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<p>The [2+2] cycloaddition reaction has been pivotal in advancing synthetic organic chemistry. However, thermal [2 + 2] cycloaddition reactions are symmetry-forbidden due to ground-state orbital symmetry constraints, making them challenging to achieve under non-photochemical conditions. Here we report a stepwise radical intramolecular thermal crossed [2 + 2] cycloaddition, enabled by the fluorine effect of in-situ-generated <i>N</i>-(homo)allyl <i>gem</i>-difluoroenamines and homoallyl <i>gem</i>-difluorovinyl ethers. Silver-catalysed <i>gem</i>-difluoroalkenylation of <i>N</i>-(homo)allylamines and homoallyl alcohols with trifluoromethyl triftosylhydrazones, respectively, followed by an intramolecular crossed [2 + 2] cycloaddition of the in-situ-generated <i>gem</i>-difluoroalkenes enables the synthesis of a range of medically relevant <i>gem</i>-difluoro heterobicyclo[<i>n</i>.1.1]alkanes, including azabicyclo[2.1.1]hexanes, azabicyclo[3.1.1]heptanes and oxabicyclo[3.1.1]heptanes. This methodology features readily available starting materials, high chemo-, regio- and stereoselectivity, excellent functional group compatibility and high yields. Notably, further conversion of the formed azabicyclo[2.1.1]hexanes into azabicyclic endoperoxides via oxygen incorporation highlights the properties of these <i>gem</i>-difluorinated bridged azabicyclic compounds. Combined experimental and computational studies support a stepwise radical mechanism for the thermal crossed [2+2] cycloaddition.</p><p></p>

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Thermal [2+2] cycloaddition as a route to gem-difluoro heterobicyclo[n.1.1]alkanes

  • 期刊论文

  • 发表日期：

    2026年1月12日

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  • Yongquan Ning,
  • Rongkai Wu,
  • Yongyue Ning,
  • Qingmin Song,
  • Jiahua Deng,
  • Qingchi Jiao,
  • Paramasivam Sivaguru,
  • Jacek Mlynarski,
  • Graham de Ruiter,
  • Xin Hong,
  • Xihe Bi

摘要

The [2+2] cycloaddition reaction has been pivotal in advancing synthetic organic chemistry. However, thermal [2 + 2] cycloaddition reactions are symmetry-forbidden due to ground-state orbital symmetry constraints, making them challenging to achieve under non-photochemical conditions. Here we report a stepwise radical intramolecular thermal crossed [2 + 2] cycloaddition, enabled by the fluorine effect of in-situ-generated N-(homo)allyl gem-difluoroenamines and homoallyl gem-difluorovinyl ethers. Silver-catalysed gem-difluoroalkenylation of N-(homo)allylamines and homoallyl alcohols with trifluoromethyl triftosylhydrazones, respectively, followed by an intramolecular crossed [2 + 2] cycloaddition of the in-situ-generated gem-difluoroalkenes enables the synthesis of a range of medically relevant gem-difluoro heterobicyclo[n.1.1]alkanes, including azabicyclo[2.1.1]hexanes, azabicyclo[3.1.1]heptanes and oxabicyclo[3.1.1]heptanes. This methodology features readily available starting materials, high chemo-, regio- and stereoselectivity, excellent functional group compatibility and high yields. Notably, further conversion of the formed azabicyclo[2.1.1]hexanes into azabicyclic endoperoxides via oxygen incorporation highlights the properties of these gem-difluorinated bridged azabicyclic compounds. Combined experimental and computational studies support a stepwise radical mechanism for the thermal crossed [2+2] cycloaddition.