Non-Catalyzed Cascade Double Imination Reaction of 2‑Fluoro-alk-3-yn-1-ones: Sustainable Synthesis of 3‑Fluoro-1,5-benzodiazepines

The cascade reactions of 2-fluoroalk-3-yn-1-ones with o-phenylenediamines provide an effective synthetic method with high atom economy for the preparation of diversely substituted 3-fluoro-3H-benzo[b][1,4]diazepines (52–81%). This noncatalytic and sustainable process embraces formal hydroamination and imination reactions, resulting in the formation of two CN and two C–H bonds. DFT modeling provided additional insight into the reaction’s mechanism, favoring the pathway involving initial cyclization of nonconjugated enaminone, o-aminoanilino-2-fluorobut-3-en-1-one. The reaction may be diverted to the formation of conjugated enaminone (o-aminoanilino-2-fluorobut-2-en-1-one), whose presence was confirmed by 1H NMR. The conformational properties of the 7-membered ring were investigated by the 1H and 19F variable temperature NMR studies in solution and by the X-ray structure determination of 3-fluoro-4-(4-methylbenzyl)-2-phenyl-3H-benzo[b][1,4]diazepine.