Novel Approach to C(sp³)–N Cross-Coupling through Copper-Mediated Alkyl-Radical-Capture Strategy

Keywords

N-alkylation - single-electron transfer - copper catalysis - alkylboronic esters - radical strategy - late-stage functionalization

Significance

While copper-catalyzed organoboron cross-couplings have achieved considerable success, N-alkylation using alkylboronic derivatives remains underdeveloped, primarily due to the sluggish boron-to-copper transmetalation. This article highlights an alternative approach that integrates single-electron transfer (SET) with copper catalysis to facilitate C(sp³)–N coupling, thereby circumventing the limits of two-electron transmetalation pathway. The success of this radical strategy hinges on a novel reductively activated reagent (1), which functions dually as a Cu(I)-to-Cu(II) oxidant and N-centered radical that promotes alkyl radical via boron abstraction. This methodology is an efficient strategy for the N-alkylation of a broad range of N-nucleophiles with alkylboronic esters demonstrating significant utility in medicinal chemistry.

 

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Comment

This protocol offers a highly efficient and user-friendly method for N-alkylation exhibiting excellent tolerance to a wide range of functional groups. As illustrated above, a broad scope of N-nucleophiles including sulfoximine and purine have been successfully employed. A variety of alkylboronic esters, including primary, secondary, and tertiary types containing complex structures and diverse functional groups, were coupled efficiently. In addition, the protocol proved effective in the late-stage functionalization of complex bioactive molecules.

 

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Publication History

Article published online:
23 September 2025