Minute-level alkylation of heteroarenes via a photo-Fenton mechanism in continuous flow

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, which is 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) using 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 afford alkylated products in yields of up to 93% yield. More importantly, continuous-flow intensification enables minute-level synthesis, achieving a productivity of 8.6 mol (h L)⁻¹. Despite the aggressive nature of ˙OH as the HAT mediator, this method tolerates sensitive motifs and enables the multigram-scale functionalization of biologically active compounds, including quinoxyfen and quinine, with a 10 min residence time.