Azoles and arenes are among the most common functional groups in pharmaceuticals and organic materials and their functionalisation relies on transition metal catalysis when considering their borylation. We sought to develop strategies able to decouple the C–B formation from metal catalysis and possibly achieve orthogonal selectivity. We discovered that amine ligated boryl radical, due to their nucleophilic and highly destabilised nature, can overcome polarity constrains and add to both electron-rich and electron-poor azoles and arenes to form new borylated materials. These strategies relies on metal free conditions and in presence of an oxidant and visible light we were able to borylate more than one hundred new substrates with selectivity orthogonal to the state of the art in most of the cases. The orthogonal selectivity arises from the fact that the process is controlled by electronics of the aromatics instead of the sterics for metal catalysed processes. This borylation strategies allowed late stage functionalisation with the borylation of 15 drugs candidates and consequent post functionalisation to forge new bonds such as C–O, C–C (Suzuki-Miyaura) and C–N (Chan-Lam) bonds.
These projects have been submitted to high impact journals.
Amines are one of the most common functional groups in bioactive molecules, pharmaceuticals and agrochemicals. Yet in synthetic chemistry, amines are almost exclusively treated as synthetic endpoints. This inefficiency originates from the poor leaving group character of amines, their high C–N BDE, and their basicity, all of which make direct deaminative functionalization elusive. We reported a strategy that relocates native amine as versatile handles for divergent cross-coupling. The platform relies on in situ activation via borane coordination and exploits a copper catalytic redox system that generates amine-ligated boryl radicals, which undergo beta-scission across the C–N bond to release alkyl radicals. These intermediates engage in copper-catalysed cross-couplings with a broad array of C-, N-, O-, and S-based nucleophiles. The method tolerates diverse amine classes and supports late-stage functionalisation of drug scaffolds. We then extended the method to cyclic amines both strained and unstrained and we developed a new general method to selectively ring-open these abundant materials into radical species, followed by divergent functionalisation exploiting metal catalysis in oxidative conditions (Cu) and photocatalysis (Ni, Ir). The radical nature of the process for strained cyclic amines provided orthogonal site selectivity for ring opening compared to common polar methods, while borane coordination to unstrained rings allowed ring opening of the amine without the use of strong activating and protecting groups allowing the synthesis of linear amines which can be exploited for further reactivity.
One project was published in Nature: Nature 2025, 647, 913. The second one was accepted in a high impact journal and the third one is going to be submitted soon.
