【作者】 张伟；

【导师】 杜云飞；

【作者基本信息】 天津大学 ， 药学， 2020， 硕士

【摘要】 噻吩和噻唑骨架在自然界中普遍存在,并且构成了广泛的生物活性天然产物和药物的核心。因此,已经报道了许多分别用于构建噻吩和噻唑骨架的合成方法。然而,据我们所知,关于同时包含噻吩和噻唑部分的稠合杂环体系的构建的研究较少。具体而言,苯并[4,5]噻吩并[2,3-d]噻唑是一种独特的含S稠合杂环系统,受到了化学家的广泛关注。因此,已经开发出许多合成方法来构建这种苯并噻吩并噻唑骨架。这些方法在苯并[4,5]噻吩并[2,3-d]噻唑骨架的合成中都有其优点,但是一个明显的缺点是所有取代的苯并[4,5]噻吩并[2,3-d]噻唑化合物必须从原料中预先存在的苯并噻吩骨架中衍生而来。在这里,我们决定开发一种由铜试剂介导的芳基取代的苯并[4,5]噻吩并[2,3-d]噻唑的新型反应。我们通过选择2-(2-溴-4,5-二甲氧基苯基)乙腈和苯甲醛作为模型底物,元素硫作为硫源,以及1,10-菲咯啉作为配体开始研究。经过一系列条件筛选,发现了最佳条件。为了研究新方法合成目标杂环化合物的普适性,我们准备了一系列取代的底物以进行反应。实验结果表明,在最佳条件下合成了20种苯并[4,5]噻吩并[2,3-d]噻唑衍生物。所有的2-芳基苯并[4,5]噻吩并[2,3-d]噻唑化合物都具有引人注目的荧光特征,这是由于它们具有现有的多环π-共轭体系。我们对所有的化合物都进行了光学检测。最后,为了研究机理,我们进行了一系列控制实验。并在先前文献研究和控制实验的结果的基础上,提出了这种新发现的三组分一锅法反应的可能机理。这项工作可能代表通过噻吩和噻唑环的连续形成的2-芳基苯并[4,5]噻吩并[2,3-d]噻唑骨架的第一个三组分结构。更多还原

【Abstract】 Both thiophene and thiazole frameworks are ubiquitous in nature and constitute the core of a wide range of biologically active natural products and pharmaceutical agents.Accordingly,many synthetic methods have been reported for the construction of thiophene and thiazol skeletons,respectively.However,to the best of our knowledge,there has been less study on the construction of the fused heterocyclic ring systems containing both thiophene and thiazole moieties.Specifically,benzo[4,5]thieno[2,3-d]thiazole,being an exclusive S-containing fused heterocyclic ring system,has received attention from both synthetic and medicinal chemists.Accordingly,a number of useful synthetic methods have been developed in pursuit of the construction of this exclusive scaffold.These methods have their own merits in the synthesis of each particular type of benzo[4,5]thieno[2,3-d]thiazole,however,one obvious drawback of these methods is that all of the substituted benzo[4,5]thieno[2,3-d]thiazole products had to be derived from the preformed benzothiophenes skeleton in the starting material.And all the reported methods were restricted to the synthesis of methyl or amino substituted benzo[4,5]thieno[2,3-d]thiazole.Herein,a novel reaction of aryl substituted benzo[4,5]thieno[2,3-d]thiazole mediated by copper reagent is developed.The investigation was started by choosing2-（2-bromo-4,5-dimethoxyphenyl）acetonitrile and benzaldehyde as model substrates,elemental sulfur as sulfur source,and 1,10-phenanthroline as ligand.The optimal condition was discovered after a series of conditions screening.So the product6,7-dimethoxy-2-phenylbenzo[4,5]thieno[2,3-d]thiazole could be achieved in a high yield by using Cu Cl as oxidant in DMSO under base condition.The synthesis of2-arylbenzo[4,5]thieno[2,3-d]thiazole was performed by means of simple substrates via one-pot three-componnets reactions.To study the adaptability of the new method to synthesize the target heterocyclic compounds,a series of substituted substrates were prepared to test the generality.Experimental results show that twenty benzo[4,5]thieno[2,3-d]thiazole derivatives have been synthesized under optimal conditions.The structures of synthesised substrates and products have been well characterized by melting point,¹H NMR,¹³C NMR and high resolution mass spectrometry.All the 2-arylbenzo[4,5]thieno[2,3-d]thiazole compounds were found to possess striking fluorescent features due to their existing polycyclicπ-conjugated systems.According to the X-ray crystal structure of 2-phenylbenzo[4,5]thieno[2,3-d]thiazole seems to be basically planar and can serve as a novel fluorophore,since the rigidity andπ-conjugation are commonly recognized as positive structural factors in enhancing the fluorophore brightness because of the reduction of the energy consumption from rotation and vibration.All those compounds exhibited very strong blue fluorescence when excited at around 365 nm.In general,the alkoxy substitution on theα-phenyl ring led to red shifts of the maximum absorbance and improvements in the Stokes shift.Substitution with the electron-donating group and halide in theβ-phenyl ring at 4-position did not lead to the substantial change of the quantum yield.The mechanism was studied through several control experiments.First,a new unreported dibenzo[b,f]thieno10,11-dicarbonitrile was produced under standard reaction conditions without the involvement of aldehyde.Second,when benzo[b]thiophen-2-amine prepared by article as starting material reacted with benzaldehyde and S₈ under standard conditions,the title2-arylbenzo[4,5]thieno[2,3-d]thiazole could be achieved in 35%yield.These results might indicate that benzo[b]thiophen-2-amine serves as the crucial intermediate for this three-component reaction,but was impractical to be detected and isolated due to its high reactivity under the conditions.Third,when introducing 3 equiv of BHT or TEMPO to the reaction under standard conditions,the yield of desired product was not significantly decreased.On the basis of results from the literature and control experiments,a plausible mechanism is proposed for this newly discovered three-component one-pot reaction.In the presence of the copper catalyst,2-（2-bromophenyl）acetonitrile was converted to benzo[b]thiophen-2（3H）-imine.Further is the nucleophilic attack to the electrophilic S₈.Finally,the condensation of intermediate with aromatic aldehyde and oxidation by sulfur delivered the target compound.In this work,we have successfully designed and developed a novel method for the synthesis of a class of 2-arylbenzo[4,5]thieno[2,3-d]thiazoles.After screening a series of conditions the final one selected was heating to 120°C and alkaline conditions,cuprous chloride as the oxidant and 1,10-phenanthroline as the ligand converted the substrates to the products.The experimental results show that under the optimal reaction conditions 20 2-arylbenzo[4,5]thieno[2,3-d]thiazoles derivatives were successfully synthesized from cheap and readily available substrates.Note that all products have fluorescence characteristics,the UV and fluorescence analysis on90%of the compounds,and a mechanism about this three-component Cu Cl-mediated one-pot synthesis of 2-arylbenzo[4,5]thieno[2,3-d]thiazoles reaction proposed followed by the accuracy checking of the reaction mechanism through verification experiments.This work may represent the first three-component synthesis of 2-arylbenzo[4,5]thieno[2,3-d]thiazoles skeleton via the successive formation of the thiophene and thiazole rings.更多还原