A New Method For Synthesis Of Imidazo [1,2 - A] Pyridine And Pyrazole Heterocyclic Compounds With "Pharmaceutical Preference"

Multicomponent reactions and tandem reactions have rapidly been developed and achieved great progress in organic synthesis due to their advantages of diversity-oriental synthesis and synthetic efficiency, which now have been widely applied in various fields including organic, medicinal and process chemistry. More and more attractive are the syntheses of those "drug-prejudiced" heterocyclic scaffolds by utilizing the strategies of multicomponent reactions and tandem reactions. On one hand, the syntheses could shorten the time required for drug discovery due to enabling to rapidly construct versatile libraries of drug-like molecules, and on the other hand, they might be cost-efficient and environment-friendly due to their atom-economics, bond-forming efficiency and simplified operation if they could further result in the listed drugs or active pharmaceutical ingredients.In the multicomponent reactions and tandem reactions, alkynes are frequently viewed as promising reaction partners, including nucleophilic addition to unsaturated bonds and electrophilic attack to nucleophiles, mediated by various metals. Therefore, based on the strategies of multicomponent reactions and tandem reactions, this thesis is mainly concentrated on exploring the new methodologies for the preparation of the two "drug-prejudiced" scaffolds, namely, imidazo[1,2-a]pyridines and pyrazoles, which respectively occur in the structures of either Zolpidem to treat sleepy disorder or Celecoxib to treat arthritis, and results as followed: Zolpidem CelecoxibAt first, the thesis has explored the new strategy for the preparation of the imidazo[1,2-α]pyridines by the three-component reaction of alkynes,2-aminopyridines and aldehydes, aiming at the core scaffold of Zolpidem. A novel approach to the synthesis of imidazo[1,2-α]pyridines via the three-component reaction have been developed under the mild conditions through the mediation of the cheap reagents CuSO4and p-TsOH, and therefore, various substituted imidazo[1,2-α]pyridines could be obtained in acceptable yields with the tolerance of a variety of functional groups. Based on the results from both the three-component reaction and the two-component reaction of the corresponding imines and alkynes to synthesize imidazo[1,2-α]pyridines, a plausible mechanism has been proposed. Subsequently, this novel method has been preliminarily attempted to synthesize the Zolpidem.Secondly, the thesis has also explored the other novel strategy for the preparation of the imidazo[1,2-α]pyridines through the tandem reaction of aryl propargylic alcohols with2-aminopyridines, which is almost of the same atom-economics as the first strategy. And then an alternative method has been established with ZnCl2/CuCl to promote this transformation, resulting in various substituted imidazo[1,2-α]pyridines in moderate to good yields. The results from the reaction mechanism investigation suggest that the propargylic alcohol might be first converted into propargylic cation in the presence of ZnCl2, and then be attacked by2-aminopyridine to lead to the corresponding propargylic amine, followed by CuCl-catalyzed intramolecular cycloisomerization to produce the corresponding imidazo[1,2-α]pyridines. Then, this novel method has been preliminarily attempted to synthesize the Zolpidem, and through the two methods, a small library of imidazo[1,2-α]pyridines has been constructed for the further biological assay.After that, the thesis attempted to explore the new strategy for the preparation of the pyrazoles, aiming at the core scaffold of Celecoxib, by the tandem reaction involving nucleophilic addition of alkynes to hydrazones and subsequently intramolecular cycloisomerization. As a result, triflate acid (TfOH) enabled to mediate the reaction of tosylhydrazones to the terminal alkynes to produce3,5-substituted pyrazoles in moderate to high yields with high region-selectivities, possibly following the unexpected approach involving TfOH-induced carbocation addition of tosylhydrazones to the terminal alkynes, subsequent cyclization and elimination of4-methylbenzenesulfinic acid (TsH). Due to no concern on handling diazo compounds, this complementary method under the acidic conditions might be intrinsic operating-safer than typical1,3-dipolar cycloaddition of tosylhydrazones to the terminal alkynes under basic conditions. Through the novel method, a small library of3,5-substituted pyrazoles has been constructed for the further biological assay.Guided by the similar strategy involving nucleophilic addition of alkynes to unsaturated bond and subsequently intramolecular cycloisomerization, the attempts have been extended to explore various tandem reactions for the preparation of other heterocyclic scaffolds, including furans, imidazoles, oxazoles, and thiazoles. Up to now, despite the failure of those extentions, some valuable results have been furnished from them, and one of the results is that1,3,4-oxadiazole and azine can unexpectedly be produced from the reaction of tosylhydrazones and benzoic acid in the presence of TfOH, which opens one novel way to access to1,3,4-oxadiazole and azine. The extension in this context will continue to proceed in our group.