Electrophilic Amination Methods in Organic Synthesis

Electrophilic amination constitutes a broadly enabling strategy for the direct construction of C–N bonds via reaction of electron‐rich carbon nucleophiles with nitrogen‐centred electrophiles. This class of transformations encompasses polar routes that employ pre‐activated aminating reagents, such as O-alkylhydroxylamines, N-chloroamines or N-sulfonyloxaziridines, and radical pathways mediated by nitrogen-centred radicals or nitrenoids. Transition-metal and organocatalytic systems have been developed to modulate reactivity and selectivity, permitting chemoselective installation of primary, secondary and tertiary amine motifs under mild conditions. Recent advances include harnessing phthalimide-derived iminoiodanes for nitrene transfer, photoredox-enabled generation of aminyl radicals, and ligand-controlled metal catalysis to achieve enantioselective amination. These methodologies have found applications in late-stage functionalisation of complex molecules, enabling streamlined assembly of pharmaceuticals, agrochemicals and nitrogen-rich materials. Mechanistic studies have elucidated key factors governing reactivity, such as radical philicity, oxidative addition and heterolytic cleavage of N–O or N–X bonds. Ongoing efforts aim to expand the scope of electrophilic aminating agents, improve stereocontrol and minimise catalyst loading, thereby enhancing the sustainability and practicality of amination sequences across diverse synthetic settings.

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Electrophilic Amination Methods in Organic Synthesis publication trend

The graph below shows the total number of articles in electrophilic amination methods in organic synthesis across all publications each year (not limited to Nature Index journals).

Technical terms

Electrophilic amination: A reaction in which a nitrogen-centred electrophile reacts with a carbon nucleophile to form a C–N bond.

Aminyl radical: A neutral nitrogen-centred radical species capable of adding to electron-rich substrates or undergoing coupling.

Amidyl radical: A nitrogen-centred radical bearing a carbonyl or sulfonyl substituent, displaying distinct electrophilic character.

Organometallic reagent: A compound containing a metal–carbon bond used as a nucleophilic partner in C–N bond-forming reactions.

Single-electron transfer (SET): A mechanistic step involving the transfer of one electron between a metal complex and an organic species, often generating radical intermediates.

References

1. Reaction of Nitrogen‐Radicals with Organometallics Under Ni‐Catalysis: N‐Arylations and Amino‐Functionalization Cascades. Angewandte Chemie International Edition (2019).
2. Synthesis of amines by the electrophilic amination of organomagnesium, -zinc, -copper, and -lithium reagents. Arkivoc (2011).