Overcoming limitations in Chan-Lam amination with alkylboronic esters via aminyl radical substitution.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 41087349.
- Also identified by DOI 10.1038/s41467-025-64155-x and PMC identifier 12521662.
- Licence recorded as CC BY-NC-ND.
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Abstract
Chan-Lam coupling represents one of the most reliable methods for constructing C(sp<sup>2</sup>)-N bonds under mild conditions. However, application of this technology as a general platform for C(sp<sup>3</sup>)-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(sp<sup>3</sup>)-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.