三苯基碳正离子介导四氢呋喃和二氢吡喃的碳氢官能团化研究

发布时间：2018-12-24 08:44

【摘要】：α取代的四氢呋喃和二氢吡喃类骨架在具有生物活性的天然产物和合成药物中普遍存在,如何有效地合成这类化合物是全世界有机化学工作者需要着力解决的问题。传统的合成该类化合物的方法已经有了很多报道,尽管这些方法反应产率较好,但是通常需要多步反应以及预先引入官能团。因此,有机化学家们仍在努力寻找发展简单直接高效的方法来合成该类化合物。近年来碳氢官能团化反应因为其操作简单、原子利用率高、与绿色化学要求相一致而得到了飞速发展。许多国内外课题组发展了各种氧化体系来实现醚的碳氢官能团化反应,例如DDQ,TBHP,过硫酸盐,T+BF4-等。但是目前这些方法仍然存在很大的局限性,首先是底物范围狭窄,大部分局限于苄醚类化合物,而四氢呋喃和二氢吡喃的碳氢官能团化报道较少。其次,氧化体系只能适用于某种特定的亲核试剂,而且反应条件剧烈,导致用于不对称的底物时选择性较差。因此,我们打算发展一种合适的氧化体系,具有温和的反应条件,能够高效多样的直接实现该类底物的碳氢官能团化。通过查阅文献我们发现三苯基碳正离子作为一种古老的氧化剂,可以氧化含氧化合物,并且目前没有报道过用三苯基碳正离子介导实现醚类的氧化碳氢官能团化与含碳亲核试剂的偶联。因此,本论文利用三苯基碳正离子作为氧化剂,来研究四氢呋喃和二氢吡喃的碳氢氧化官能团化反应。具体工作如下:首先我们选择简单易得的四氢呋喃为底物,苯乙炔的三氟硼酸钾盐为亲核试剂,构建模型反应。通过对氧化体系的筛选,我们采用Ph3CCl作为三苯基碳正离子源,GaCl3为路易斯酸,原位产生三苯基碳正离子参与反应。随后,我们又对反应的溶剂和温度等条件进行筛选,获得最优的反应条件。接着我们对亲核试剂范围进行了研究,发现炔基、烯基以及芳基三氟硼酸钾盐都能够得到良好收率的产物。我们进一步研究发现,亲核试剂用苯乙炔,通过一锅两步法,该氧化体系也可以用于实现四氢呋喃的CDC反应。对于二氢吡喃底物,用于该条件同样有可观的收率。对于非对称的底物,我们研究了反应的选择性。通过实验发现,针对不同的底物可以调控三苯基碳正离子的活性,使得该氧化体系对这类底物具有良好的区域选择性和立体选择性,并且反应能够获得良好的产率。最后,我们做了分子间和分子内的KIE实验,并提出了可能的反应机理。我们成功地实现了三苯基碳正离子作为氧化剂介导四氢呋喃和二氢吡喃的碳氢官能团化。该方法条件温和,具有不同官能团的底物能够适用,对于非对称的底物能获得优秀的区域选择性和立体选择性。该方法高效实用,不仅提供了直接有效的途径来合成具有生物活性的复杂分子,而且通过核心结构衍生的策略可以构建化合物库,从而为发现先导化合物提供了可能。
[Abstract]:伪 substituted tetrahydrofuran and dihydropyrans are widely used in natural products and synthetic drugs with biological activity. How to synthesize these compounds effectively is a problem that the organic chemists all over the world need to solve. There have been many reports on the traditional methods for the synthesis of this kind of compounds. Although the yields of these methods are good, they usually require multi-step reactions and the introduction of functional groups in advance. Therefore, organic chemists are still trying to develop simple, direct and efficient methods for the synthesis of these compounds. In recent years, hydrocarbon functionalization has been developed rapidly because of its simple operation, high atomic utilization rate and consistent with the requirements of green chemistry. Many domestic and foreign research groups have developed various oxidation systems to realize the hydrocarbon functional reactions of ethers, such as DDQ,TBHP, persulfate, T BF4- and so on. However, there are still many limitations in these methods. Firstly, the substrate range is narrow, most of them are confined to benzyl ether compounds, but there are few reports of hydrocarbon functionalization of tetrahydrofuran and dihydropyran. Secondly, the oxidation system can only be applied to a particular nucleophilic reagent, and the reaction conditions are severe, resulting in poor selectivity for asymmetric substrates. Therefore, we intend to develop a suitable oxidation system with mild reaction conditions, which can directly realize the hydrocarbon functional groups of this kind of substrates. By looking up the literature, we found that triphenyl carbon cations, as an ancient oxidant, can oxidize oxygenated compounds. At present, it has not been reported that triphenyl carbon cationic ions are used to mediate the coupling of oxidative hydrocarbon functionalization of ethers with carbon-containing nucleophilic reagents. In this paper, triphenyl carbon cations are used as oxidants to study the functionalization of tetrahydrofuran (THF) and dihydropyran (DHP). The main work is as follows: firstly, we choose tetrahydrofuran as the substrate and potassium trifluoroborate of phenylacetylene as nucleophilic reagent to construct the model reaction. Through the screening of oxidation system, we used Ph3CCl as the source of triphenyl carbon positive ions, GaCl3 as Lewis acid, in situ to produce triphenyl carbon ions to participate in the reaction. Then we screened the solvent and temperature of the reaction to obtain the optimal reaction conditions. Then we studied the range of nucleophilic reagents and found that alkynyl alkenyl and potassium salt aryl trifluoroborate could obtain good yield. We further found that the oxidation system can also be used to realize the CDC reaction of tetrahydrofuran by one-pot two-step method using phenylacetylene as nucleophilic reagent. For dihydropyran substrates, the yield is also considerable when used in this condition. For asymmetric substrates, we have studied the selectivity of the reaction. It was found that the activity of triphenyl carbon cations could be regulated by different substrates, which made the oxidation system have good regioselectivity and stereoselectivity to these substrates, and the reaction could obtain good yield. Finally, we have done intermolecular and intramolecular KIE experiments, and proposed a possible reaction mechanism. We have successfully realized the hydrocarbon functionalization of tetrahydrofuran and dihydropyran mediated by triphenyl carbon cations as oxidants. The conditions of this method are mild, the substrates with different functional groups can be applied, and excellent regioselectivity and stereoselectivity can be obtained for asymmetric substrates. This method is efficient and practical. It not only provides a direct and effective way to synthesize complex molecules with biological activity, but also can be constructed by the strategy of core structure derivation, which provides the possibility for the discovery of leading compounds.
【学位授予单位】：山东大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R914
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本文编号：2390415