進階搜尋


下載電子全文  
系統識別號 U0026-0308201717011900
論文名稱(中文) 在溫和環境下利用Seyferth-Gilbert試劑合成α-重氮烷基膦酸酯的研究探討
論文名稱(英文) A new method to synthesize α-diazoalkylphosphonates with Seyferth-Gilbert reagent under a mild environment
校院名稱 成功大學
系所名稱(中) 化學系
系所名稱(英) Department of Chemistry
學年度 105
學期 2
出版年 106
研究生(中文) 練秀芸
研究生(英文) Hsiu-Yun Lien
學號 L36041157
學位類別 碩士
語文別 英文
論文頁數 90頁
口試委員 指導教授-周鶴軒
口試委員-陳喧應
口試委員-鄭沐政
中文關鍵字 重氮化合物  有機磷  重氮甲基膦酸二甲酯  1,8-二氮雜二環[5.4.0]十一碳-7-烯  醛基  炔鍵形成 
英文關鍵字 Diazo compound  Organophosphorus compound  Dimethyl (diazomethyl)- phosphonate  Diazabicyclo[5.4.0]undec-7-ene  Aldehyde  Alkyne formation 
學科別分類
中文摘要 本研究主要針對重氮甲基膦酸二甲酯(dimethyl(diazomethyl) phosphonate, 3) 的反應性以及選擇性進行探討。在以往的文獻中,大多數皆使用強鹼 (t-BuOK) 搭配極低溫 (-78 ℃) 的環境,能將重氮甲基膦酸二甲酯去質子化,形成具有親核性的碳負離子,再經由霍納爾-沃茲沃思-埃蒙斯反應 (Horner–Wadsworth–Emmons reaction),將醛基轉化成炔基產物。然而,利用具有親核性的重氮甲基膦酸二甲酯來進行親核性加成反應,得到α位具有取代基產物的相關文獻卻非常少,甚至必須使用到金屬催化。因此,不同於以往的反應路徑,我們設計了一個新的合成方法,使用較溫和的1,8-二氮雜二環[5.4.0]十一碳-7-烯 (DBU) 來活化重氮甲基膦酸二甲酯的α-陰離子,並在活化後將反應溫度由0 ℃提升至室溫,經由親核性加成反應後,得到在α位具有卞基或烷基取代的相應產物。此反應條件的官能基容忍度也相當好,無論是卞基上包含推電子基或拉電子基都能獲得對應的產物。這個新的合成方法兼具許多優點,不僅改善了以往嚴苛的反應條件,甚至沒有使用金屬催化,還能有效的提升產率。
在最後一部分的實驗中,我們測試了整體反應條件的選擇性,選用1,4-溴甲基苯甲醛作為選擇性反應的起始物,與經由DBU活化後的重氮甲基膦酸二甲酯反應,將分離後的產物透過NMR圖譜得知DBU活化的碳陰離子對於卞基溴的反應性較好,並且因為整體反應環境較溫和,使得醛基能完整的被保留; 然而,若是在強鹼環境下,則是醛基有較好的反應性形成了炔基產物,而位於對位的卞基溴則被溶劑甲醇置換成卞基甲基醚。經由一連串的測試證明了我們的反應條件相較於以往具有良好的選擇性,可以獲得強鹼無法合成的產物。
整體而言,我們新研發的合成路徑不僅具有反應選擇性,甚至改善了以往反應的缺點,像是反應環境相對溫和、具有良好的產率、價格較便宜且官能基容忍度高。
英文摘要 The reactivity and selectivity of dimethyl (diazomethyl) phosphonate 3 (DAMP) were explored in this research. The chemistry of DAMP has been investigated for several decades. In previous literature reports, the strong base (t-BuOK) was selected to deprotonation DAMP at the low temperature (-78 ℃), and then the aldehyde group could be transferred into the alkyne group by the DAMP anion via the Horner-Wadsworth-Emmons type reaction. However, there were very few literature reports about the DAMP anion used for nucleophilic substitution reactions and it even needed metal to catalyze the reaction. Based on the concept of friendly environment, we designed a new synthesis method to prevent the harsh condition. The more mild base, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), was used to promote DAMP under 0 ℃ to room temperature (28 ℃) and the corresponding α-substituted dimethyl(diazomethyl)phosphonate compounds were synthesized. The tolerance of functional group in this reactive condition was also tested. The result revealed that products contained the electron-withdrawing group or electron-donating group all had the better yield than before.
