Studies On Domino Reactions Of Polysubstituted Unsymmetrical1,4-Enediones

The1,4-enedione scaffold not only exists in natural products and pharmaceutical compounds, but also has broad applications in organic synthesis as a versatile building block. Considering its importance in pharmaceutical research and organic chemistry, several methods have been developed for their synthesis. However, the previous synthetic methods for1,4-enediones, especially for polysubstituted unsymmetrical1,4-enediones, still have several drawbacks, such as harsh reaction conditions, difficultly available substrates, complex procedures and poor functional group compatibilities. Therefore, it’s highly desirable to develop novel and efficient synthetic methods for polysubstituted unsymmetrical1,4-enediones, which could be further used for synthesis of important compounds and developing new reactions.In this thesis, we first developed a novel and efficient synthetic method for preparation of tetrasubstituted unsymmetrical1,4-enediones, which were further used in novel domino reactions for synthesis of important chemical compounds. The reaction mechanisms for these novel synthetic methods were also investigated. The main contents are as follows:In chapter1, we first briefly introduced the synthetic methods for2-ene-1,4-diones, then described in detail on the applications of1,4-enediones in organic synthesis. Based on the previous studies, we proposed our research strategy for this thesis.In chapter2, much attention has been paid to develop green and sustainable chemistry as environment protection is becoming an increasingly serious issue. Copper-catalyzed aerobic oxidative synthetic strategy has incomparable advantages in atom economy, bond forming efficiency and environmental benignity. Based on this excellent strategy, we developed an efficient method for the synthesis of tetrasubstituted unsymmetrical1,4-enediones. Notably, various N-nucleophiles are compatible with this reaction, such as pyrazole, imidazole, benzimidazole, benzotriazole, arylamines,2-amino pyridines, morpholine, pyrrolidine and piperidine.In chapter3,"auto-tandem catalysis", which involves two or more mechanistically different transformations promoted by a single catalyst, could greatly improve the catalyst utilization efficiency. In this work, we developed an efficient method for the synthesis of4H-pyrido[1,2-α]-pyrimidin-4-ones via "auto-tandem catalysis" strategy from1,4-enediones and2-amino pyridines. It’s noteworthy that the copper catalyst in this reaction could promote three mechanistically distinct transformations of aza-Michael addition, aerobic dehydrogenation and intramolecular amidation. Wide substrate scope, mild reaction conditions, and air as oxidant are also significant advantages of this reaction.In chapter4, the synthesis of novel heterocyclic skeletons is always a hot topic in chemistry because it can provide enormous opportunities for discovery of new drugs and materials.2-Imino-1H-imidazol-5(2H)-one derivatives are important intermediates in cellular metabolism, but their synthetic methods have been rarely investigated. Considering their important roles in biological study and potential applications in pharmaceutical industry, we firstly developed a general method for the preparation of2-imino-1H-imidazol-5(2H)-one derivatives from unsymmetrical1,4-enediones and guanidines via domino integration of aza-Michael addition/intramolecular cyclization/aerobic dehydrogenation/1,2-rearrangement/carbon-carbon bond cleavage reactions.In chapter5, carbon-carbon bond cleavage reactions have attracted much attention of chemists because of their broad applications in synthetic chemistry. However, it is still one of the most challenging topics in synthetic chemistry because of the inertness of carbon-carbon bond. In this work, a novel copper-catalyzed carbon-carbon bond cleavage strategy has been developed for the synthesis of a variety of quinoxaline from readily available unsymmetrical1,4-enediones and o-phenylenediamines.In chapter6, the utilization of green and sustainable resources as reagents is one of the important strategies for minimizing chemical wastes. Water as a green resource has extraordinary advantages in great abundance and environmentally benign. Thus, using water as the reagent or solvent has emerged as a hot topic in green synthetic chemistry. In this work, a green and efficient method has been developed for the synthesis of diversely substituted1,4-diketones via phosphine-mediated reduction of1,4-enediones with water as hydrogen source from unsymmetrical or symmetrical1,4-enediones.In chapter7, tetrasubstituted furans are not only key skeletons in a variety of natural products and pharmaceutical compounds, but also versatile building blocks in organic synthesis. In this work, an facile and efficient method has been developed for the synthesis of tetrasubstituted furans via phosphine-mediated intramolecular cyclization of1,4-enediones. This reaction has significant advantages in easily available substrates, wide substrate scope, mild reaction conditions, and high reaction efficiency. It’s noteworthy that different N-heteroaryl groups could be easily introduced at3-or4-positions of the furan ring.In chapter8, most of the domino reactions in literature proceed along a linear path, for example, substrate A could pass through intermediate B to produce the intermediate C, which further undergoes the linear reaction path to finally generate product P. We suppose there are other more efficient domino strategies, for example, a substrate could simultaneously involve in two or more different domino sequences and generate suitably functionalized intermediates to converge on the product. This designed strategy is more efficient than the domino reaction proceeded along a linear path. In this work, a highly efficient method for the synthesis of1,2,3-triaroylindolizines has been established from readily available methyl ketones and pyridines. This reaction is the first example of convergent integration of three domino sequences for the synthesis of complex molecules from one substrateIn chapter9, considering stoichiometric reagents are still needed for many organic reactions to guarantee their efficiency and stoichiometric byproducts were subsequently generated in these processes, which would result in environmental pollution. Therefore, we envisioned that their stoichiometric byproducts could be internally recycled to catalyze the subsequent reaction in one process to maximize reaction efficiency and minimize the wastes. In this work, we developed a highly efficient and regioselective method for the direct synthesis of a-iodoketals from aryl/vinyl methyl ketones based on sustainable orthogonal-tandem catalysis strategy, in which the excess or partly regenerated reagent in the upstream reaction could be internally recycled to catalyze the downstream reaction.In chapter10, considering2-aroyl-3-hydroxy-4-iodonaphthalene derivatives are versatile building blocks in organic synthesis because of their multifunctional groups, and there was no direct method for their synthesis in the literature. In this work, we developed a novel method for the direct synthesis of2-aroyl-3-hydroxy-4-iodonaphthalene derivatives from easily available (Z)-2-(hetero)arylidene-l-(hetero)arylbutane-1,3-diones. It was proposed the reaction proceeded through the following domino reaction sequence:CuO catalyzed iodination of methyl ketone, iodine-catalyzed isomerization of carbon-carbon double bond, hydrogen bond-assisted6π-electrocyclization, aromatization by HI elimination and regioselective iodination of electron rich arenes.In chapter11, the summary of this thesis was given.