Borane Trick Cracks Stubborn Aziridines Open for Cleaner Drug Building

Aziridines are among the most versatile three-membered rings in the organic chemist’s toolkit. These strained heterocycles, in which a nitrogen atom bridges two carbon atoms, can be pried open to deliver beta-substituted amines, structural motifs that appear throughout pharmaceuticals, agrochemicals and other bioactive molecules. Yet for all their promise, aziridines have long carried a frustrating catch: the most useful members of the family, so-called N-alkyl aziridines, have stubbornly resisted the ring-opening and cross-coupling chemistry that makes their cousins so valuable. A team of chemists at RWTH Aachen University led by Daniele Leonori now reports a way around this decades-old obstacle, using nothing more exotic than borane coordination and a carefully choreographed radical cascade.

The difficulty lies in how aziridines are activated. In classical approaches, chemists attach strongly electron-withdrawing groups such as tosyl or nosyl to the ring nitrogen. These groups weaken the carbon-nitrogen bonds, making the ring susceptible to attack by nucleophiles or to activation by transition metals. The problem is that the activating group must then be stripped away and replaced with the desired N-substituent, typically through alkylation or reductive amination, adding steps, waste and cost to every synthesis. For N-alkyl aziridines, which already carry the nitrogen substituent one actually wants, this detour is impossible by definition, and the rings have remained essentially inert under established transition-metal catalytic manifolds.

The Leonori group’s solution, published in Nature Chemistry, begins with a simple Lewis acid-base interaction. Borane, BH3, coordinates to the nitrogen atom of the aziridine, forming a stable aziridine-ligated borane complex. This complex can then be converted into an aziridine-ligated boryl radical, a species in which the unpaired electron sits on the boron centre. That radical undergoes a regioselective beta-scission, cleaving the more substituted carbon-nitrogen bond and releasing the strain of the three-membered ring to generate a beta-aminoalkyl radical. Crucially, this radical intermediate is exactly the kind of species that modern cross-coupling catalysis is built to capture.

The idea has deep roots. In pioneering low-temperature electron paramagnetic resonance studies, Brian Roberts and colleagues showed decades ago that amine-borane complexes could undergo hydrogen-atom abstraction to form amine-ligated boryl radicals, which rapidly fragmented across the aziridine ring. But that reactivity had never been exploited synthetically. The Aachen team recognised that if the fragmentation could be tamed and the resulting radicals funnelled into catalytic cross-couplings, the entire activating-group economy of aziridine chemistry could be rewritten.

Before running a single reaction, the researchers turned to computation to interrogate a subtle stereochemical hazard. Because the aziridine nitrogen is pyramidalised in the borane complex, two diastereomeric boryl radicals, trans and cis, can form. Roberts’ data had suggested these diastereomers fragment across different carbon-nitrogen bonds, which threatened to produce messy mixtures of regioisomeric products. The team’s calculations, performed at the UM06-2X/def2-QZVP level with solvation corrections, told a more encouraging story. For aziridines bearing a beta-phenyl substituent, both diastereomers fragment with complete regioselectivity toward the stabilised benzylic radical, in processes that are highly exothermic and essentially barrierless. For beta-alkyl substrates the picture is more nuanced: the trans diastereomer selectively delivers the desired secondary radical, aided by favourable orbital overlap between the boryl radical’s singly occupied molecular orbital and the sigma-star orbital of the more substituted carbon-nitrogen bond, while the cis isomer risks promiscuous cleavage. Fortunately, borane coordination was found to deliver the trans diastereomer exclusively or predominantly in practice.

With the mechanism mapped, the team built two complementary catalytic platforms. The first is an oxidative copper system. A copper(I) catalyst reacts with a silyl peroxide oxidant, cumylO2TMS, to generate an electrophilic cumyloxyl radical. This radical performs a polarity-matched hydrogen-atom abstraction on the aziridine-borane complex, forging the boryl radical that fragments to the beta-aminoalkyl radical. Meanwhile, a nucleophile such as an aryl boronic acid transmetalates with copper(II) to form an aryl-copper species that captures the radical. Reductive elimination, either through a discrete copper(III) intermediate or by direct carbon-carbon bond formation, delivers the beta-arylated product, which is unmasked to the free N-alkylamine during hydrolytic work-up. A clever design feature is that the arylated intermediate formed before work-up shields the alpha-nitrogen positions from further hydrogen abstraction, protecting the product from over-functionalisation under the oxidative conditions.

