喹啉2位的烷烃化反应及β-羟基砜类化合物合成的研究

发布时间：2018-06-19 11:00

本文选题：喹啉氮氧 + H-亚磷酸酯　；参考：《郑州大学》2017年硕士论文

【摘要】：喹啉及其衍生物是一类非常重要的有机化合物,具有抗菌、消炎、抗高血压、抗过敏、抗抑郁、抗肿瘤、抗癌及抗HIV等多种生物及药物活性,在有机化学、天然产物及药物化学等领域具有非常重要的应用。然而,喹啉类化合物很容易在人体内被氧化形成2-羟基衍生物,从而大大降低甚至失去了它的药物活性及生物活性,因此常常通过对喹啉的2位进行修饰,从而阻止这样一个氧化过程的发生。以往人们主要通过在喹啉的2位构建碳杂键的方式对其进行修饰,而通过在2位构建C-C键修饰喹啉的方法数量有限,且主要集中于喹啉2位芳基化的改造,而喹啉2位烷基化烷烃化的改造方法却十分有限。本文提出了一种利用原子经济性极高的交叉脱氢偶联反应实现喹啉2位烷基化的方案,具有绿色、廉价、实用等优势。即:使用一锅煮的方法在常温常压敞口条件下,将喹啉氮氧化物、活泼亚甲基试剂、H-亚磷酸二乙酯以及四氯化碳和碳酸钾置于DMF溶液中,搅拌三小时,萃取分离即可得到目标化合物。该方法具有原料廉价易得、反应快速、条件温和、区域选择性高等优点,为制备2-烷基喹啉衍生物提供了一种方便的途径。β-羟基砜类化合物是一种常见的有机合成中间体,广泛应用于生物活性分子的不对称合成中。除此之外,β-羟基砜类化合物还具有抗癌、抗真菌等药物活性。传统合成β-羟基砜类化合物的方法主要有:(i)亚磺酸钠盐与环氧衍生物的亲核反应。(ii)β-羰基砜的还原反应(iii)α,β-不饱和砜的羟基化反应。(vi)烯烃与亚磺酸(盐)、磺酰衍生物的加成氧化反应等。本文首次利以叔丁基亚磺酰胺为砜源和苯乙烯类化合物在40 o C条件下反应,一锅煮一步合成β-羟基砜类化合物,为β-羟基砜类化合物的合成提供了一种新思路。与以往方法相比,本方法具有反应物便宜易得,反应条件温和步骤简单的优势。本论文的主要研究内容如下:(一)喹啉2位烷基化新方法研究:1.对喹啉及其衍生物的性质、合成方法及实际应用进行了总结。2.以喹啉氮氧和乙酰乙酸乙酯为底物,对反应时间、反应温度、原料的比例、磷试剂的种类和用量、碱的种类和用量、四氯化碳的用量、溶剂的种类及用量进行了筛选。优化的条件为:喹啉氮氧0.4 mmol,乙酰乙酸乙酯0.4 mmol,H-亚磷酸二乙酯0.8 mmol,碳酸钾0.8 mmol,四氯化碳0.5 m L及1.0 m L的DMF,在40 o C条件下反应3 h。3.在优化的反应条件下,以含有不同取代基的喹啉化合物和含有不同吸电子基的活泼亚甲基化合物为底物,考察了反应的适用范围。共合成23个目标化合物,其结构均通过了~1H,~(13)C NMR和HR MS的表征。4.通过自由基阻断等手段对反应的机理进行了深入探究。(二)β-羟基砜合成新方法研究:1.以苯乙烯类化合物和叔丁基亚磺酰胺为底物,对反应的时间、温度、底物比例、催化剂、磷试剂、酸以及溶剂的种类和用量进行了筛选优化。结果为:苯乙烯0.5 mmol,叔丁基亚磺酰胺0.5 mmol,五水硫酸铜20 mmol%,亚磷酸0.75 mmol,三氟乙酸1.0 mmol,无溶剂40 o C条件下搅拌反应12 h。2.在最优条件下,考察了反应对不同苯乙烯类化合物的适用性,合成了一系列β-羟基砜类化合物,目标产物均经过~1H,~(13)C NMR和HR MS的表征。3.对反应机理进行了探究。
[Abstract]:Quinoline and its derivatives are very important organic compounds. They have many biological and drug activities, such as antibacterial, anti-inflammatory, anti hypertension, antiallergic, antidepressant, antitumor, anticancer and anti HIV, and have very important applications in organic chemistry, natural products and drug chemistry. However, quinoline compounds are very easy to be in human body. The oxidation of 2- hydroxyl derivatives, thus greatly reducing or even losing its drug activity and biological activity, often modifies the 2 sites of quinoline to prevent such an oxidation process. In the past, it was mainly modified by 2 bits of quinoline to construct carbon heterozygous bonds, and by the construction of 2 bits of C-C. The method of modifying quinoline by key is limited and mainly concentrates on the transformation of quinoline 2 bit arylation, while the modification methods of alkylation of quinoline 2 bit alkylalkylation are very limited. In this paper, a scheme to realize 2 bit alkylation of quinoline by cross dehydrogenation coupling reaction with high atomic economy has been proposed, which has the advantages of green, cheap and practical. In one pot, the target compound can be obtained by mixing quinoline nitrogen oxide, active methylene reagent, two ethyl H- phosphite, carbon tetrachloride and potassium carbonate in DMF solution at normal temperature and atmospheric pressure. The target compound can be obtained by extraction and separation for three hours. The method has the advantages of easy to obtain low price, rapid reaction, mild conditions and high regional selectivity. It provides