新型过硫化试剂的设计及其应用研究

发布时间：2018-01-01 15:19

  本文关键词：新型过硫化试剂的设计及其应用研究　出处：《华东师范大学》2017年博士论文　论文类型：学位论文

  更多相关文章： 非对称过硫化物 过硫化反应 过硫试剂 归中反应 药物后期修饰

【摘要】：过硫化合物是一类非常重要的化合物,它广泛存在于自然界中,并且在化学生物学、药物化学、食品化学等学科具有重要应用。因此,过硫化物的合成受到有机化学家们的广泛关注。在对称过硫化物合成方法中,反应较为简单,最主要是通过硫醇(酚)的氧化反应构建。而非对称过硫化物的合成相对而言存在一定的难度,高效构建非对称过硫的方法较少,主要原因有几点。首先,使用的原料大部分都是硫醇(酚)或其衍生物,大部分硫醇(酚)具有强烈的恶臭味,并且毒性大、污染大,使用不方便。其次,反应类型较少并且各自存在一些不足,氧化反应类型制备非对称过硫化物的效率大部分不高,主要是因为氧化的选择性不高及氧化过程生成的产物能被继续氧化;对称过硫的交换反应类型中需使用贵金属作为催化剂;亲核取代反应类型中,需将硫醇(酚)进行预官能团化,步骤经济性降低,并且反应过程中反应条件较苛刻如低温、强碱、无水等条件,反应实用性降低。此外,一些反应中需要使用当量的预先制备的金属硫化合物作为过硫化试剂,不利用大规模应用。因此,发展高效绿色应用性强的过硫化试剂及反应迫在眉睫。博士论文研究期间,我主要工作集中于设计和发展过硫化试剂,并将其运用于非对称过硫化物的合成。具体如下:第一部分:无机硫盐参与的归中反应构建非对称过硫化合物的反应研究在无过渡金属催化和未额外添加氧化还原试剂的空气条件下,利用低化合价的硫代硫酸钠盐与高化合价的亚磺酸钠盐作为无机硫源,实现了归中反应构建非对称过硫化反应。该反应体系官能团兼容性良好,并且能够高效的实现过硫甲基化;此外该方法可以运用于樟脑磺酸和雌酚酮衍生物的后期过硫化。在后期的反应机理研究中,进一步证明了该归中反应过程。第二部分:亲核过硫化试剂的设计及其应用研究通过设计亲核过硫化试剂和发展简单快捷实用的方法建立过硫试剂库,实现了高效的一步同时引入双硫原子的非对称过硫化策略。该非对称过硫化策略是通过芳基硼酸或硅试剂与亲核过硫试剂发生氧化偶联反应实现的。在反应过程中,使用廉价的硫酸铜作为催化试剂,通过控制过硫试剂的醇解速率,完成了选择性碳硫键断裂这一难题,从而实现温和条件下的非对称过硫化反应。该反应体系的底物普适性优秀,并且实现了氨基酸、糖等生命体重要结构单元及药物的后期修饰。通过面具效应和碱效应的考察,确定了乙酰基为优秀的面具基团,并且合适的pH条件是实现非对称过硫化的关键,即醇解速率要与转金属交换速率相匹配。第三部分:亲电过硫化试剂的设计及其应用研究通过极性翻转的策略,设计合成了一系列亲电过硫试剂,并且实现了克级规模制备反应,在此反应过程中催化剂的用量降至千分之一摩尔。该过硫试剂的反应性良好,通过适当催化体系的选择,可以实现多种亲核试剂的过硫衍生化,如吲哚、富电子芳烃、双羰基化物及氨基衍生物。同时也可以将其运用于多硫化物的合成。以上反应体系条件柔和,无需使用过渡金属催化剂和碱,高效的构建了多种过硫及多硫化合物。
[Abstract]:Sulfur compounds are an important class of compounds, it widely exists in the nature, and medicinal chemistry in chemistry, biology, chemistry and other disciplines of food has important application. Therefore, the synthesis of persulfide attracted wide attention of organic chemists. In a symmetric sulfide synthesis method, the reaction is simple, the most important is through the construction of mercaptan (phenol) oxidation reaction. But the asymmetric synthesis of sulfide had relatively difficulty, less efficient construction method for asymmetric sulfur, mainly there are several reasons. First, the use of raw materials are mostly mercaptan (phenol) or its derivatives, most thiols (phenol) with odor strong smell, and high toxicity, high pollution, inconvenient use. Secondly, less reaction types and each has some deficiencies, the efficiency of oxidation type preparation of asymmetric persulfides most is not high, mainly Because the products of the oxidation selectivity is not high and the oxidation process can be generated to oxidation; axisymmetric use noble metals as catalyst type sulfur exchange reaction; nucleophilic substitution reaction type, the thiol (phenol) for group officer, economic steps decreased, and reaction conditions harsh such as low temperature, alkali, water and other conditions, practical reaction decreased. In addition, need to use the equivalent of pre made metal sulfur compounds were used as vulcanization reagents in the reaction, no use of large-scale applications. Therefore, the development of efficient green practical vulcanization reagents and the reaction is imminent. Doctoral dissertation of the study period, I the main work focuses on the design and development of vulcanization reagents, and applied to the asymmetric synthesis of persulfide. As follows: the first part: the reaction of inorganic sulfur salt in return to the construction of asymmetric sulfur Study on non compound reaction catalyzed by transition metal and without additional redox reagents under the condition of air, the use of low valence thiosulfate sodium and high valence sulfinic acid sodium salt as the inorganic sulfur source, can realize the construction of asymmetric reaction in the vulcanization reaction. The reaction system of functional group compatibility, and can efficiently realize sulfur methylation; late in addition the method could be used in camphorsulfonic acid and estrone derivatives overcure. In study of reaction mechanism of late, further proved that the reaction of the return process. The second part: the design and application of nucleophilic reagent vulcanization by nucleophilic vulcanization reagents and design development of simple and practical the method of establishing sulfur library, realizes asymmetric overcure efficient strategy step while introducing the double sulfur atom. The asymmetric overcure strategy is through Aryl boric acid or silicon reagents with nucleophilic sulfur reagents to achieve oxidative coupling reaction. In the reaction process, using copper sulfate as catalyst by cheap reagents, rate control of sulfur alcoholysis reagent, the selectivity of carbon sulfur bond breaking this problem, so as to realize the asymmetric vulcanization reaction under mild conditions the reaction substrate universality is excellent, and the realization of the amino acid, sugar and other life weight should be later modified structural units and drugs. Through the investigation of the mask effect and the effect of alkali, the acetyl groups to mask excellent, and the appropriate pH condition is the key to realize asymmetric vulcanization, i.e. alcoholysis rate to match to the metal exchange rate. The third part: the design and application of electrophilic reagents of sulfide by the polarity reversal strategy, a series of electrophilic sulfur reagents were designed and synthesized, and the realization of the Gram scale preparation of catalyst in this reaction, the reaction process amount to 1/1000 Moore. The reaction of sulfur reagent, through proper selection of catalyst, can achieve a variety of nucleophiles with sulfur derivatization, such as indole, electron rich aromatic hydrocarbons, double carbonylation and amino derivatives can also. Used in the synthesis of sulfide. The above reaction condition is gentle, without the use of transition metal catalyst and alkali, efficiently constructed many kinds of sulfur and polysulfide.

【学位授予单位】：华东师范大学
【学位级别】：博士
【学位授予年份】：2017
【分类号】：TQ421.12
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本文编号：1365055