In the last part of our research, 4-(bromomethyl)benzaldehyde was taken as the starting material which respectively reacted with DBU and KOH to compare the reaction selectivity between two conditions. The isolated products were identified by NMR spectrum and the result demonstrated that DBU-promoted DAMP selectively reacted with benzyl bromide but reserved the aldehyde group. However, when 4-(bromomethyl) benzaldehyde reacted with the DAMP anion deprotonated by KOH, the aldehyde group became the alkyne group, and the bromide was replaced by the methoxy group which was from methanol.
Overall, we had developed a new synthetic method that not only has the selectivity but also improves the drawbacks from the previous methods, such as mild reaction condition, good yield, cheaper price, and good functional groups tolerance.
論文目次 畢業審查證明 I
摘要 II
Abstract IV
Acknowledgment VI
Table of Contents VII
List of Tables X
List of Schemes XI
Abbreviation XII
1. Introduction 1
1.1. Organophosphorus compounds 1
1.2. Diazo compounds 3
1.3. α-Diazocarbonyl compounds 6
1.4. Seyferth-Gilbert Reagent 8
1.5. Bestmann-Ohira Reagent 10
1.6. Motivation 12
2. Results and Discussion 16
2.1. Optimization of Reaction Conditions 17
2.2. Various α-Substituted DAMP Compounds 28
2.3. Reaction with Acetal 33
2.4. Reaction with Various Aldehydes and Ketones 34
2.5. Test for Selectivity of Reaction 36
3. Summary 39
4. Experimental Section 40
4.1. General Information 40
4.1.1. Materials 40
4.1.2. Methods 40
4.1.3. Machines 40
4.2. Synthesis of Dimethyl (diazomethyl) phosphonate (DAMP) 3 41
4.2.1. Imidazole-1-sulfonyl azide 16 41
4.2.2. Dimethyl (1-diazo-2-oxopropyl) phosphonate (Bestmann-Ohira Reagent) 17 42
4.2.3. Dimethyl (diazomethyl) phosphonate (DAMP) (Seyferth-Gilbert Reagent) 3 43
4.3. General Procedure for the Synthesis of α-Substituted Dimethyl (diazomethyl)phosphonate compounds 43
4.4. Synthesis of Hex-5-yn-1-ol 54
4.5. Synthesis of 1-Ethynyl-4-nitrobenzene 29 55
4.6. Synthesis of 4-Hydroxymethylbenzaldehyde 56
4.7. Reaction of 4-Hydroxymethylbenzaldehyde with KOH 58
5. Reference 60
6. Appendix 64
參考文獻 1. (a) Albrecht, L.; Albrecht, A.; Krawczyk, H.; Jorgensen, K. A., Organocatalytic Asymmetric Synthesis of Organophosphorus Compounds. Chem. Eur. J. 2010, 16, 28-48; (b) Kim, D. H.; Lees, W. J.; Kempsell, K. E.; Lane, W. S.; Duncan, K.; Walsh, C. T., Characterization of a Cys115 to Asp Substitution in the Escherichia Coli Cell Wall Biosynthetic Enzyme UDP-GlcNAc Enolpyruvyl Transferase (MurA) that Confers Resistance to Inactivation by the Antibiotic Fosfomycin. Biochemistry. 1996, 35, 4923-4928; (c) Ju, K. S.; Doroghazi, J. R.; Metcalf, W. W., Genomics-Enabled Discovery of Phosphonate Natural Products and Their Biosynthetic Pathways. J. Ind. Microbiol. Biotechnol. 2014, 41, 345-56; (d) Pradere, U.; Garnier-Amblard, E. C.; Coats, S. J.; Amblard, F.; Schinazi, R. F., Synthesis of Nucleoside Phosphate and Phosphonate Prodrugs. Chem. Rev. 2014, 114, 9154-9218.
2. Horiguchi, M.; Kandatstu, M., Isolation of 2-Aminoethane Phosphonic Acid from Rumen Protozoa. Nature. 1959, 184, 901-902.
3. Di, M.; Rein, K. S., Aza Analogs of Kainoids by Dipolar Cycloaddition. Tetrahedron Lett. 2004, 45, 4703-4705.
4. Creary, X., Tosylhydrazone Salt Pyrolyses: Phenyldiazomethanes. Org. Synth. 1986, 207.
5. (a) Buchner, E.; Curtius, T., Synthese von Ketonsäureäthern aus Aldehyden und Diazoessigäther. Ber. Dtsch. Chem. Ges. 1885, 18, 2371-2377; (b) Schlotterbeck, F., Umwandlung von Aldehyden in Ketone durch Diazomethan. (Erwiderung an Hrn. H. Meyer). Ber. Dtsch. Chem. Ges. 1907, 40, 1826-1827.
6. Doyle, M. P.; McKervey, M. A.; Ye, T., Modern Catalytic Methods for Organic Synthesis with Diazo Compounds. Wiley: 1998.
