具有“面具效應”的硫化試劑研究及應用
發(fā)布時間：2018-11-13 19:33
【摘要】：碳-雜原子鍵的形成在有機合成中是一類重要的化學反應,也吸引著越來越多的有機合成工作者投入其中。在各類碳-雜原子鍵中,碳-硫鍵的構建具有重要意義。因為碳-硫鍵廣泛存在于藥物分子、農(nóng)藥產(chǎn)品、食品香料、材料結構中。傳統(tǒng)方法構建碳-硫鍵是通過具有親核性質的硫和具有親電性的碳反應。但是,硫醇、苯硫酚等參與的硫化過程中可能會遇到如下挑戰(zhàn):(1)硫原子上孤對電子對金屬的毒化作用;(2)極易氧化成過硫;(3)單一的親核性。除此之外,這類有機硫化物的使用,常常面臨著制備困難、刺激惡臭、有毒有害等生產(chǎn)窘境。我博士論文的研究《具有"面具效應"的硫化試劑研究及應用》,側重探索研究實用、綠色、安全的硫化試劑來解決生命分子、藥物、材料、農(nóng)藥等硫化問題。第1部分硫代硫酸鈉Na_2S_2O_3'5H_2O作為硫化試劑該研究實現(xiàn)了鈀催化的條件下,Na_2S_2O_3'5H_2O作為硫化試劑構建雙碳-硫鍵。1,4-苯并噻嗪衍生物是一類重要的結構骨架,通過這一方法可以高效地合成。對比試驗和DFT計算闡述了該轉化可能的機制。進一步,非對稱硫醚化合物可以通過芳基鹵化物、烷基鹵化物及Na_2S_2O_3'5H_2O以交叉偶聯(lián)的形式得到。該體系兼容各類雜環(huán),包括吡啶、呋喃、噻吩、香豆酮、苯并惡唑、苯并噻吩、苯并噻唑、吡嗪等。此外,活性分子通過該策略能夠實現(xiàn)后期硫化。第2部分氧化交叉耦合反應該研究報道了銅催化下的硼酸與具有"面具效應"的芳基硫代硫酸鈉ArS_2O_3Na形成硫醚化合物的過程。其中,作為面具的SO_3~-和CO_2氣體氛圍,有效地避免了過硫化物的產(chǎn)生。底物兼容性廣泛展現(xiàn)了該方法的實用性。應用此硫化方法,可以實現(xiàn)藥物的后期修飾和非對稱并二噻吩類材料分子的合成。我們對有機硅試劑與芳基/烷基硫代硫酸鹽選擇性氧化偶聯(lián)做了進一步研究。在配體的調控下,可以選擇性地獲得Hiyama形式的產(chǎn)物或者一碳元插入的產(chǎn)物。實驗發(fā)現(xiàn),在無配體條件下,該反應可以避免過硫的產(chǎn)生,高效得到硫醚產(chǎn)物;CO氛圍,在使用雙齒配體的條件下,可以避免硫酯生成后的逆氧化加成,原位核磁實驗對該過程進行了跟蹤。第3部分新穎、安全、綠色的甲基硫化過程甲基硫、甲基亞砜、甲基砜廣泛存在于生命分子、天然產(chǎn)物、藥物農(nóng)藥中。甲基硫基團的引入可以改變生命分子的電子效應,進而改變生命體內(nèi)藥物熱力學和藥物動力學的作用過程。然而,甲基硫化過程受限于沒有合適甲基硫源或是甲基源。該研究采用無機鹽硫代乙酸鉀KSAc與碳酸二甲酯DMC的組合,形成甲基硫的替代物與芳基氯化物反應來實現(xiàn)甲基硫化過程。引人注目的是,該方法可以對未保護的核苷進行甲基硫化,含氯藥用的硫化衍生化,多雜原子農(nóng)藥的一步合成,反應高效放大。
[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.
【學位授予單位】：華東師范大學
【學位級別】：博士
【學位授予年份】：2017
【分類號】：TQ421
，
本文編號：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.
【學位授予單位】：華東師范大學
【學位級別】：博士
【學位授予年份】：2017
【分類號】：TQ421
，
本文編號：2330221
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