In Situ Generated Active Intermediates To Construct Carbon (Hetero) Ring Structures Via Cycloaddition Strategy

Cycloaddition reaction is a direct and efficient method for the construction of mono or polycyclic structures, and also consistent with the requirement of green synthesis for simple, efficient, and atom economy. Thus, much attention has being paid to the development of cycloaddition reaction. Currently, it is becoming one of the hot topics in chemical research that exploring novel cycloaddition reaction and expanding its application in organic synthesis. In addition, based on self-sorting reaction network strategy, we have been committed to the self-organization synthesis of complex structures. That is, a highly active intermediate is in situ generated via multiple reaction sequences from simple starting materials, which could be captured by different reagents to synthesize target molecules in one-pot. We attempt to combine cycloaddition reaction with self-sorting reaction network, that is, using cycloaddition as a key strategy to transform multiple active intermediates generated in situ via self-sorting model into complex structures from simple and avaliable starting substrates. This protocol provides new synthetic methods and strategies for the synthesis of active natural products and biologically pharmaceutical molecules.In this thesis, we constructed diverse heterocyclic and carbocyclic rings via in situ capturing a-diazo ketones, arynes and 1,4-enediones intermediates, respectively. The main contents are as follows:In chapter 1, we briefly outlined the research status and applications in organic synthesis. Based on the integration of cycloaddition reaction with self-sorting reaction network, we proposed our research mentality for the development of new methods and approaches of organic synthesis.In chapter 2, on the basis of literatures about the synthesis and applications of a-diazo carbonyl compound, we developed a new safe and efficient method for the synthesis of a-diazo ketones from arylglyoxal monohydrates and tosylhydrazine at room temperature. This synthetic method has significant advantages in broad substrate scope, mild conditions, time-saving, and simple operation,In chapter 3, although a-diazo carbonyl compounds have good reactivity, its application has certain limitations due to the hazardous, potentially explosive, and unstable properties. In order to avoid these disadvantages of a-diazo carbonyl compounds,1,3-dipolar cycloaddition reactions of in situ generated a-diazoketones with electron-deficient alkenes, naphthoquinones and coumarins were used to construct polyfunctional pyrazoles, 1H-benzo[f]indazole-4,9-dione, and chromeno[3,4-c]pyrazol-4(3H)-one derivatives. Additionally, further research on the crystal packing properties of these molecules suggested that the crystal packing patterns of 1H-benzo[f]indazole-4,9-dione derivatives are of certain peculiarity that their one-dimensional molecular packing demonstrated a helical chain formation along the c direction via N-H·O hydrogen-bonding.In chapter 4, based on our developed new approach for the synthesis of a-diazoketones, a 1,3-dipolar cycloaddition reaction has been developed for the construction of polyfunctional pyrazole derivatives via capturing in situ generated a-diazoketones by aldehydes or ketones. Compared to the reported synthetic methods, this strategy has significant advantages in broad substrate scope, excellent regioselectivity, and simple operation. And all of these products are only one configuration without isomer.In chapter 5, a transition-metal-free formal [2+2+2] cycloaddition was explored giving access to cinnoline derivatives from 2-(trimethylsilyl)aryl triflates, tosylhydrazine, and a-bromo ketones under mild conditions. With the detailed studies for the reaction mechanism, we found that the diazene intermediate was involved in the cycloaddition, which was generated from the decomposition of tosylhydrazine in the presence of CsF. Three chemical bonds were formed-two C-N bonds and one C-C bond-in a single step. Advantages of this method include the use of commercially available starting materials, and mild reaction conditions.In chapter 6, a transition-metal-free multicomponent coupling annulation has been reported involving benzyne generated in situ from 2-(trimethylsilyl)aryl triflates. By this formal [2+2+2] cycloaddition reaction, a wide variety of naphthalene derivatives were conveniently constructed in one-pot with high efficiency under mild conditions, and the 1-phenanthrenol derivatives were achieved via the aromatization of the 3,4-dihydrophenanthren-1(2H)-ones. Furthermore, this method provides a potential and instructive approach to the synthesis of arylnaphthalene lignans.In chapter 7, it's weir known that polysubstituted benzenes and related systems are highly important structural units in natural products, active pharmaceuticals and agrochemicals, and also widely used in optical and functional materials. Herein, we have developed a transition-metal-free multicomponent benzannulation reaction to construct polysubstituted benzene derivatives from readily available ketones, nitroolefins, and diester acetylenedicarboxylate. Compared to classical synthetic methods that certain groups can be difficult to incorporate into benzene rings, this method can be used to directly synthesize benzene ring structures containing cyano group, carbonyl group, or ester group, and so on.In chapter 8, we initially exploited a novel bicyclization reaction for the efficient synthesis of 3a,6a-dihydrofuro[2,3-?furans from 1,4-enediones and malononitrile. Considering the facile access to unsymmetrical 1,4-enediones from methyl ketones and 1,3-dicarbonyl compounds, we have also explored a one-pot strategy to directly construct the 3a,6a-dihydrofuro[2,3-b]furan derivatives.In chapter 9, a manganous acetate tetrahydrate mediated formal intermolecular [2+2+2+1] cycloaddition was developed for the synthesis of fused cycloheptatriene derivatives from N-(acylmethyl)pyridinium iodides and naphthoquinone. To the best of our knowledge, this is the first report on the use of transition-metal manganese (II) as a promoter for formal cycloaddition reactions. Meanwhile, we further explored the facile acetylation of products. And these acetylated derivatives were expected to have potential applications in medicine or materials chemistry.In chapter 10, the summary of this thesis and the outlook of future work were given.