Cyclopropanation of 3,4-dihydro-1 H-benzo[e][1,4]diazepine-2,5-diones

A two step parallel synthesis protocol for the preparation of 1N-substituted spirobenzodiazepineones is described. Treatment of 4-methyl-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione with a series of alkyl halides using a microwave-assisted heating protocol provided N-derivatized compounds, which were transformed to the corresponding cyclopropylamines employing modified Kulinkovich-type reaction conditions. X-ray structural analysis gave conclusive evidence of the newly created spiro centre and revealed a significant flattening of the seven-membered ring system compared with the benzodiazepinedione system providing a characteristically different pattern of bond exit vectors. The physicochemical parameters log D, pKa, solubility and membrane permeability of both cyclopropanated and precursor compounds were assessed.