Journal Article

Iron-catalyzed three-component amino(radio)fluorination of alkenes to unprotected β-(radio)fluoroamines

Zheng, Chao, Le, Hannah, Cheng, Gui-Juan, Zhou, Yu, Zhang, Qian, Liu, Dezhi, Wang, Zhitong, Zhang, Xiaoxuan, Fu, Junkai, Ni, Jie, Vasdev, Neil, Li, Yang, Bortolus, Mark R., Esezobor, Oaikhena Z.

2025

Overview

Unprotected β-fluoroamines are important motifs in synthetic chemistry, offering versatility for the development of β-fluorinated nitrogen-containing compounds. Existing methods to these motifs require tedious operations and suffer from low efficiencies, which has prevented their use in biologically active molecules, such as drug discovery and positron emission tomography (PET) radiotracer development. Herein, an iron-catalyzed three-component aminofluorination of alkenes using a hydroxylamine reagent and Et 3 N · 3HF is reported, offering a direct entry to unprotected β-fluoroamines. Both aryl and unactivated alkenes are compatible, and the mild conditions along with a short reaction time enable its application in alkene aminoradiofluorination. The synthetic utility of this methodology is demonstrated by diverse follow-up derivatizations, efficient access to drug candidate LY503430, and the radiosynthesis of [ 18 F]KP23, a cannabinoid subtype 2 (CB2) PET radioligand. Mechanistic investigations reveal a radical pathway involving ferryl amino and aziridinium intermediates, and highlight the dual roles of Et 3 N · 3HF as both fluorine source and reductive promotor. Unprotected β-fluoroamines are important motifs in synthetic chemistry, offering versatility for the development of β-fluorinated nitrogen-containing compounds. Here, the authors disclose an iron-catalyzed three-component aminofluorination of alkenes using a hydroxylamine reagent and Et3N · 3HF, offering a direct entry to unprotected β-fluoroamines.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 639/638/403/933 / 639/638/77/888 / Alkenes / Alkenes - chemistry / Amines - chemistry / Biological activity / Cannabinoid CB2 receptors / Catalysis / Drug development / Fluorides / Fluorination / Fluorine / Fluorine Radioisotopes - chemistry / Fluoroamines / Halogenation / Humanities and Social Sciences / Hydroxylamine / Intermediates / Iron / Iron - chemistry / multidisciplinary / Nitrogen / Positron emission / Positron emission tomography / Radioactive tracers / Radiopharmaceuticals - chemical synthesis / Radiopharmaceuticals - chemistry / Reagents / Science / Science (multidisciplinary) / Versatility