The Research On Metastable-state Intermediate:the New Methodology For The Synthesis Of Diverse Heterocycles By Capturing The In Situ Generated α-Arylglyoxal

Metastable-state intermediate is one of the most important molecules, which has the characters of high reactivity, storage difficult and easily transforming to diverserse novel structures. Therefore, we paid our attention on the metastable-state intermediate. Because it was easy to construct novel molecular scaffold. Moreover, it also was an important approach to establish new reaction. Through rational logical design, multifundamental reactions were assembled in one-pot. We have constructed diverse heterocycles by capturing the in situ generated metastable-state intermediates, including2-acyl benzothiazoles, bisindoles,2,2-bis(4-(dimethylamino)phenyl)-1-aryl ethanones, imidazo[1,2-a]pyridines,2-aminothiozoles, a-formyloxy/acetoxy ketones,1,4-enediones,1-indanones, β-carbolines, quinazolin-4(3H)-one. We firstly accomplished the total synthesis of natural products eudistomin Y1-Y6, pityiacitrin, and luotonin F through capturing the metastable-state intermediates approach. This efficient strategy could have significance for directing further research into one-pot synthesis of many natural products.In this dissertation, we described our works about the metastable-state intermeddiate a-arylglyoxal. At first, we have developed some novel methods for the synthesis of diverse heterocycles by capturing the in situ generated metastable-state intermediate a-arylglyoxal. Furthermore, we have established multipathway coupled domino strategy, focus-oriented domino strategy and sustainable byproduct catalyzed domino strategy. Finally, we have applied the developed methods and strategies to natural products total synthesis. The key discoveries are listed below.In chapter1, we first summarized the relevant progress about metastable-state intermediates in recent years, and then overviewed of the major synthetic methods to access intermediate a-arylglyoxal and its application in organic synthesis. Subsequently, we proposed the design idea of this dissertation.In chapter2, transition-metal-catalyzed C-H activation and functionalization has drawn considerable interest in recent years. To further develop diverse methods for direct C-H bond functionalization are still both desirable and valuable. During studying the reaction of aromatic ketones with2-aminothiophenols, we found that molecular iodide could promote sp3C-H of aromatic ketones directly coupling with2-aminothiophenols to afford2-acyl benzothiazoles. After several experimental iterations, the desired product2-benzoyl benzothiazole was furnished in86%yield. Subsequently, the scope of the substrates was investigated in detail, different substituted aromatic ketones, hetero aryl ketones and naphthyl methyl ketones all well suitable in the reaction. We further expanded the scope of the substrates to a,p-unsaturated methyl ketones. We also monitored the reaction process and intermediates via on-line NMR and kinetic experiments. The results disclosed that the reaction underwent a-iodo aryl methyl ketones and a-arylglyoxal intermediates, in which multiple fundamental reactions (iodination, Kornblum oxidation and annulation) were self-sequentially assembled in a single reactor.In chapter3, based on the multipathway coupled domino strategy, multiform substrates arylethenes, arylacetylenes,2-hydroxy-aromatic ketones, and carbinols were firstly converted into the same intermediates a-arylglyoxals via four distinct pathways. Then, a-arylglyoxals were captured by2-aminothiophenol to afford2-acyl benzothiazoles. Through a logical charging manner, diverse fundamental reactions were integrated in one-pot. The reaction has well tolerant to the multiform substrates (arylethenes, arylacetylenes,2-hydroxy-aromatic ketones, and carbinols), both electron-donating and-withdrawing groups attached to the aryl of substrates were all suitable for this protocol.In chapter4, indole as privileged scaffold has attracted considerable attention. Moreover, bisindoles as molecular stars were pursued by many synthetic chemists and pharmacologists. We selected aromatic ketones and indole derivatives as starting materials, developed I2-promoted sp3C-H bond dual-(het)arylation protocol for the synthesis of2,2-bisindolyl-l-arylethanones. Compared with the classical metal-catalyzed C-H functionalization, this protocol could directly coupling sp3C-H bond with sp2C-G bond without metal, base, and ligand.In chapter5, An I2-CF3SO3H synergistic promoted sp3C-H bond diarylation protocol was developed for the synthesis of2,2-bis(4-(dimethylamino)phenyl)-1-aryl ethanones from simple and readily available aryl methyl ketones and N,N-dialkylanilines. We investigated the mechanism and reaction process via on-line NMR and control experiments. The mechanism revealed that the reaction underwent iodination, Kornblum oxidation and hydroarylation three fundamental reactions.In chapter6, A tunable synthetic protocol was proposed for selective synthesis of2-aryl-imidazo[1,2-a]pyridines and2-aryl-3-(pyridine-2-ylamino)imidazo[1,2-a]pyridines from the same starting materials:aromatic ketones and2-aminopyridines. The reaction