7. Davies, H. M. L.; Manning, J. R., Catalytic C-H Functionalization by Metal Carbenoid and Nitrenoid Insertion. Nature. 2008, 451, 417-424.
8. Pellicciari, R.; Natalini, B.; Sadeghpour, B. M.; Marinozzi, M.; Snyder, J. P.; Williamson, B. L.; Kuethe, J. T.; Padwa, A., The Reaction of α-Diazo-β-hydroxy Esters with Boron Trifluoride Etherate: Generation and Rearrangement of Destabilized Vinyl Cations. A Detailed Experimental and Theoretical Study. J. Am. Chem. Soc. 1996, 118, 1-12.
9. Hoppe, D.; Schöllkopf, U., Ethyl 2‐Oxazoline‐5‐carboxylate from Ethyl Isocyanoacetate and Carbonyl Compounds. Angew. Chem. Int. Ed. 1970, 9, 300-301.
10. Jiang, N.; Qu, Z.; Wang, J., 1, 2-Aryl and 1, 2-Hydride Migration in Transition Metal Complex Catalyzed Diazo Decomposition: a Novel Approach to α-Aryl-β-enamino Esters. Org. Lett. 2001, 3, 2989-2992.
11. Wenkert, E.; McPherson, C. A., Condensations of Acyldiazomethanes with Aldehydes, Ketones, and Their Derivatives. J. Am. Chem. Soc. 1972, 94, 8084-8090.
12. Jiang, N.; Wang, J., DBU-Promoted Condensation of Acyldiazo-Methanes to Aldehydes and Imines under Catalytic Conditions. Tetrahedron Lett. 2002, 43, 1285-1287.
13. Seyferth, D.; Marmor, R. S., Dimethyl Diazomethylphosphonate: Its Preparation and Reactions. Tetrahedron Lett. 1970, 11, 2493-2496.
14. Colvin, E. W.; Hamill, B. J., A Simple Procedure for the Elaboration of Carbonyl Compounds into Homologous Alkynes. J. Chem. Soc. Perkin Trans. 1. 1977, 8, 869-874.
15. (a) Gilbert, J.; Weerasooriya, U., Elaboration of Aldehydes and Ketones to Alkynes: Improved Methodology. J. Org. Chem. 1979, 44, 4997-4998; (b) Gilbert, J.; Weerasooriya, U., Diazoethenes: Their Attempted Synthesis from Aldehydes and Aromatic Ketones by Way of the Horner-Emmons Modification of the Wittig Reaction. A Facile Synthesis of Alkynes. J. Org. Chem. 1982, 47, 1837-1845.
16. Eymery, F.; Iorga, B.; Savignac, P., The Usefulness of Phosphorus Compounds in Alkyne Synthesis. Synthesis. 2000, 2000, 185-213.
17. Habrant, D.; Rauhala, V.; Koskinen, A. M., Conversion of Carbonyl Compounds to Alkynes: General Overview and Recent Developments. Chem. Soc. Rev. 2010, 39, 2007-2017.
18. Chaturvedi, A. K.; Kant, R.; Rastogi, N., Access to the Phosphorylindenopyrazole Scaffold via a Metal-Free Domino Reaction of Diazoalkylphosphonates with 3-Bromophthalides. J. Org. Chem. 2016, 81, 11291-11296.
19. Ohira, S., Methanolysis of Dimethyl (1-diazo-2-oxopropyl)phosphonate: Generation of Dimethyl (diazomethyl)phosphonate and Reaction with Carbonyl Compounds. Synth. Commun. 1989, 19, 561-564.
20. (a) Muruganantham, R.; Mobin, S. M.; Namboothiri, I. N., Base-Mediated Reaction of the Bestmann–Ohira Reagent with Nitroalkenes for the Regioselective Synthesis of Phosphonylpyrazoles. Org. Lett. 2007, 9, 1125-1128; (b) Pramanik, M. M.; Kant, R.; Rastogi, N., Synthesis of 3-Carbonyl Pyrazole-5-Phosphonates via 1, 3-Dipolar Cycloaddition of Bestmann–Ohira Reagent with Ynones. Tetrahedron. 2014, 70, 5214-5220; (c) Ahamad, S.; Kant, R.; Mohanan, K., Three‐Component Domino HWE Olefination/ 1, 3‐Dipolar Cycloaddition/ Oxidation Strategy for the Rapid Synthesis of Trisubstituted Pyrazoles. ChemistrySelect. 2016, 1, 5276-5280.
