壹、區位選擇性合成 2-胺基-3-芳香基喹唑啉-4-酮及 2-芳香胺基喹唑啉-4-酮及其生物活性評估 / 貳、碘化亞銅催化經由腈胺的氮-腈鍵的裂解進行苯乙炔分子內胺化及腈化反應 / 參、氰化鈉活化 1,3-二甲基尿嘧啶進行五、六號位氫氘交換反應

Regioselective Synthesis and Biological Evaluation of N-Substituted 2-Aminoquinazolin-4-ones / CuI-catalyzed Intramolecular Aminocyanation of Terminal Alkynes by N-Tosyl-N-Phenylcyanamide Derivatives / Sodium Cyanide Activated Hydrogen-Deuterium Exchange Reaction at 5,6 Position of 1,3-Dimethyluracil

廖鎮垣(Liao Zhen-Yuan)

指導教授 ： 簡敦誠

國立臺灣師範大學/理學院/化學系/博士(2018年)

https://doi.org/10.6345/DIS.NTNU.DC.065.2018.B05

摘要

第一章、區位選擇性合成 2-胺基-3-芳香基喹唑啉-4-酮及 2-芳香胺基喹唑啉-4-酮及其生物活性評估
利用不同取代基的芳香基腈胺 (arylcyanamide)，與 2-胺基苯甲酸甲酯 (methyl 2-aminobenzoate) 在添加劑對甲苯磺酸 (p-TsOH) 與溶劑第三丁醇加熱迴流，得到主產物為 3-芳香基-2-胺基喹唑啉-4-酮 (3-aryl-2-aminoquinazolin-4-one) 及少量區位異構物 (regioisomer) 2-芳香胺基喹唑啉-4-酮 (2-(arylamino)quinazolin-4-one)。另外，一鍋化反應使用不同取代基的芳香基腈胺與 2-胺基苯甲酸甲酯於添加劑三甲基氯矽烷 (TMSCl) 和溶劑第三丁醇下加熱 60 度反應，先得到較高的區位異構混合物總產率，接著將混合物直接加入 2N 氫氧化鈉溶液 (水:乙醇 = 1 : 1) 進行加熱迴流，在鹼性情況下使混合物中的 3-芳香基-2-胺基喹唑啉-4-酮進行 Dimroth 重排反應，將 3-芳香基-2-氨基喹唑啉-4-酮 (3-aryl-2-aminoquinazolin-4-one) 不可逆地轉變成 2-芳香胺基喹唑啉-4-酮 (2-(arylamino)quinazolin-4-one) 產物。在純化過程中，由於兩種異構物的極性相近且對於各種溶劑溶解度差，因此在管柱層析中純化效果非常有限，我們經由觀察發現異構物對於鹼性溶解度的不同，於萃取過程將 2-芳香胺基喹唑啉-4-酮溶進鹼性水溶液中達到分離兩種異構物的目的。

第二章、碘化亞銅催化經由氮-腈鍵裂解的苯乙炔分子內胺化及腈化反應
我們設計了在鄰位具有炔基取代的 N-苯基-N-甲苯磺醯基腈胺 (N-phenyl-N-tosylcyanamide) 衍生物，利用 2-鹵苯胺 (2-haloaniline) 作為起始物，先進行 Sonogashira 反應將 2 位修飾成炔基，與氰酸鈉 (sodium cyanate) 反應後會在胺基上加成，得到苯基尿素中間物。接著苯基尿素中間物與過量甲苯磺醯氯 (TsCl) 反應，反應過程中第一當量甲苯磺醯氯進行脫水反應形成苯基腈胺中間物，而第二當量甲苯磺醯氯直接加成至腈胺上，得到 N-(2-炔基苯基)-N-甲苯磺醯基腈胺。在催化劑量碘化亞銅與溶劑二噁烷的標準條件下，N-(2-乙炔基苯基)-N-甲苯磺醯基腈胺的末端炔基和催化劑一價銅形成銅乙炔鍵結 (Cu-acetylide)，被活化的乙炔基 β 碳上 π 電子對鄰位的 N-甲苯磺醯基腈胺進行分子內的取代反應使腈-氮鍵斷裂得到腈基轉移的中間物，而鄰位脫去腈基的氮再與乙炔基 α 碳進行加成得到產物 3-腈基-1-甲苯磺醯基吲哚 (3-cyano-1-tosylindole)。此外，我們推論的反應機構中，金屬銅最後會停留在中間物吲哚二號位，利用烯丙基溴作為添加劑於標準條件下反應，並捕捉到具有銅的中間物得到2-烯丙基-3-腈基-1-甲苯磺醯基吲哚 (2-allyl-3-cyano-1-tosylindole) 以證明反應機構的推論。

