Structural Identification between Phthalazine-1,4-Diones and N-Aminophthalimides via Vilsmeier Reaction: Nitrogen Cyclization and Tautomerization Study

Abstract

N-aminophthalimides and phthalazine 1,4-diones were synthesized from isobenzofuran-1,3-dione, isoindoline-1,3-dione, furo [3,4-b] pyrazine-5,7-dione, or 1H-pyrrolo [3,4-c] pyridine-1,3-dione with monohydrate hydrazine to carry out the 5-exo or 6-endo nitrogen cyclization under the different reaction conditions. Based on the control experimental results, 6-endo thermodynamic hydrohydrazination and kinetical 5-exo cyclization reactions were individually selective formation. Subsequently, Vilsmeier amidination derivatization was successfully developed to probe the structural divergence between N-aminophthalimide 2 and phthalazine 1,4-dione 3. On the other hand, the best tautomerization of N-aminophthalimide to diazinone was also determined under acetic acid mediated solution.

A Reaction of N-Substituted Succinimides with Hydroxylamine as a Novel Approach to the Synthesis of Hydroxamic Acids

“…The fact that hydrazine reacts with phthalimide was first observed at the end of the 19th century [38] and was used as the basis for the Ing-Manske procedure (the Gabriel synthesis) [39]. Additionally, there are many examples of using the mentioned reaction for N-aminophthalimide synthesis [40][41][42]. It is known that hydrazine hydrate reacts with phthalimide even at -20 • C [42], which is important to exclude the transformation of N-amino phthalimide into 2,3-dihydrophthalazine-1,4-dione.…”

“…Additionally, there are many examples of using the mentioned reaction for N-aminophthalimide synthesis [40][41][42]. It is known that hydrazine hydrate reacts with phthalimide even at -20 • C [42], which is important to exclude the transformation of N-amino phthalimide into 2,3-dihydrophthalazine-1,4-dione. This fact is a further confirmation that reactions between five-membered cyclic imides and ammonia derivatives (in particular, the reaction between N-substituted succinimides and hydroxylamine) can easily undergo without heating.…”

Role of pharmacological active phthalazine scaffolds in medicinal chemistry

“…The phthalazinones are used to make a variety of well-known medicinal compounds such as Hydralazine, Budralazine, Azelastine, Ponalrestat, and Zopolrestat. The wide range of biological activities of phthalazinone pharmacophores prompted us to develop novel molecular systems with biologically active compounds [83][84][85][86][87][88].…”

Unravelling the synthetic and therapeutic aspects of five, six and fused heterocycles using Vilsmeier–Haack reagent

“…In 2021, Chung and co-workers 100 synthesized N , N -dimethylformimidamide-7-aminopyrazolopyrrolopyridine-6,8-dione and dichloropyridazine from N -aminophthalimides and N -phthalazine-1,4-diones by using V. H. reagent by stirring the reaction mixture at 50 to 80 °C for 0.5 to 4 hours, in moderate to excellent yield. Using the V. H. reagent, the structural difference between N -aminophthalimides and phthalazine 1,4-diones was successfully determined ( Scheme 65 ).…”