Overcoming limitations in Chan-Lam amination with alkylboronic esters via aminyl radical substitution

Huanyu Xiao, Panting Cao, Wenhui Xiong and Tao Yang ()
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Huanyu Xiao: Nanchang University
Panting Cao: Nanchang University
Wenhui Xiong: Nanchang University
Tao Yang: Nanchang University

Nature Communications, 2025, vol. 16, issue 1, 1-10

Abstract: Abstract Chan-Lam coupling represents one of the most reliable methods for constructing C(sp2)−N bonds under mild conditions. However, application of this technology as a general platform for C(sp3)−N bond assembly remains a longstanding challenge due to the inherent limitation in boron-to-copper transmetalation. In contrast to the conventional two-electron process, the rapid capture of alkyl radicals by copper(II) complex affording the reactive high-valent copper(III) intermediate, has become a key part of the emerging approaches to forge C(sp3)−N bonds. Here, we report an N-alkylation protocol that overcomes the limitations of Chan-Lam coupling by using versatile alkylboronic pinacol esters (APEs) as radical precursors via aminyl radical-mediated boron abstraction. This distinct approach enables a versatile N-alkylation applicable to a wide range of APEs and N-nucleophiles with diverse functional groups. Synthetic utility of this protocol is further demonstrated by its ease of scalability, sequential N-alkylation of substrate with multiple reactive sites, and the late-stage modification of several complex bioactive materials.

Date: 2025
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DOI: 10.1038/s41467-025-64155-x

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