康 · 学术 | Reaction of the Day No. 1492

（来源：康龙化成）

转自：康龙化成

Boryl Radical b-Scission Enables Divergent Deaminative Cross-Coupling of Amines

Zhenhua Zhang,1†Giovanni Lonardi,1† Thomas Sephton,1†Yusuf C. Guersoy,1Chiara Stavagna,1Massimo Bietti2 and Daniele Leonori1*

Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52056, Aachen, Germany; Dipartimento di Scienze e Tecnologie Chimiche, Università “Tor Vergata”, Via della Ricerca Scientifica, 1 I-00133 Rome, Italy

—10.26434/chemrxiv-2025-ch3wj

Recommended by Xuemei Yao_ MC3

KEYWORDS: deamination, Deaminative Cross-Coupling, Cu catalysis(反应类型), amines, boronic acids (原料), C(sp3)- C(sp2), C(sp3)- C(sp3), C(sp3)-CN, C(sp3)-N, C(sp3)-O, C(sp3)-S (成键类型) BH3-SMe2 (其他)

ABSTRACT: Amines are among the most common functional groups in bioactive molecules and pharmaceuticals, yet they are almost universally treated as synthetic endpoints. Here we report a strategy that repositions native primary, secondary, and tertiary amines 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 borylradicals, which undergo beta-scission across the C(sp³)–N bond to release alkyl radicals. These intermediates engage in copper-catalyzed cross-couplings with a broad array of C-, N-, O-, and S-based nucleophiles. The method tolerates diverse amine classes, enables modular functionalization, and supports late-stage editing of complex drug scaffolds. In addition, amides can be incorporated into the manifold via reductive funneling. This work establishes a general approach to deaminative C–N bond functionalization and introduces a new logic for retrosynthetic diversification and pharmacophore remodeling.

Substrate scope of amines

Substrate scope of boronic acids

Divergent use of nucleophiles to enable direct deaminative cross-coupling

Proposed copper catalytic manifold for deaminative cross-coupling via b-scission of amine-ligated borylradicals

Daniele Leonori and co-worker have developed a strategy for radical-mediated deaminative cross-coupling that applies to all classes of amines (primary, secondary and tertiary) and is currently optimized for systems that proceeds through benzylic and stabilized carbon radicals. This transformation exploits the unique ability of amine-ligated boryl radicals to undergo b-scission as blueprint for C(sp3)–N bond activation. This converts amines into alkyl radicals that engage in Cu-catalyzed C(sp3)–C, –N, –O, and –S bond formation. The methodology tolerates a wide range of amine classes, enables selective fragmentation even in complex environments, and demonstrates high chemoselectivity. The approach is applicable to late-stage diversification of pharmaceuticals, providing divergent access to analogues that would otherwise require individual synthetic efforts. While certain nucleophile classes remain challenging, the development of a modular amine-to-sulfide conversion offers a powerful workaround, enabling downstream diversification with otherwise incompatible nucleophiles under orthogonal conditions.