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<p><i>N</i>-trifluoromethyl compounds, featuring a CF<sub>3</sub> group directly attached to nitrogen, are valuable in medicinal chemistry. Despite substantial advances in their synthesis over the past decade, the efficient preparation of inherently unstable <i>N</i>-CF<sub>3</sub> secondary amines remains a challenge in synthetic chemistry. Herein, we present a mild and practical method for synthesizing these compounds via oxidative fluorination of isocyanides using iodine as the oxidant, silver fluoride as the fluorinating reagent, and <i>tert</i>-butyldimethylsilane as the proton precursor. This approach benefits from simple workup, as all reagents and by-products can be easily removed through simple filtration and evaporation. This protocol features a broad substrate scope, good functional group tolerance, and good to excellent yields. Additionally, the resulting products can be readily converted into <i>N</i>-CF<sub>3</sub> carbamoyl fluorides, valuable building blocks for the synthesis of diverse <i>N</i>-CF<sub>3</sub> carbonyl derivatives.</p>

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A mild and practical approach to N-CF3 secondary amines via oxidative fluorination of isocyanides

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年5月26日

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  • Jia-Luo Fu,
  • Jun-Yunzi Wu,
  • Juan-Fen Shi,
  • Long-Ling Huang,
  • Honggen Wang,
  • Qingjiang Li

摘要

N-trifluoromethyl compounds, featuring a CF3 group directly attached to nitrogen, are valuable in medicinal chemistry. Despite substantial advances in their synthesis over the past decade, the efficient preparation of inherently unstable N-CF3 secondary amines remains a challenge in synthetic chemistry. Herein, we present a mild and practical method for synthesizing these compounds via oxidative fluorination of isocyanides using iodine as the oxidant, silver fluoride as the fluorinating reagent, and tert-butyldimethylsilane as the proton precursor. This approach benefits from simple workup, as all reagents and by-products can be easily removed through simple filtration and evaporation. This protocol features a broad substrate scope, good functional group tolerance, and good to excellent yields. Additionally, the resulting products can be readily converted into N-CF3 carbamoyl fluorides, valuable building blocks for the synthesis of diverse N-CF3 carbonyl derivatives.