performed through different reaction pathways in MeOH and DMSO. When the reaction was carried out in MeOH, aromatic ketones underwent a-halogenation to afford intermediate a-iodo ketones in situ, which were captured by2-aminopyrimidines to obtain2-aryl-imidazo[1,2-a]pyridines. While the reaction performed in DMSO, aromatic ketones were first converted to a-arylglyoxals intermediates. This step was likely followed by condensation with two molecules of2-aminopyrimidines to yield2-aryl-3-(pyridine-2-ylamino)imidazo[1,2-a]pyridines. This protocol could afford different imidazo[1,2-a]pyridines from the same substrates via tunable intermediates in MeOH and DMSO.In chapter7, we developed a direct protocol for the synthesis of2-aminothiozoles from aromatic ketones and thioureas in the mediate of I2-CuO. First, I2-CuO promoted aromatic ketones to afford a-iodo ketones intermediates, which were captured by thiourea to furnish2-aminothiozoles. Next, we examined the scope of the substrates, and found that α,β-unsaturated methyl ketones, P-keto esters,1,3-diketones and N-methyl thiourea were all suitable for this protocol. When α,β-unsaturated methyl ketones were selected as substrates, the reaction could high selectively obtain the E-conformation products.In chapter8, we developed a suitable byproduct catalyzed domino strategy, in which the byproducts generated from upstream domino reactions could be utilized to catalyze the downstream domino reactions. Moreover, the solvent also as a substrate took part in the reaction. This strategy can greatly increase the atom-economic of the whole reaction. First,I2-CuO promoted aromatic ketones to afford a-iodo ketones and byproduct CuI. Subsequently, byproduct CuI catalyzed a-iodo ketones reacting with solvent DMF or DMA to afford a-formyloxy and acetoxy ketones. The protocol could highly efficient synthesis of a-formyloxy and acetoxy ketones from aromatic ketones and solvent DMF or DMA.In chapter9, inspired by the diversity-oriented synthesis and multipathway synthesis strategy, we proposed a multisubstrate focus-oriented synthetic strategy. In the process, different substrates a-halo aromatic ketones,2-hydroxy-aromatic ketones and methyl carbinols were converted into the same intermediate arylglyoxal in situ through different reaction pathways, which was captured by1,3-dicarbonyl compounds to afford1,4-enediones. The on-line NMR monitoring, control experiments and the X-ray structure of intermediate disclosed that the reaction may undergo Cu(I)/Cu(II) catalytic cyclization process. Moreover, we examined the efficiency of Cu(II)-complex with different a-halo aromatic ketones without additional catalyst. After several experimental iterations, we found that diverse substrates a-halo aromatic ketones,2-hydroxy-aromatic ketones and methyl carbinols could self-organized react with1,3-dicarbonyl compounds to afford1,4-enediones through different pathways in one-pot. The result demonstrated that multisubstrate focus-oriented synthetic strategy is feasible under suitable conditions.In chapter10, we proposed an AlCl3promoted Nazarov cyclization protocol from1,4-enediones to afford1-indanones, in which there were two chiral center. Moreover, the reaction could furnish the product in quantitative yields with high dr (99:1). We observed that the substituent groups of substrates have strong influence on the reaction efficiency. We also investigated the reaction mechanism by NMR spectrum and observed the complexing action between substrate and AlCl3in solution. Furthermore, we studied the influence of solvents and found the reaction only took place in EtNO2.In chapter11,β-carboline is an important class of heterocycle, which exists widely in natural products and drug molecules. Therefore, the development of a practical and efficient protocol to access β-carboline is both desirable and valuable. We developed a molecular iodide promoted C-H and N-H coupling protocol to access P-carbolines from easy available aromatic ketones and tryptamine derivatives. This method could efficiently obtain diverse β-carbolines. When tryptophan was selected as substrate, the reaction also underwent to furnish P-carbolines in high yields via decarboxylation. We also monitored the reaction process and intermediates via on-line NMR and control experiments. The results disclosed that the reaction underwent a-iodo aryl methyl ketones, a-arylglyoxal and4,9-dihydro-3H-pyrido[3,4-b]indole intermediates. Finally, we directly applied this method to total synthesis of natural product eudistomin Y1-Y6and pityiacitrin. This method could efficiently furnish the desired natural products in one-pot.In chapter12, based on the previous developed protocols and reaction models, we further applied them to one-pot synthesis of natural products. Through a rational logical design, we assembled multifundamental reactions (iodination, Kornblum oxidation, and annulation) in one-pot and realized the total synthesis of natural product luotonin F in one-pot. The protocol could efficiently synthesize the natural product luotonin F and derivatives from simple and readily available aromatic ketones and2-aminobenzamides.In chapter13, the summary and outlook of this dissertation was given.