2D-NMR, X-ray crystallography and theoretical studies of the reaction mechanism for the synthesis of 1,5-benzodiazepines from dehydroacetic acid derivatives and o-phenylenediamines

Abstract The synthesis of 1,5-benzodiazepines by the reaction of o -phenylenediamines ( o -PDAs) with dehydroacetic acid DHAA [3-acetyl-4-hydroxy-6-methyl-2 H -pyran-2-one] or conjugate analogues is largely reported in the literature, but still with uncontrolled stereochemistry. In this work, a comprehensive mechanistic study on the formation of some synthesized 1,5-benzodiazepine models following different organic routes is established based on liquid-state 2D NMR, single-crystal X-ray diffraction and theoretical calculations allowing the classification of two prototropic forms A (enaminopyran-2,4-dione) and B (imino-4-hydroxypyran-2-one). Evidences are presented to show that most of the reported 1,5-benzodiazepine structures arising from DHAA and derivatives preferentially adopt the ( E )-enaminopyran-2,4-diones A .