第三章、氰化鈉活化 1,3-二甲基尿嘧啶進行五、六號位氫氘交換反應
利用氰化鈉作為氘化的促進劑與 1,3-二甲基尿嘧啶 (1,3-dimethyluracil) 在具有氘質子的溶劑下加熱反應，得到5,6-二氘-1,3-二甲基尿嘧啶 (5,6-dideutero-1,3-dimethyluracil)。測試了部分強鹼例如氫氧化鈉，也能成為氘化的促進劑。標準條件下測試 1,3-二甲基尿嘧啶衍生物如 1,3,5-三甲基尿嘧啶 (1,3,5-trimetyluracil)、1,3,6-三甲基尿嘧啶 (1,3,6-trimethyluracil)、1,3-二甲基-5-苯基尿嘧啶 (1,3-dimethyl-5-phenyluracil)、1,3-二甲基-6-苯基尿嘧啶 (1,3-dimethyl-6-phenyluracil)、尿苷 (uridine)、2'-去氧尿苷 (2’-deoxyuridine)、胞苷 (cytidine) 以及修飾保護基的尿苷等，均能在優化條件下進行嘧啶碳上的氫-氘交換反應。

關鍵字：喹唑啉-4-酮、腈胺、Dimroth 重排反應、Sonogashira 偶合反應、銅-乙炔、氫-氘交換

關鍵字

腈胺 ； 氫-氘交換 ； 銅-乙炔 ； Dimroth 重排反應 ； 喹唑啉-4-酮 ； Sonogashira偶合反應

並列摘要

Chapter 1. Regioselective Synthesis and Biological Evaluation of N-Substituted 2-Aminoquinazolin-4-ones
N-Arylcyanamides reacted with methyl 2-aminobenzoates in the presence of p-TsOH in t-BuOH under reflux temperature to afford 3-aryl-2-aminoquinazolin-4-ones as the major products with a limited amount of the regioisomer 2-(N-arylamino)quinazolin-4-ones. In contrast, the one pot reaction of the same starting reactants with TMSCl in t-BuOH at 60 oC produced higher yields of two regioisomers. When the isomers were heated in aqueous ethanolic sodium hydroxide under reflux temperature, 3-aryl-2-aminoquinazolin-4-ones in the mixture irreversibly underwent Dimroth rearrangement reaction under alkaline conditions to give exclusively the regioisomer 2-(N-arylamino)quinazolin-4-ones. Due to the similar polarity of the two regioisomers and their poor solubility in various solvents, the purification by column chromatography was limited. We observed that the isomers has different basic solubilities in aqueous basic solution, which allowed the separation of two isomers by dissolving the 2-(N-arylamino)quinazolin-4-ones in alkaline aqueous solution during the extraction process.

Chapter 2. CuI-catalyzed Intramolecular Aminocyanation of Terminal Alkynes by N-Tosyl-N-Phenylcyanamide Derivatives
N-(2-Ethynylphenyl)-N-tosylcyanamide derivatives were designed and tested for the intramolecular aminocyanation reaction. 2-Haloanilines underwent Sonogashira reaction to give 2-alkynylanilines followed by addition to sodium cyanate to give the N-(2-ethynylphenyl)urea intermediates. The urea intermediates reacted with an excess amount of tosyl chloride, of which the first equivalent of TsCl dehydrated the urea intermediates to give cyanamide intermediates, and the second equivalent TsCl was added directly to cyanamide to afford the N-tosylcyanamide adducts. Under the catalysis of CuI in the 1,4-dioxane, the reaction of N-(2-ethynylphenyl)-N-tosylcyanamides was initiated by the formation of Cu–acetylide to trigger N–CN bond cleavage of the N-sulfonylcyanamide moiety followed by CN migration to form a β-cyano Cu–vinylidene intermediate. Subsequently, the indole ring closure furnished the corresponding 1-sulfonyl-3-cyanoindoles. In addition, we utilized the allyl bromide to trap the hypothetical 3-cyano-2-indolyl-copper complex to give the 2-allyl-3-cyano-1-tosylindole to prove our supposed mechanism.

Chapter 3. Sodium Cyanide Activated Hydrogen-Deuterium Exchange Reaction at 5,6 Position of 1,3-Dimethyluracil
NaCN was found as a promotor of for the hydrogen-deuterium exchange reaction of 1,3-dimethyluracil in the solvents with deuterium source to give 5,6-dideutero-1,3-dimethyluracil. Some bases such as NaOH can also act as a promotor for deuteration. Uracil derivatives such as 1,3-Dimethyluracil, 1,3,5-trimetyluracil, 1,3,6-trimethyluracil, 1,3-dimethyl-5-phenyluracil, 1,3-dimethyl-6-phenyluracil, uridine, 2’-deoxyuridine cytidine and protected uridines were test under the optimized condition and the hydrogen-deuterium exchange can occur at the ring carbon of the pyrimidine heterocycles.

