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

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.