Synthesis of N-acylated 1,5-benzodiazepines: Differentiation between two possible acylation sites via hydrogen bonding

Temperature-dependent regioselectivity between amino and hydroxyl groups mediated by hydrogen bonding was observed in the reaction of acetic anhydride with 2-(2,3-dimethoxyphenyl)-4-(2-hydroxyphenyl)-2,3-dihydro-1H-1,5-benzodiaz epine (1), obtaining 1-acetyl-2-(2,3-dimethoxyphenyl)-4-(2-hydroxyphenyl)-2,3-dihydro-1H-1,5- benzodiazepine (1a), when these were reacted at room temperature, and 4-(2-acetoxyphenyl)-1-acetyl-2-(2,3-dimethoxyphenyl)-2,3-dihydro-1H-1,5- benzodiazepine (1b), when they were refluxed (148-150 °C). Acylation of the less hindered analog 4-(2-hydroxyphenyl)-2-phenyl-2,3-dihydro-1H-1,5-benzodiazepine (2) via crotonyl chloride (a bulky acylating agent compared with acetic anhydride) afforded by refluxing only 1-crotonyl-4-(2-hydroxyphenyl)-2-phenyl-2,3-dihydro-1H-1,5-benzodiazepin e (2a). All compounds were characterized spectroscopically, and the molecular structures of compounds 1a and 2a were determined by X-ray diffraction analysis.