The scope of this copper manifold proved impressively broad. Using an N-propyl aziridine and phenylboronic acid as benchmarks, the team obtained the beta-phenylated amine in good yield, including on gram scale. Electron-rich and electron-poor para-substituted boronic acids, meta-substituted and disubstituted reagents, 2-naphthyl, benzofuranyl and even pyridyl boronic acids all coupled successfully. On the aziridine side, both electron-rich and electron-poor beta-aryl groups were tolerated, including a cyclobutane-annulated system, and the N-substituent could be methyl, hexyl, benzyl, isopropyl or cyclohexyl. The same catalytic blueprint also accepted other nucleophiles: trimethylsilyl cyanide delivered beta-nitrile amines, valuable because the nitrile can be hydrolysed to beta-amino acids, while diphenyl disulfide furnished beta-thioether derivatives in high yield, and proof-of-concept azidation and phthalimidooxylation reactions were also demonstrated.

Perhaps the most striking feature of the chemistry is its regioselectivity. In classical aziridine ring openings, the substrate dictates the outcome: benzylic systems cleave at the more substituted position to give branched products, whereas beta-alkyl systems prefer the less substituted bond and deliver linear products. Methods that override this intrinsic bias are exceedingly rare. The boryl radical fragmentation does exactly that, consistently cleaving the more substituted carbon-nitrogen bond across both beta-aryl and beta-alkyl substrates. Every substrate examined in the cyanation series, including derivatives based on the antiarrhythmic drug mexiletine, a glycine derivative, an atorvastatin intermediate and a medicinally relevant N-Boc-piperidinyl motif, delivered the branched product exclusively. Even an unsubstituted aziridine, proceeding through a primary radical, could be opened, and gem-disubstituted systems gave access to alpha,beta-difunctionalised amines and tertiary nitriles.

Where the copper system falters, a second platform picks up the slack. Beta-alkyl aziridines coupled only modestly under copper catalysis, so the team embedded the same hydrogen-atom abstraction and fragmentation steps into a dual photo-nickel manifold. Triplet-excited diaryl ketone photocatalysts, activated by purple light-emitting diodes, abstract the hydrogen atom from the borane complex, while a nickel catalyst handles the cross-coupling with aryl bromides, a widely available class of electrophilic partners. After oxidative addition of the aryl bromide to nickel(0), the beta-aminoalkyl radical is captured by the aryl-nickel(II) complex, and reductive elimination from the resulting nickel(III) intermediate delivers the product, with the ketyl radical by-product closing both catalytic cycles through single-electron transfer. This umpolung variant, pairing the aziridine with electrophiles rather than nucleophiles, lifted the yield of the model beta-alkyl arylation to 54 percent and tolerated a wide panel of aryl and heteroaryl bromides, including pyridyl and thiazole systems, although strongly electron-donating substituents and highly stabilised benzylic radicals proved limiting.

Together, the two manifolds offer chemists a choice of partner and catalyst matched to the radical at hand, all flowing from a single mechanistic blueprint. By eliminating the historical dependence on electron-withdrawing N-activating groups, the work streamlines access to beta-functionalised N-alkylamines, compounds that sit at the heart of countless bioactive molecules, and establishes aziridine-ligated boryl radicals as a genuinely useful class of synthetic intermediates. The Aachen team anticipates that the generality of the activation mode will accelerate the synthesis of biologically relevant targets and inspire broader exploration of amine-ligated boryl radicals, a reactivity logic that sat dormant in the literature for four decades before finally being put to work.

Subject of Research: Radical ring-opening and divergent functionalization of N-alkyl aziridines via aziridine-ligated boryl radicals

Article Title: Divergent ring opening and functionalization of N-alkyl aziridines via boryl radical fragmentation

Article References: Peng, P., Roure, B., Lulli, T., Stavagna, C., Lonardi, G., & Leonori, D. (2026). Divergent ring opening and functionalization of N-alkyl aziridines via boryl radical fragmentation. Nature Chemistry, 18(10), 1755-1762. https://doi.org/10.1038/s41557-026-02247-x

Image Credits: AI Generated

DOI: 10.1038/s41557-026-02247-x

Keywords: aziridines, boryl radicals, ring opening, copper catalysis, nickel catalysis, photocatalysis, cross-coupling, beta-aminoalkyl radicals, regioselectivity, borane coordination, organic synthesis, medicinal chemistry