Nickel-catalyzed hydroxymethylation with α-silicon N-methoxyphthalimides via radical Brook rearrangement

🔗 원문 전체 보기 → Royal Society of Chemistry

요약

Chem. Sci., 2026, Advance ArticleDOI: 10.1039/D6SC00986G, Edge Article Open Access &nbsp This article is licensed under a Creative Commons Attribution 3.0 Unported Licence.Xiao-Bo Liu, Muhammad Bilal, Jiaying Zuo, Ya-Xin Yu, Yu-Juan Wu, Boming Shen, Peng-Hui …

본문

Nickel-catalyzed hydroxymethylation with α-silicon N-methoxyphthalimides via radical Brook rearrangement

* Corresponding authors

a School of Chemistry and Chemical Engineering, Shandong University, Jinan 250100, China
E-mail: [email protected]

b Henan-Macquarie University Joint Centre for Biomedical Innovation, School of Life Sciences, Henan University, Kaifeng 475004, China

c Department of Chemistry, Southern University of Science and Technology, Shenzhen 518055, China
E-mail: [email protected]

d School of Food and Biological Engineering, Hefei University of Technology, Hefei, China
E-mail: [email protected]

Abstract

The hydroxymethyl group is an important functional motif frequently found in the core structures of natural products and drugs. However, efficient and general methods for its direct introduction remain underexplored, especially within reductive cross-electrophile coupling frameworks. Herein, we report a nickel-catalyzed reductive hydroxymethylation of aryl halides and triflates enabled by a radical Brook rearrangement strategy. Key to this method is a newly designed, bench-stable α-trialkylsilyl N-methoxyphthalimide reagent, which acts as a masked hydroxymethyl radical precursor upon reductive N–O bond cleavage and subsequent 1,2-radical Brook rearrangement. The reaction proceeds under mild conditions, exhibits broad functional-group tolerance, and is applicable to a wide range of aryl bromides, iodides, triflates, heteroaryl substrates, and complex bioactive derivatives. Mechanistic studies support a radical pathway involving zinc-mediated single-electron transfer, alkoxyl radical formation, Brook rearrangement, and nickel-catalyzed cross-electrophile coupling. The synthetic utility of this protocol is further demonstrated through gram-scale synthesis and downstream diversification, highlighting its potential for late-stage hydroxymethylation and applications in medicinal chemistry.