Benzo[<i>d</i>]oxazoles from Anilides by <i>N</i>-Deprotonation–<i>O</i>-S_NAr Cyclization

Abstract

A synthesis of benzo[d]oxazoles by an N-deprotonation–O-SNAr cyclization sequence from anilide precursors is reported. Anilides derived from 2-fluorobenzaldehydes, activated toward SNAr 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 SNAr 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.

Keywords

• benzo[<i>d</i>]oxazoles
• <i>N</i>-deprotonation–<i>O</i>-S_NAr cyclization
• ring formation
• annulation