Ge, Xiaobin-1, Yuan, Lijun, Sun, Qiqi, Lin, Ting, Chen, Weihao-1, Sun, Ji-1, Yu, Huangchao, Jin, Jian, Liu, Feng, He, Hui, Xu, Guoqiang, Gallou, Fabrice, Ye, Ning, Mo, Yiming and Shen, Xiaodong (2026) Minute-scale Alkylation of Heteroarenes via Photo-Fenton Mechanism in Continuous Flow. Green chemistry. ISSN 1463-9270; 1463-9262

Abstract

The development of cost-effective, operationally simple, and rapid late-stage alkylation of heteroarenes is pivotal to both medicinal and process chemistry. Inspired by the facile hydroxyl radical (•OH) generation via Fenton chemistry broadly used in environmental wastewater remediation, we developed a visible-light photo-Fenton flow protocol that converts inexpensive H2O2 into •OH for downstream hydrogen atom transfer (HAT) with a ferrocenyl diphenylphosphine-oxide photocatalyst. The transient •OH executes selective C-H abstraction from unactivated alcohols, alkanes, ethers, and aldehydes, furnishing carbon-centered radicals that engage N-heteroarenes in Minisci coupling to give alkylated products in up to 93% yield. More importantly, continuous-flow intensification enabled minute-level synthesis, achieving a productivity of 8.6 mol/(h•L). Despite the aggressive nature of •OH as the HAT mediator, this method tolerates sensitive motifs and enables multigram-scale functionalization of biologically active compounds, including voriconazole and quinine, with <10 min residence time.

Item Type:	Article
Keywords:	photo-Fenton; Minisci reactions, continuous-flow; iron catalysis; scalable
Date Deposited:	10 Jan 2026 00:46
Last Modified:	10 Jan 2026 00:46
URI:	https://oak.novartis.com/id/eprint/58266