles.

Electrochemical dehydrogenation: A process whereby an electric current removes hydrogen atoms to promote bond formation, often yielding high atom economy.

References

1. Skeletal editing of pyridines through atom-pair swap from CN to CC. Nature Chemistry (2024).
2. Skeletal metalation of lactams through a carbonyl-to-nickel-exchange logic. Nature Communications (2023).
3. Insertion of ammonia into alkenes to build aromatic N-heterocycles. Nature Communications (2022).
4. Photochemically Mediated Ring Expansion of Indoles and Pyrroles with Chlorodiazirines: Synthetic Methodology and Thermal Hazard Assessment. Angewandte Chemie International Edition (2023).
5. Unified Access to Pyrimidines and Quinazolines Enabled by N–N Cleaving Carbon Atom Insertion. Journal of the American Chemical Society (2022).
6. Methylene Insertion into Nitrogen‐Heteroatom Single Bonds of 1,2‐Azoles via a Zinc Carbenoid: An Alternative Tool for Skeletal Editing. Advanced Science (2023).