Construction Of 1,4-Enediones And Heterocycles Via Self-sorting Integration Of Domino Reactions

Based on the requirement of environmentally benign, efficient and atom-economic synthetic methods in modern society, domino reaction strategy has been developed to perform multiple reactions simultaneously in a single reaction vessel and afford the target molecules without seperating reaction intermediates. Although there were many reviews about domino reactions, it’s still an important and interesting topic to develop novel domino reaction strategies, which could help pepople for their design and improving the synthetic efficiency of domino reactions. Inspired by the self-sorting behavior of group molecules in nature, we suppose that two or more self-sorting domino reaction routes could coexist in a reaction system and proceed independently to afford their corresponding terminal intermediates, which could further converge on the target molecules. This "convergent domino strategy" would be more efficient than the traditional "linear domino strategy", which involved only one domino route.Based on the self-sorting integration of domino reactions, we proposed several novel domino reaction strategies in this thesis for the efficient synthesis of 1,4-enediones and various novel heterocycles. The main content is as follows:In chapter 1, we summarized the novel domino reaction strategies developed in recent years and the synthetic methods and applications of 1,4-enediones. Subsequently, we put forward our research topics based on the idea of self-sorting integration of domino reactions.In chapter 2, Inspired by the striking efficiency of focusing domino strategy utilized in nature, which consists of two or more distinct pathways from diverse substrates to focus on one common intermediate and follow the subsequent same pathway to afford target molecules, we wanted to prepare unsymmetrical 1,4-enediones via this excellent strategy. In this reaction, simple and readily available methyl ketones or terminal aryl alkenes were used as substrates to focus on the same a-ketoaldehydes intermediates, which further reacted with 1,3-dicarbonyl compounds to afford unsymmetrical 1,4-enediones via a common pathway. This synthetic strategy would not only allow changes in substrates, but also help chemists for their flexibility in synthetic plans.In chapter 3, as many important reactions still need "stoichiometric" reagents to guarantee their efficiency and "stoichiometric" wastes were generated in these processes, we hypothesized that "stoichiometric" and "catalytic" domino processes could be integrated in one-pot, and the byproducts generated from "stoichiometric" upstream domino reactions could be utilized to catalyze the downstream "catalytic" domino reactions, which is a very convenient approach to complex architectures via a multiplicative effect, and the atom-economy of "stoichiometric" reactions could be efficiently improved. On the basis of this hyposis, a highly efficient synthesis of hydantoins has been developed from simple and commercially available 1,3-dicarbonyl compounds, ureas and methyl ketones or terminal aryl alkenes. In this protocol, stoichiometric I2 was used to promote the upstream domino reaction I to afford unsymmetrical 1,4-enedione intermediates, then the excess or partly regenerated I2 was internally recycled to catalyze the downstream catalytic domino reactionⅡof 1,4-enedione intermediates with ureas to give the 1,3,5,5-tetrasubstituted hydantoins. This domino reaction comprises six mechanistically different steps:iodination-Kornblum oxidation-Knoevenagel condensation-Michael addition/1,2-addition-oxidative dehydrogenation-1,2-rearrangement reaction.In chapter 4, as molecular complexity could be easily achieved via the multiplicative effect of two or more coupled domino processes, we proposed that self-sorting substrates could be used to integrate upstream and downstream domino reactions in one-pot. Based on this strategy, a highly efficient synthesis of isoxazoles from a-nitro ketones and methyl ketones or terminal aryl alkenes has been developed. In this reaction, self-sorting a-Nitro ketones could be divided in two parts:one part of a-nitro ketones could react with methyl ketones or terminal aryl alkenes to afford 2-nitro-1,4-enedione intermediates, then the other part of a-nitro ketones could react with 2-nitro-1,4-enedione intermediates to give the polysubstituted isoxazoles.In chapter 5, as many reactions are not compitable with each other in one domino process, a practical synthetic strategy usually have to consist of step-wise reactions. In this context, we envision that a series of coupled domino processes could be rationally designed for target molecules to minimize reaction steps and maximize synthetic efficiency. Considering the necessity of step-wise reactions for complex architectures, the "focusing domino reaction" and "linear Fridel-Crafts/Paal-Knorr domino reaction" were first integrated in two-step reactions for the efficient synthesis of biheterocyclic 3-(furan-3-yl)indole derivatives from indoles, methyl ketones and 1,3-dicarbonyl compounds.In chapter 6, a series of polyenic 1,4-diones were synthesized fromα,β-unsaturated methyl ketones via homo-substrate self-sorting domino reaction strategy, which were further transfomred to 3-methylthio-2,5-diarylvinylfurans (pyrroles or thiophenes) via selective reduction and Paal-Knorr reaction. The efficient integration of diverse arylene units and heteroatom into these oligomers would allow easy control of their electronic and mechanical properties, which is important for their potential applications.In chapter 7, the summary and outlook of this thesis was given.