21. (a) Nicolle, S. M.; Moody, C. J., Potassium N‐Iodo p‐Toluenesulfonamide (TsNIK, Iodamine‐T): A New Reagent for the Oxidation of Hydrazones to Diazo Compounds. Chem. Eur. J. 2014, 20, 4420-4425; (b) Pramanik, M. M.; Chaturvedi, A. K.; Rastogi, N., Substituent Controlled Reactivity Switch: Selective Synthesis of α-Diazoalkyl- phosphonates or Vinylphosphonates via Nucleophilic Substitution of Alkyl Bromides with Bestmann–Ohira Reagent. Chem. Commun. 2014, 50, 12896-12898; (c) Pramanik, M. M.; Rastogi, N., Synthesis of α-Diazo-β-keto Esters, Phosphonates and Sulfones via Acylbenzotriazole-Mediated Acylation of a Diazomethyl Anion. Org. Biomol. Chem. 2016, 14, 1239-1243.
22. Zhang, Z.; Wang, J., Recent Studies on the Reactions of α-Diazocarbonyl Compounds. Tetrahedron. 2008, 64, 6577-6605.
23. Seyferth, D.; Marmor, R. S., Copper-Catalyzed Decomposition of Some Dimethylphosphono-Substituted Diazoalkanes. J. Org. Chem. 1971, 36, 128-136.
24. Ye, F.; Wang, C.; Zhang, Y.; Wang, J., Synthesis of Aryldiazoacetates through Palladium (0)‐Catalyzed Deacylative Cross‐Coupling of Aryl Iodides with Acyldiazoacetates. Angew. Chem. Int. Ed. 2014, 53, 11625-11628.
25. Bonge, H. T.; Pintea, B.; Hansen, T., Highly Efficient Formation of Halodiazoacetates and Their Use in Stereoselective Synthesis of Halocyclopropanes. Org. Biomol. Chem. 2008, 6, 3670-3672.
26. Roiser, L.; Robiette, R.; Waser, M., Benzylic Ammonium Ylide Mediated Epoxidations. Synlett. 2016, 27, 1963-1968.
27. Montgomery, J. H., Groundwater Chemicals Desk Reference. CRC Press: 2007.
28. Goddard-Borger, E. D.; Stick, R. V., An Efficient, Inexpensive, and Shelf-Stable Diazotransfer Reagent: Imidazole-1-Sulfonyl Azide Hydrochloride. Org. Lett. 2007, 9, 3797-3800.
29. Boibessot, T.; Bénimèlis, D.; Jean, M.; Benfodda, Z.; Meffre, P., Synthesis of a Novel Rhizobitoxine-Like Triazole-Containing Amino Acid. Synlett. 2016, 27, 2685-2688.
30. Nahrwold, M.; Bogner, T.; Eissler, S.; Verma, S.; Sewald, N., “Clicktophycin-52”: a Bioactive Cryptophycin-52 Triazole Analogue. Org. Lett. 2010, 12, 1064-1067.
31. De Miguel, I.; Velado, M.; Herradón, B.; Mann, E., Synthesis of Functionalized Bicyclic Imines via Intramolecular Azide‐Alkene 1, 3‐Dipolar Cycloaddition/ Intramolecular Stork Alkylation Cascade Reaction. Adv. Synth. Catal. 2013, 355, 1237-1242.
32. Kikuchi, K.; Tatewaki, Y.; Okada, S., Self-Assembling and Solid-State Polymerization of Butadiyne Derivatives with Amide and Trialkoxyphenyl Groups. Bull. Chem. Soc. Jpn. 2016.
33. Kalhor-Monfared, S.; Beauvineau, C.; Scherman, D.; Girard, C., Synthesis and Cytotoxicity Evaluation of Aryl Triazolic Derivatives and Their Hydroxymethine Homologues Against B16 Melanoma Cell Line. Eur. J. Med. Chem. 2016, 122, 436-441.
34. Mingozzi, M.; Manzoni, L.; Arosio, D.; Dal Corso, A.; Manzotti, M.; Innamorati, F.; Pignataro, L.; Lecis, D.; Delia, D.; Seneci, P., Synthesis and Biological Evaluation of Dual Action Cyclo-RGD/ SMAC Mimetic Conjugates Targeting αvβ3/ αvβ5 Integrins and IAP Proteins. Org. Biomol. Chem. 2014, 12, 3288-3302.
35. Loim, N.; Kelbyscheva, E., Synthesis of Dendrimers with Terminal Formyl Groups. Russ. Chem. Bull. 2004, 53, 2080-2085.
論文全文使用權限
  • 同意授權校內瀏覽/列印電子全文服務,於2019-02-03起公開。
  • 同意授權校外瀏覽/列印電子全文服務,於2019-02-03起公開。


  • 如您有疑問,請聯絡圖書館
    聯絡電話:(06)2757575#65773
    聯絡E-mail:etds@email.ncku.edu.tw