【摘要】：α取代的四氫呋喃和二氫吡喃類骨架在具有生物活性的天然產(chǎn)物和合成藥物中普遍存在,如何有效地合成這類化合物是全世界有機(jī)化學(xué)工作者需要著力解決的問題。傳統(tǒng)的合成該類化合物的方法已經(jīng)有了很多報(bào)道,盡管這些方法反應(yīng)產(chǎn)率較好,但是通常需要多步反應(yīng)以及預(yù)先引入官能團(tuán)。因此,有機(jī)化學(xué)家們?nèi)栽谂ふ野l(fā)展簡(jiǎn)單直接高效的方法來(lái)合成該類化合物。近年來(lái)碳?xì)涔倌軋F(tuán)化反應(yīng)因?yàn)槠洳僮骱?jiǎn)單、原子利用率高、與綠色化學(xué)要求相一致而得到了飛速發(fā)展。許多國(guó)內(nèi)外課題組發(fā)展了各種氧化體系來(lái)實(shí)現(xiàn)醚的碳?xì)涔倌軋F(tuán)化反應(yīng),例如DDQ,TBHP,過硫酸鹽,T+BF4-等。但是目前這些方法仍然存在很大的局限性,首先是底物范圍狹窄,大部分局限于芐醚類化合物,而四氫呋喃和二氫吡喃的碳?xì)涔倌軋F(tuán)化報(bào)道較少。其次,氧化體系只能適用于某種特定的親核試劑,而且反應(yīng)條件劇烈,導(dǎo)致用于不對(duì)稱的底物時(shí)選擇性較差。因此,我們打算發(fā)展一種合適的氧化體系,具有溫和的反應(yīng)條件,能夠高效多樣的直接實(shí)現(xiàn)該類底物的碳?xì)涔倌軋F(tuán)化。通過查閱文獻(xiàn)我們發(fā)現(xiàn)三苯基碳正離子作為一種古老的氧化劑,可以氧化含氧化合物,并且目前沒有報(bào)道過用三苯基碳正離子介導(dǎo)實(shí)現(xiàn)醚類的氧化碳?xì)涔倌軋F(tuán)化與含碳親核試劑的偶聯(lián)。因此,本論文利用三苯基碳正離子作為氧化劑,來(lái)研究四氫呋喃和二氫吡喃的碳?xì)溲趸倌軋F(tuán)化反應(yīng)。具體工作如下:首先我們選擇簡(jiǎn)單易得的四氫呋喃為底物,苯乙炔的三氟硼酸鉀鹽為親核試劑,構(gòu)建模型反應(yīng)。通過對(duì)氧化體系的篩選,我們采用Ph3CCl作為三苯基碳正離子源,GaCl3為路易斯酸,原位產(chǎn)生三苯基碳正離子參與反應(yīng)。隨后,我們又對(duì)反應(yīng)的溶劑和溫度等條件進(jìn)行篩選,獲得最優(yōu)的反應(yīng)條件。接著我們對(duì)親核試劑范圍進(jìn)行了研究,發(fā)現(xiàn)炔基、烯基以及芳基三氟硼酸鉀鹽都能夠得到良好收率的產(chǎn)物。我們進(jìn)一步研究發(fā)現(xiàn),親核試劑用苯乙炔,通過一鍋兩步法,該氧化體系也可以用于實(shí)現(xiàn)四氫呋喃的CDC反應(yīng)。對(duì)于二氫吡喃底物,用于該條件同樣有可觀的收率。對(duì)于非對(duì)稱的底物,我們研究了反應(yīng)的選擇性。通過實(shí)驗(yàn)發(fā)現(xiàn),針對(duì)不同的底物可以調(diào)控三苯基碳正離子的活性,使得該氧化體系對(duì)這類底物具有良好的區(qū)域選擇性和立體選擇性,并且反應(yīng)能夠獲得良好的產(chǎn)率。最后,我們做了分子間和分子內(nèi)的KIE實(shí)驗(yàn),并提出了可能的反應(yīng)機(jī)理。我們成功地實(shí)現(xiàn)了三苯基碳正離子作為氧化劑介導(dǎo)四氫呋喃和二氫吡喃的碳?xì)涔倌軋F(tuán)化。該方法條件溫和,具有不同官能團(tuán)的底物能夠適用,對(duì)于非對(duì)稱的底物能獲得優(yōu)秀的區(qū)域選擇性和立體選擇性。該方法高效實(shí)用,不僅提供了直接有效的途徑來(lái)合成具有生物活性的復(fù)雜分子,而且通過核心結(jié)構(gòu)衍生的策略可以構(gòu)建化合物庫(kù),從而為發(fā)現(xiàn)先導(dǎo)化合物提供了可能。
[Abstract]:偽 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.
【學(xué)位授予單位】：山東大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類號(hào)】：R914
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本文編號(hào)：2390415