含氮雜環(huán)芳基氟化物的合成研究
發(fā)布時間：2018-08-17 19:04
【摘要】：含氮雜環(huán)芳基化合物廣泛的應用于醫(yī)藥及光電材料領域,向其結構中引入氟原子或含氟基團后,能夠顯著的改變其物理、化學及生理活性。由于氟化試劑的高反應活性及C-F鍵極大的化學鍵能,已合成的雜環(huán)芳基氟化物種類并不豐富,且在合成方法中也存在著步驟繁雜、成本較高的不足。因此,探索高效實用的含氮雜環(huán)芳基氟化物合成方法,并通過C-F鍵選擇性活化的方法對其結構進行修飾,可以完善有機氟化物的制備方案,并豐富產(chǎn)物的種類。此外,對C-F鍵選擇性活化的機理進行研究,有助于加深對C-F鍵活化的理解,具有重要的理論價值。本文的主要研究內(nèi)容如下:本文以2-羥基喹啉/喹喔啉衍生物為原料,通過對溴化方法進行篩選,以中等到良好的產(chǎn)率得到了對應的2-溴喹啉/喹喔啉衍生物。然后通過對催化劑、配體、鍵及溶劑進行篩選,實現(xiàn)了2-溴喹啉/喹喔啉衍生物與貧電子型多氟芳烴的偶聯(lián)反應,反應具有很好的底物適用性。獲得的最優(yōu)反應條件為:n(2-溴喹啉/喹喔啉衍生物):n(多氟芳烴):n(碘化亞銅):n(1,10-菲Up啉):n(磷酸鉀)=1.0:1.5:0.1:0.1:2.0,以二甲基甲酰胺-二甲苯(1/1,V/V)為溶劑,110 oC下反應12 h。在該反應條件的基礎上,進行了放大量合成,研究了該體系在規(guī)模化制備時的實用性。本文開展了C-F鍵活化法對含氮雜環(huán)芳基氟化物進行結構修飾的研究。以氟代苯甲酸為原料,經(jīng)縮合反應、關環(huán)反應制備了一系列含有導向基團的氟代苯基VA唑啉,然后以之為底物,通過C-F鍵活化的方法實現(xiàn)了與苯胺衍生物的偶聯(lián)反應,能夠在不使用過渡金屬催化劑的條件下以優(yōu)秀的產(chǎn)率獲得一系列含VA唑啉環(huán)的氟代二苯胺衍生物,并對產(chǎn)物進行了核磁氫譜、碳譜、氟譜及高分辨質(zhì)譜表征。該反應體系可以對VA唑啉環(huán)鄰位的單個C-F鍵進行活化,對含不同取代基團(-F,-Cl,-CH3,-OCH3等)的苯胺衍生物均具有很好的實用性,且適用于含有較少氟原子的氟代芳基VA唑啉。研究了反應時間及投料比例對C-F鍵活化選擇性的影響,延長反應時間及增加偶聯(lián)試劑的投料比例后,并沒有其他位點的C-F鍵發(fā)生活化,產(chǎn)物結構具有很好的可控性。本文對多氟苯基VA唑啉C-F鍵選擇性活化的反應機理進行了研究。通過合成含有不同雜環(huán)結構的氟代苯基化合物,對導向基團的導向作用進行研究;通過對照實驗與理論計算結合的方法,獲得了配位中間體的最優(yōu)幾何構型,研究了配位效應對C-F鍵活化的影響;通過對分子內(nèi)氫鍵作用進行研究,探索其在C-F鍵選擇性活化中對C-F鍵活化數(shù)目的影響。綜合分析導向基團、配位效應及分子內(nèi)氫鍵作用,提出了該體系中C-F鍵選擇性活化的反應機理。
[Abstract]:Nitrogen-containing heterocyclic aryl compounds are widely used in the field of medicine and optoelectronic materials. When fluorine atoms or fluorine groups are introduced into their structures, the physical, chemical and physiological activities of nitrogen-containing heterocyclic aryl compounds can be significantly changed. Due to the high reactivity of fluorinated reagents and the great chemical bond energy of C-F bond, the kinds of heterocyclic aryl fluoride synthesized are not abundant, and there are many complicated steps and high cost in the synthesis method. Therefore, to explore an efficient and practical method for the synthesis of nitrogen-containing heterocyclic aryl fluoride, and to modify its structure by C-F bond selective activation, can improve the preparation of organic fluorides and enrich the kinds of products. In addition, the study on the mechanism of selective activation of C-F bond is helpful to further understand the activation of C-F bond and has important theoretical value. The main contents of this paper are as follows: in this paper, 2-hydroxyquinoline / quinoxaline derivatives were used as raw materials, and the corresponding 2-bromoquinoline / quinoxaline derivatives were obtained by bromination method. Then the coupling reaction of 2-bromoquinoline / quinoxaline derivatives with electron-poor polyfluorinated aromatic hydrocarbons was realized by screening catalysts ligands bonds and solvents. The optimal reaction conditions were obtained as follows: 1: n (2-bromoquinoline / quinoxaline derivative): n (polyfluorinated aromatic hydrocarbon): n (cuprous iodide): n (1n (1-10 -phenanthroline): n (potassium phosphate) 1.0: 1.5: 0.1: 0.1: 0.12.0The reaction was carried out at 110oC with dimethylformamide / xylene (1 / 1 V / V) as solvent for 12 h. On the basis of the reaction conditions, a large amount of synthesis was carried out, and the practicability of the system in large-scale preparation was studied. In this paper, the structure modification of nitrogen-containing heterocyclic aryl fluoride by C-F bond activation method has been studied. Using fluorobenzoic acid as raw material, a series of fluorophenyl VA azoline containing guiding groups were prepared by condensation reaction and closed ring reaction. Then the coupling reaction with aniline derivatives was realized by C-F bond activation with fluorobenzoic acid as substrate. A series of fluorinated diphenylamine derivatives containing VA azoline ring can be obtained in excellent yield without using transition metal catalyst. The products were characterized by NMR, carbon, fluorine and high resolution mass spectrometry. The reaction system can activate a single C-F bond at the ortho position of VAZoline ring, and has good practicability for aniline derivatives containing different substituents (-FF- Cl-Cl-CH3-OCH3, etc.) and is suitable for fluoroarylVA azoline containing less fluorine atoms. The effects of reaction time and feed ratio on the activation selectivity of C-F bond were studied. When the reaction time was prolonged and the ratio of coupling reagent was increased, there was no activation of C-F bond at other sites, and the structure of the product had good controllability. The mechanism of selective activation of polyfluorophenyl Vazoline C-F bond was studied. Through the synthesis of fluorophenyl compounds with different heterocyclic structures, the orientation of the guiding groups was studied, and the optimal geometric configuration of the coordination intermediates was obtained by combining the experimental results with the theoretical calculations. The effect of coordination effect on the activation of C-F bond was studied, and the effect of coordination effect on the number of C-F bond activation in selective activation of C-F bond was investigated. The mechanism of selective activation of C-F bonds in the system was proposed by synthetically analyzing the guiding group, the coordination effect and the intramolecular hydrogen bond interaction.
