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<p>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<sub>3</sub>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 [<sup>18</sup>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<sub>3</sub>N · 3HF as both fluorine source and reductive promotor.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月5日

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

摘要

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 Et3N · 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 [18F]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 Et3N · 3HF as both fluorine source and reductive promotor.