An experimental and theoretical study on the regioselectivity of successive bromination sites of 7,8-dimethyl-2,4-diphenyl-3H-1,5-benzodiazepine. Efficient microwave assisted solventless synthesis of 4-phenyl-3H-1,5-benzodiazepines

Abstract

A facile synthesis of 4-phenyl-1H-1,5-benzodiazepines from o-phenylenediamines and 1,3diketones in the presence of a catalytic amount of acetic acid has been achieved, in excellent yields, under microwave irradiation. This method is very simple and the reaction conditions are mild, environmentally friendly and more important, quick. Moreover, the complete assignment of 1 H-and 13 C-NMR signals was achieved using 1D and 2D experiments in conjunction with DFT/GIAO calculated isotropic magnetic shieldings at the B3LYP density functional level. The geometries of selected compounds were optimized using the 6-31G(d) basis set, whereas the nuclear shielding constants were calculated using the 6-311G(d) basis set. The theoretical values were found very close to the experimental data. In addition, the allylic versus benzylic bromination as well as the regioselectivity of the successive bromination sites was studied on 7,8-dimethyl-2,4-diphenyl-1H-1,5-benzodiazepine, whereupon the enhanced reactivity of the 3-CH 2 group was established. Semiempirical (AM1, PM3) and DFT calculations confirmed that the free radical bromination selectivity of the above benzodiazepine is related to the stability of the intermediate radicals formed during the bromination process. In addition, the inversion energy of H 2 C(3) group was calculated by AM1 or PM3 using the reaction path method and was found to be ~8.6 or ~9.0 kcal/mol, respectively, very close to the experimental value of ca. 12.4 kcal/mol.