Overcoming limitations in Chan-Lam amination with alkylboronic esters via aminyl radical substitution
Huanyu Xiao, Panting Cao, Wenhui Xiong, Tao Yang
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. The application of Chan-Lam coupling reactions as a general platform for C(sp3)−N bond assembly remains a longstanding challenge due to the inherent limitation in boron-to-copper transmetalation. Here, the authors report an N-alkylation protocol that overcomes the limitations of Chan-Lam coupling by using versatile alkylboronic pinacol esters as radical precursors via aminyl radical-mediated boron abstraction.