Deaminative cross-coupling of amines by boryl radical β-scission
Article meta
Article Date: 15 October 2025
DOI: https://doi.org/10.1038/s41586-025-09725-1
Authors: Zhenhua Zhang, Giovanni Lonardi, Thomas Sephton, Yusuf C. Guersoy, Chiara Stavagna, Giovanni V. A. Lenardon, Massimo Bietti, Daniele Leonori et al.
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Summary
The authors present a general strategy that repurposes native amines (primary, secondary and tertiary) as direct handles for cross-coupling. Activation occurs in situ by borane coordination to form amine‑ligated boryl radicals. These undergo β‑scission at the C(sp3)–N bond to release alkyl radicals, which then enter copper‑catalysed cross‑couplings with a wide range of C, N, O and S nucleophiles. The platform tolerates diverse amine classes, supports late‑stage editing of complex drug scaffolds and can incorporate amides via reductive funneling. Overall, it establishes a broadly applicable approach to deaminative C–N bond functionalisation and a new route to modify drug‑like molecules.
Key Points
- Native amines (1°, 2°, 3°) are activated in situ by borane coordination to form boryl radicals.
- Boryl radicals undergo β‑scission across the C(sp3)–N bond to liberate alkyl radicals.
- Alkyl radicals engage in copper‑catalysed cross‑couplings with a broad panel of C, N, O and S nucleophiles.
- The method tolerates diverse amine classes and enables modular functionalisation of complex targets.
- Late‑stage editing of drug scaffolds is demonstrated, expanding medicinal chemistry options.
- Amides can be funnelled into the manifold via reductive conditions, widening substrate scope.
Content summary
The paper describes the mechanistic design (borane coordination → amine‑ligated boryl radical → β‑scission → alkyl radical) and shows how a copper redox catalytic system intercepts the resulting radicals for productive cross‑couplings. Experimental scope covers many common amine types and a variety of nucleophiles, with examples highlighting late‑stage modification of druglike molecules. Supplementary information provides full experimental details, mechanistic probes and Cartesian coordinates for key species.
Context and relevance
Amines are ubiquitous in bioactive compounds but are usually treated as synthetic end points. Turning them into versatile coupling partners addresses a major gap in synthetic strategy: direct deaminative functionalisation simplifies routes to modified scaffolds and can shorten medicinal chemistry campaigns. This approach sits alongside recent radical and single‑electron toolkits that aim to increase modularisation and late‑stage diversification in drug discovery and complex molecule synthesis.
Author style
Punchy: the authors deliver a clear, mechanistically grounded platform that could reshape how chemists think about native amines — from dead‑end groups to useful synthetic handles. If you work on method development or medicinal chemistry, the detailed scope and late‑stage examples make this paper worth digging into.
Why should I read this?
Short answer: if you make or tweak molecules (especially drugs), this gives you a new trick for swapping out amines without tedious pre‑activation. It’s practical, broadly applicable and you can see exactly how it might shave steps off syntheses or enable edits you previously avoided. We’ve done the skimming — this one is a keeper for synthetic and medicinal chemists.