Photoinduced Difluoromethylation Cyclization to Generate Medium-Sized Difluoro-benzo[b]azepines

Compared with the energetically favorable 5- or 6-membered fluoro-functionalized heterocycles, the construction of medium-sized fluoro-heterocycles is relatively under-researched because of their inherently unfavorable enthalpic and entropic nature. Based on rational design and DFT calculations, a novel photocatalytic difluoromethyl radical-initiated intramolecular 7-endo-trig cyclization was realized, thus affording a sustainable route for the synthesis of challenging fluoro-functionalized medium-sized N-heterocycles. Depending on atomic dipole moment corrected Hirshfeld population (ADCH) charge calculations, the chemoselective 6-exo-trig radical cyclizations were further replenished. Large-scale synthesis and derivatization demonstrated the wide utility of this method.