【學位授予單位】：江南大學
【學位級別】：碩士
【學位授予年份】：2017
【分類號】：O626
本文編號：2188595
[Abstract]:Nitrogen-containing heterocyclic aryl compounds are widely used in the field of medicine and optoelectronic materials. When fluorine atoms or fluorine groups are introduced into their structures, the physical, chemical and physiological activities of nitrogen-containing heterocyclic aryl compounds can be significantly changed. Due to the high reactivity of fluorinated reagents and the great chemical bond energy of C-F bond, the kinds of heterocyclic aryl fluoride synthesized are not abundant, and there are many complicated steps and high cost in the synthesis method. Therefore, to explore an efficient and practical method for the synthesis of nitrogen-containing heterocyclic aryl fluoride, and to modify its structure by C-F bond selective activation, can improve the preparation of organic fluorides and enrich the kinds of products. In addition, the study on the mechanism of selective activation of C-F bond is helpful to further understand the activation of C-F bond and has important theoretical value. The main contents of this paper are as follows: in this paper, 2-hydroxyquinoline / quinoxaline derivatives were used as raw materials, and the corresponding 2-bromoquinoline / quinoxaline derivatives were obtained by bromination method. Then the coupling reaction of 2-bromoquinoline / quinoxaline derivatives with electron-poor polyfluorinated aromatic hydrocarbons was realized by screening catalysts ligands bonds and solvents. The optimal reaction conditions were obtained as follows: 1: n (2-bromoquinoline / quinoxaline derivative): n (polyfluorinated aromatic hydrocarbon): n (cuprous iodide): n (1n (1-10 -phenanthroline): n (potassium phosphate) 1.0: 1.5: 0.1: 0.1: 0.12.0The reaction was carried out at 110oC with dimethylformamide / xylene (1 / 1 V / V) as solvent for 12 h. On the basis of the reaction conditions, a large amount of synthesis was carried out, and the practicability of the system in large-scale preparation was studied. In this paper, the structure modification of nitrogen-containing heterocyclic aryl fluoride by C-F bond activation method has been studied. Using fluorobenzoic acid as raw material, a series of fluorophenyl VA azoline containing guiding groups were prepared by condensation reaction and closed ring reaction. Then the coupling reaction with aniline derivatives was realized by C-F bond activation with fluorobenzoic acid as substrate. A series of fluorinated diphenylamine derivatives containing VA azoline ring can be obtained in excellent yield without using transition metal catalyst. The products were characterized by NMR, carbon, fluorine and high resolution mass spectrometry. The reaction system can activate a single C-F bond at the ortho position of VAZoline ring, and has good practicability for aniline derivatives containing different substituents (-FF- Cl-Cl-CH3-OCH3, etc.) and is suitable for fluoroarylVA azoline containing less fluorine atoms. The effects of reaction time and feed ratio on the activation selectivity of C-F bond were studied. When the reaction time was prolonged and the ratio of coupling reagent was increased, there was no activation of C-F bond at other sites, and the structure of the product had good controllability. The mechanism of selective activation of polyfluorophenyl Vazoline C-F bond was studied. Through the synthesis of fluorophenyl compounds with different heterocyclic structures, the orientation of the guiding groups was studied, and the optimal geometric configuration of the coordination intermediates was obtained by combining the experimental results with the theoretical calculations. The effect of coordination effect on the activation of C-F bond was studied, and the effect of coordination effect on the number of C-F bond activation in selective activation of C-F bond was investigated. The mechanism of selective activation of C-F bonds in the system was proposed by synthetically analyzing the guiding group, the coordination effect and the intramolecular hydrogen bond interaction.
【學位授予單位】：江南大學
【學位級別】：碩士
【學位授予年份】：2017
【分類號】：O626
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