Benzo[d]oxazoles from Anilides by N-Deprotonation-O-S_NAr Cyclization

A synthesis of benzo[d]oxazoles by an N-deprotonation-O-S_NAr cyclization sequence from anilide precursors is reported. Anilides derived from 2-fluorobenzaldehydes, activated toward S_NAr ring closure by C5 electron-withdrawing groups, were prepared and subjected to deprotonation-cyclization using 2 equiv. of K₂CO₃ in anhydrous DMF. Following deprotonation at nitrogen, the delocalized anion cyclized from the amide oxygen to give high yields of benzo[d]oxazoles. The temperature required for the cyclization of benzanilides correlated with the potency of the C5 activating group on the S_NAr acceptor ring with nitro (most potent) reacting at 90 °C (1 h), cyano reacting at 115 °C (1 h), methoxycarbonyl reacting at 120 °C (2 h), and trifluoromethyl (least potent) reacting at 130 °C (3 h). Acetanilides were more difficult to cyclize but generally required 4-6 h at these same temperatures for completion. Product purification was accomplished by recrystallization or chromatography.