具有“面具效应”的硫化试剂研究及应用
发布时间：2018-11-13 19:33
【摘要】：碳-杂原子键的形成在有机合成中是一类重要的化学反应,也吸引着越来越多的有机合成工作者投入其中。在各类碳-杂原子键中,碳-硫键的构建具有重要意义。因为碳-硫键广泛存在于药物分子、农药产品、食品香料、材料结构中。传统方法构建碳-硫键是通过具有亲核性质的硫和具有亲电性的碳反应。但是,硫醇、苯硫酚等参与的硫化过程中可能会遇到如下挑战:(1)硫原子上孤对电子对金属的毒化作用;(2)极易氧化成过硫;(3)单一的亲核性。除此之外,这类有机硫化物的使用,常常面临着制备困难、刺激恶臭、有毒有害等生产窘境。我博士论文的研究《具有"面具效应"的硫化试剂研究及应用》,侧重探索研究实用、绿色、安全的硫化试剂来解决生命分子、药物、材料、农药等硫化问题。第1部分硫代硫酸钠Na_2S_2O_3'5H_2O作为硫化试剂该研究实现了钯催化的条件下,Na_2S_2O_3'5H_2O作为硫化试剂构建双碳-硫键。1,4-苯并噻嗪衍生物是一类重要的结构骨架,通过这一方法可以高效地合成。对比试验和DFT计算阐述了该转化可能的机制。进一步,非对称硫醚化合物可以通过芳基卤化物、烷基卤化物及Na_2S_2O_3'5H_2O以交叉偶联的形式得到。该体系兼容各类杂环,包括吡啶、呋喃、噻吩、香豆酮、苯并恶唑、苯并噻吩、苯并噻唑、吡嗪等。此外,活性分子通过该策略能够实现后期硫化。第2部分氧化交叉耦合反应该研究报道了铜催化下的硼酸与具有"面具效应"的芳基硫代硫酸钠ArS_2O_3Na形成硫醚化合物的过程。其中,作为面具的SO_3~-和CO_2气体氛围,有效地避免了过硫化物的产生。底物兼容性广泛展现了该方法的实用性。应用此硫化方法,可以实现药物的后期修饰和非对称并二噻吩类材料分子的合成。我们对有机硅试剂与芳基/烷基硫代硫酸盐选择性氧化偶联做了进一步研究。在配体的调控下,可以选择性地获得Hiyama形式的产物或者一碳元插入的产物。实验发现,在无配体条件下,该反应可以避免过硫的产生,高效得到硫醚产物;CO氛围,在使用双齿配体的条件下,可以避免硫酯生成后的逆氧化加成,原位核磁实验对该过程进行了跟踪。第3部分新颖、安全、绿色的甲基硫化过程甲基硫、甲基亚砜、甲基砜广泛存在于生命分子、天然产物、药物农药中。甲基硫基团的引入可以改变生命分子的电子效应,进而改变生命体内药物热力学和药物动力学的作用过程。然而,甲基硫化过程受限于没有合适甲基硫源或是甲基源。该研究采用无机盐硫代乙酸钾KSAc与碳酸二甲酯DMC的组合,形成甲基硫的替代物与芳基氯化物反应来实现甲基硫化过程。引人注目的是,该方法可以对未保护的核苷进行甲基硫化,含氯药用的硫化衍生化,多杂原子农药的一步合成,反应高效放大。
[Abstract]:The formation of carbon-heteroatom bond is an important chemical reaction in organic synthesis and attracts more and more organic synthesis workers. The construction of carbon-sulfur bond is of great significance in all kinds of carbon-hetero-atomic bonds. Because carbon-sulfur bonds are widely found in drug molecules, pesticide products, food spices, materials and structures. The traditional method of constructing carbon-sulfur bond is through the reaction of nucleophilic sulfur and electrophilic carbon. However, the following challenges may be encountered in the vulcanization process involving mercaptan and phenythiophenol: (1) the toxicity of electrons on sulfur atoms to metals; (2) the oxidation easily to persulphur; and (3) the single nucleophilic property. In addition, the use of these organic sulfides is often faced with production difficulties, such as production difficulties, irritation of odor, toxic and harmful. The research of my doctoral thesis, "the study and Application of Sulfide Reagent with" Mask effect ", focuses on exploring practical, green and safe sulphide reagents to solve the vulcanization problems of life molecules, drugs, materials, pesticides and so on. Part 1: sodium thiosulfate (Na_2S_2O_3'5H_2O) was used as sulphide reagent. Na_2S_2O_3'5H_2O is used as a sulfidation reagent to form dicarbon-sulfur bonds. 1) 4-benzothiazide derivatives are a kind of important structural skeleton, which can be synthesized efficiently by this method. The possible mechanism of this transformation is illustrated by comparative experiments and DFT calculations. Furthermore, asymmetric sulfide compounds can be obtained by cross-coupling of aryl halides, alkyl halides and Na_2S_2O_3'5H_2O. The system is compatible with various heterocyclic compounds, including pyridine, furan, thiophene, coumarone, benzoxazole, benzothiophene, benzothiazole, pyrazine, etc. In addition, the active molecules can achieve later vulcanization through this strategy. Part 2 oxidative cross-coupling reaction the process of the formation of thioether compounds from boric acid catalyzed by copper and aryl sodium thiosulfate (ArS_2O_3Na) with "mask effect" was reported. Among them, SO_3~- and CO_2 gas atmosphere, as masks, effectively avoid the generation of over sulfides. Substrate compatibility extensively demonstrates the practicability of the method. By using this vulcanization method, the late modification of drugs and the synthesis of asymmetric dithiophene materials can be realized. The selective oxidative coupling of organosilicon reagents with aryl / alkyl thiosulfate has been further studied. Under the control of ligands, the products of Hiyama form or one carbon element insertion can be obtained selectively. It was found that the reaction could avoid the formation of persulphur and obtain the sulfides efficiently under the condition of no ligand. In CO atmosphere, the inverse oxidation addition after the formation of thioesters can be avoided under the condition of using didentate ligands, and the process has been tracked by in situ NMR experiments. The third part is a novel, safe, green methyl sulfoxide, methyl sulfoxide and methyl sulfone, which are widely found in life molecules, natural products and pharmaceutical pesticides. The introduction of methyl thiocarbamate can change the electronic effect of living molecules and then change the pharmacodynamics and pharmacokinetic process in vivo. However, the methyl sulfidation process is limited by the absence of suitable methyl sulfur sources or methyl sources. In this study, the reaction of methyl sulfide substitute with aryl chloride was carried out by the combination of inorganic salt potassium thioacetate KSAc and dimethyl carbonate DMC. It is noted that this method can be used for methyl sulfidation of unprotected nucleosides, derivatization of chlorinated medicinal products, one-step synthesis of polyheteratomic pesticides, and high efficiency amplification of the reaction.