a convenient way for the preparation of 2- alkyl quinoline derivatives. The beta hydroxyl sulfone is a common organic synthesis intermediate and is widely used in the asymmetric synthesis of bioactive molecules. In addition, the beta hydroxy sulfone compounds also have antitumor and antifungal activity. The traditional synthesis of beta hydroxyl sulfone is a kind of traditional synthesis of beta hydroxyl sulfone. The main methods are: (I) nucleophilic reaction of sodium sulfonic acid sodium salt and epoxy derivatives. (II) reduction reaction of beta carbonyl sulfone (III) alpha, hydroxylation of beta unsaturated sulfone. (VI) olefin and sulfonic acid (salt), sulfonyl derivative oxidation reaction, etc. This article first used tert butyl sulfonamide as sulfone source and styrene compound in 40 The synthesis of beta hydroxy sulfone compounds in one pot one pot under the condition of O C, provides a new idea for the synthesis of beta hydroxyl sulfone compounds. Compared with the previous methods, this method has the advantages of cheap and easy reactant and simple reaction conditions. The main contents of this paper are as follows: (I) new methods of quinoline 2 bit alkylation 1. the properties, synthesis methods and practical applications of quinoline and its derivatives were summarized. The reaction time, reaction temperature, proportion of raw materials, types and dosage of phosphorus reagents, types and dosage of alkali, the amount of carbon tetrachloride, the type and dosage of solvent were selected and optimized by.2., which was used as the substrate of quinoline nitrogen and oxygen and ethyl acetoacetate as substrates. Conditions are: quinoline nitrogen oxygen 0.4 mmol, ethyl acetoacetate 0.4 mmol, H- phosphoric acid two ethyl 0.8 mmol, potassium carbonate 0.8 mmol, carbon tetrachloride 0.5 m L and 1 m L DMF, 3 under 40 o C conditions, under the optimized reaction conditions, with different substituents of quinoline compounds and active methylene compounds containing different absorbing electronic groups. The application scope of the reaction was investigated. A total of 23 target compounds were synthesized and their structures were investigated through ~1H, ~ (13) C NMR and HR MS by.4. through free radical blockage. (two) a new method for the synthesis of beta hydroxyl sulfone: 1. with styrene and tert butyl sulfonamide as the substrate. The optimum time, temperature, substrate ratio, catalyst, reagent, acid and solvent were selected and optimized. The results were as follows: styrene 0.5 mmol, tert butyl sulfonamide 0.5 mmol, five water copper sulfate 20 mmol%, phosphoric acid 0.75 mmol, three FLUOROACETIC acid 1 mmol, and solvent 40 o C under the optimum conditions of 12 h.2. under optimum conditions A series of beta hydroxyl sulfone compounds were synthesized by the reaction to different styrene compounds. The target products were all investigated by ~1H, ~ (13) C NMR and HR MS, and the reaction mechanism was investigated.
【学位授予单位】：郑州大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R914

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