Green Multicomponent Synthesis Of Phthalazinetrione Derivatives

The environmental pollution has become a global problem. It is one of the best solutions to control pollution at the source. Therefore, it’s urgent to carry out the study of green chemistry. Recently, multicomponent reactions, which are three or more different types of raw materials to form a product directly without separation of intermediates, have received much attention and emerged as avaluable synthetic tool towards the rapid synthesis of diverse and complex heterocyclic compounds. Multicomponent reactions have many advantages, such as cheap raw materials, simple experimental operation, efficiency, short reaction time, atom economy and environmental friendliness.Phthalazinetrione derivatives have important bioactivities, such as antimicrobial, anti-inflammatory, anticancer activities, etc. In addition, these compounds show considerable promise as new luminescence materials and fluorescence probes. The existing methods for the synthesis of phthalazinetrione and derivatives have more or less shortcomings. So from the viewpoint of green chemistry, it is necessary to develop green synthesis of phthalazinetrione derivatives. In this dissertation, we studied the one-pot three-component and one-pot four-component reactions to synthesize phthalazinetrione derivatives.Firstly, the synthesis of 2H-indazolo[2,1-b]phthalazine-triones by a one-pot three-component condensation reaction of phthalhydrazide, dimedone or cyclohexane-1,3-dione and aldehydes catalyzed by ionic liquid was studied. We screened kinds of ionic liquids, the loading of catalyst, solvent, temperature and the molar ratio of reactants. The optimum reaction conditions were that ionic liquid 4-(3-methyl-l-imidazolio)-1-butanesulfonic acid hydrogen sulfate ([BSO3HMIm]HSO4) (0.15 mmol), phthalhydrazide (1.0 mmol), dimedone or cyclohexane-1,3-dione (1.4 mmol), aldehyde (1.6 mmol) in PEG 600 (1.0 mL) were stirred at 120℃. The catalyst/solvent system could be easily recovered only through distillation and reused for at least 5 times without noticeable loss of activity, and the recyclable yields were 95%,94%,94%,92%,87%, successively. The advantages of this strategy are simple, efficient and environmentally friendly.Secondly, the synthesis of 2H-indazolo[2,1-b]phthalazine-triones by a one-pot three-component condensation reaction of phthalhydrazide, dimedone or cyclohexane-1,3-dione and aldehydes catalyzed by molecular iodine was studied. The optimum reaction conditions were gained by screening solvent, temperature, the molar ratio of reactants and the loading of catalyst, which were molecular iodine (0.25 mmol), phthalhydrazide (1.0 mmol), dimedone or cyclohexane-1,3-dione (1.5 mmol), aldehyde (1.7 mmol) in the mixed solvent of H2O (1.2 mL) and ethanol (0.8 mL) under reflux conditions. After the completion of the condensation reaction, we also tested the possibility about the recycling of the catalyst and gained good results. We recycled three times and the the recyclable yields were 95%,88%,73%.Finally, the synthesis of 1H-Pyrazolo[1,2-b]phthalazine-5,10-dione derivatives by a one-pot four-component condensation reaction of phthalimid, hydrazine hydrate, malononitrile or ethyl cyanoacetate and aromatic aldehydes catalyzed by Lewis acid was studied. After the screening of kinds of Lewis acids on model reaction, NiCl2·6H2O expressed a special catalytic effect and gave an excellent yield of 95%. This strategy gained satisfactory yields only through simple optimizing experiment and the the optimum reaction conditions were NiCl2·6H2O (0.1 mmol), phthalimid (1.0 mmol), hydrazine hydrate (1.0 mmol), malononitrile or ethyl cyanoacetate (1.0 mmol) and aromatic aldehydes (1.0 mmol) uner refluxing ethanol (3.0 mL). The one-pot four-component reaction for the synthesis of 1H-Pyrazolo[1,2-b]phthalazine-5,10-dione derivatives was reported for the first time and the phthalimid is also used as a reactant to prepare phthalazinetrione derivatives for the first time.