Aziridine Synthesis and Reactivity in Organic Chemistry

Aziridines are three-membered nitrogen heterocycles distinguished by significant ring strain and versatile chemical behaviour. Their synthesis encompasses nitrene transfer to olefins, intramolecular cyclisations of haloamines and epoxide-to-aziridine rearrangements, as well as organocatalytic and transition-metal-mediated approaches that deliver enantioenriched products. Once formed, aziridines undergo regioselective and stereospecific ring-opening reactions with a wide array of nucleophiles, enabling preparation of amino alcohols, β-amino acids and complex nitrogenous frameworks. Recent advances have improved control over stereochemistry, broadened functional-group tolerance and introduced traceless activating groups, thereby enhancing access to bioactive scaffolds, agrochemicals and building blocks for medicinal chemistry. Computational studies have shed light on transition-state geometries and substituent effects, further informing the design of catalytic systems. The field continues to evolve towards milder conditions, greener protocols and modular strategies that integrate aziridine formation with subsequent downstream functionalisation.

Research from Nature Portfolio

A new two-step protocol employs N-aminopyridinium reagents for olefin aziridination, generating N-pyridinium aziridine intermediates that undergo nickel-catalysed C–N cross-coupling with aryl boronic acids to furnish N-aryl aziridines. This strategy overcomes limitations of conventional nitrene sources by using a traceless activating group and delivers a broad scope of aryl and heteroaryl products. Mechanistic investigations reveal an unusual sequence of aziridine opening by bromide, C–N bond formation and ring reclosure, and also demonstrate that the pyridinium intermediates are amenable to ring-opening by external nucleophiles, enabling one-pot 1,2-aminofunctionalisation under mild conditions.

Aziridine Synthesis and Reactivity in Organic Chemistry publication trend

The graph below shows the total number of articles in aziridine synthesis and reactivity in organic chemistry across all publications each year (not limited to Nature Index journals).

Technical terms

Aziridine: A three-membered ring containing one nitrogen atom, notable for high ring strain and reactivity.

Nitrene transfer: Insertion of an NR fragment into an olefin to install a C–N bond and generate an aziridine.

Ring-opening: Cleavage of the aziridine ring by nucleophiles, leading to open-chain amino derivatives.

Regioselectivity: Preference for bond formation or cleavage at one position over another within a molecule.

Cross-coupling: Catalytic formation of a new bond between two partners, often mediated by transition-metal catalysts.

References

1. Access to 2-Fluorinated Aziridine-2-phosphonates from α,α-Halofluorinated β-Iminophosphonates—Spectroscopic and Theoretical Studies †. Molecules (2023).
2. Palladium-catalyzed regioselective and stereo-invertive ring-opening borylation of 2-arylaziridines with bis(pinacolato)diboron: experimental and computational studies. Chemical Science (2016).
3. Synthetic Applications of Aziridinium Ions. Molecules (2021).
4. N-Aminopyridinium reagents as traceless activating groups in the synthesis of N-Aryl aziridines. Nature Communications (2022).