Synthesis Of Spiropyrazoline Oxindoles By A Formal [4+1] Annulation Reaction Between 3-Bromooxindoles And In Situ-Derived 1,2-Diaza-1,3-Dienes

Spirooxindoles, especially these spiro[indoline-3-heterocycle]-2-one scaffolds,represent a privileged family of heterocycles with prevalence in many natural products and pharmaceutically active compounds. As a result, a large number of methods involving isatins and alkylidene oxindoles as starting materials have been invented toward their synthesis during the past several decades. Interestingly, despite the fact that several spiropyrazoline oxindoles have recently been identified to exhibit fascinating biological profiles, however, the efficient synthesis of such type of spirooxindoles have been less explored.Recently, 1,2-diaza-1,3-dienes that can be easily generated in situ from the corresponding a-halogeno hydrazones in the presence of stoichiometric base have been established as a powerful class of synthetic building blocks, and have found broad applications in various cycloadditions toward nitrogen heterocycles synthesis. In this thesis, we developed a formal [4+1] annulation reaction of 3-bromooxindoles and in situ-derived azoalkenes in the presence of Cs2CO3 as the base. This protocol provides an efficient and mild approach to various biologically interesting spiropyrazoline oxindoles with generally high yields.First, we indentified the optimal condition for spirooxindoles synthesis through investigating the reaction parameters such as bases, solvents, the ratio of substrates. We identified the producedure as follows: 3-bromooxindoles,a-halogeno hydrazones, and Cs2CO3 were stirred at room temperature in CH2Cl2 as the solvent with Cs2CO3 as the bases. Next, we probed the substrate scope under the opitimal reaction conditions and the results showed that this reaction was compatible with various 3-bromooxindoles. Moreover, a one-pot, three-component variant also works smoothly to give the desired products in comparable yields. A plausible mechanism was also hypothesized,wherein the base promoted Michael-type addition of enolate to 1,2-diaza-1,3-dienes and intramolecular nucleophilic SN2-subsitution of Br atom by hydrazonyl anion to generate the formal [4+1] annulation products.All the desired products were fully characterized by 1H NMR, 13C NMR,HRMS, IR and two of them were unambiguously determined by X-ray diffraction analysis. This research has been published on Org. Chem. Front..