【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
，
本文编号：2330221
[Abstract]:The formation of carbon-heteroatom bond is an important chemical reaction in organic synthesis and attracts more and more organic synthesis workers. The construction of carbon-sulfur bond is of great significance in all kinds of carbon-hetero-atomic bonds. Because carbon-sulfur bonds are widely found in drug molecules, pesticide products, food spices, materials and structures. The traditional method of constructing carbon-sulfur bond is through the reaction of nucleophilic sulfur and electrophilic carbon. However, the following challenges may be encountered in the vulcanization process involving mercaptan and phenythiophenol: (1) the toxicity of electrons on sulfur atoms to metals; (2) the oxidation easily to persulphur; and (3) the single nucleophilic property. In addition, the use of these organic sulfides is often faced with production difficulties, such as production difficulties, irritation of odor, toxic and harmful. The research of my doctoral thesis, "the study and Application of Sulfide Reagent with" Mask effect ", focuses on exploring practical, green and safe sulphide reagents to solve the vulcanization problems of life molecules, drugs, materials, pesticides and so on. Part 1: sodium thiosulfate (Na_2S_2O_3'5H_2O) was used as sulphide reagent. Na_2S_2O_3'5H_2O is used as a sulfidation reagent to form dicarbon-sulfur bonds. 1) 4-benzothiazide derivatives are a kind of important structural skeleton, which can be synthesized efficiently by this method. The possible mechanism of this transformation is illustrated by comparative experiments and DFT calculations. Furthermore, asymmetric sulfide compounds can be obtained by cross-coupling of aryl halides, alkyl halides and Na_2S_2O_3'5H_2O. The system is compatible with various heterocyclic compounds, including pyridine, furan, thiophene, coumarone, benzoxazole, benzothiophene, benzothiazole, pyrazine, etc. In addition, the active molecules can achieve later vulcanization through this strategy. Part 2 oxidative cross-coupling reaction the process of the formation of thioether compounds from boric acid catalyzed by copper and aryl sodium thiosulfate (ArS_2O_3Na) with "mask effect" was reported. Among them, SO_3~- and CO_2 gas atmosphere, as masks, effectively avoid the generation of over sulfides. Substrate compatibility extensively demonstrates the practicability of the method. By using this vulcanization method, the late modification of drugs and the synthesis of asymmetric dithiophene materials can be realized. The selective oxidative coupling of organosilicon reagents with aryl / alkyl thiosulfate has been further studied. Under the control of ligands, the products of Hiyama form or one carbon element insertion can be obtained selectively. It was found that the reaction could avoid the formation of persulphur and obtain the sulfides efficiently under the condition of no ligand. In CO atmosphere, the inverse oxidation addition after the formation of thioesters can be avoided under the condition of using didentate ligands, and the process has been tracked by in situ NMR experiments. The third part is a novel, safe, green methyl sulfoxide, methyl sulfoxide and methyl sulfone, which are widely found in life molecules, natural products and pharmaceutical pesticides. The introduction of methyl thiocarbamate can change the electronic effect of living molecules and then change the pharmacodynamics and pharmacokinetic process in vivo. However, the methyl sulfidation process is limited by the absence of suitable methyl sulfur sources or methyl sources. In this study, the reaction of methyl sulfide substitute with aryl chloride was carried out by the combination of inorganic salt potassium thioacetate KSAc and dimethyl carbonate DMC. It is noted that this method can be used for methyl sulfidation of unprotected nucleosides, derivatization of chlorinated medicinal products, one-step synthesis of polyheteratomic pesticides, and high efficiency amplification of the reaction.
【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
，
本文编号：2330221
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