Keywords: quinazolin-4-one, cyanamide, Dimroth rearrangement, Sonogashira coupling, Cu-acetylide, hydrogen-deuterium exchange.

並列關鍵字

cyanamide ； Hydrogen-Deuterium Exchange ； Cu-acetylide ； Dimroth rearrangement ； quinazolin-4-one ； Sonogashira coupling

參考文獻

1-5. 參考文獻

1. (a) Shakhidoyatov K. M.; Elmuradov B. Z. Chem. Nat. Compd. 2014, 50, 781; (b) Demir, A. S.; Emrullahoglu, M. Curr. Org. Synth. 2007, 4, 223.

2. (a) Pendergast, W; Dickerson, S. H.; Dev, I. K.; Ferone, R.; Duch, D. S.; Smith, G. K. J. Med. Chem. 1994, 37, 838; (b) Pendergast, W.; Dickerson, S. H.; Johnson, J. V.; Dev, I. K.; Ferone, R.; Duch, D. S.; Smith, G. K. J. Med. Chem. 1993, 36, 3464; (c) Pendergast, W; Johnson, J. V.; Dickerson, S. H.; Dev, I. K.; Duch, D. S.; Ferone, R.; Hall, W. R.; Humphreys, J.; Kelly, J. M.; Wilson, D. C. J. Med. Chem. 1993, 36, 2279.

3. (a) Padia, J. K.; Field, M.; Hinton, J.; Meecham, K. ; Pablo, J.; Pinnock, R.; Roth, B. D. ; Singh, L.; Suman-Chauhan, N.; Trivedi, B. K.; Webdale, L. J. Med. Chem. 1998, 41, 1042; (b) Padia, J. K.; Chilvers, H.; Daum, P.; Pinnock, R. ; Suman-Chauhan, N.; Webdaleb L.; Trivedi B. K. Bioorg. Med. Chem. Lett. 1997, 7, 805; (C) Miller, S. C.; Mitchison, T. J. ChemBioChem. 2004, 5, 1010; (d) DeRuiter, J.; Brubaker, A. N.; Millen, J.; Riley, T. N. J. Med. Chem. 1986, 29, 627. (e) Selvam, T. P.; Kumar, P. V. Research in Pharmacy. 2011, 1, 1; (f) Leivers, A. L.; Tallant, M.; Shotwell, J. B.; Dickerson, S.; Leivers, M. R.; McDonald, O. B.; Gobel, J.; Creech, K. L.; Strum, S. L.; Mathis, A.; Rogers, S.; Moore, C. B.; Botyanszki, J. J. Med. Chem. 2014, 57, 2091; (g) Bojjireddy, N.; Botyanszki, J.; Hammond, G.; Creech, D.; Peterson, R.; Kemp, D. C.; Snead, M.; Brown, R.; Morrison, A.; Wilson, S.; Harrison, S.; Moore, C.; Balla. T. J. Biol. Chem. 2014, 289, 6120; (h) Rasina, D.; Otikovs, M.; Leitans, J.; Recacha, R.; Borysov, O. V.; Kanepe-Lapsa, I.; Domraceva, I.; Pantelejevs, T.; Tars, K.; Blackman, M. J.; Jaudzems, K.; Jirgensons, A. J. Med. Chem. 2016, 59, 374; (i) Rizza, P.; Pellegrino, M.; Carusoa, A.; Iacopetta, D.; Sinicropi, M. S.; Rault, S.; Lancelot, J. C.; El-Kashef, H.; Lesnard, A.; Rochais, C.; Dallemagne, P.; Saturnino, C.; Giordano, F.; Catalano, S.; Andò, S. Eur. J. Med. Chem. 2016, 107, 275; (j) Guiles, J.; Sun, X.; Critchley, I. A.; Ochsner, U.; Tregay, M.; Stone, K.; Bertino, J.; Green, L.; Sabin, R.; Dean, F.; Dallmann, H. G.; McHenry, C. S.; Janjic, N. Bioorg. Med. Chem. Lett. 2009, 19, 800; (k) Somers, F.; Ouedraogo, R.; Antoine, M.-H.; Tullio, P. d.; Becker, B.; Fontaine, J.; Damas, J.; Dupont, L.; Rigo, B.; Delarge, J.; Lebrun, P.; Pirotte, B. J. Med. Chem. 2001, 44, 2575; (l) Hou, J.; Wan, S.; Wang, G.; Zhang, T.; Li, Z.; Tian, Y.; Yu, Y.; Wu, X.; Zhang, J. Eur. J. Med. Chem. 2016, 118, 276.

4. (a) Lange, N. A.; Sheibley, F. E. J. Am. Chem. Soc. 1932, 54, 1994; (b) Curd, F. H. S.; Landquist, J. K.; Rose, F. L. J. Chem. Soc. 1947, 775; (c) Butler K.; Partridge M. W. J. Chem. Soc. 1959, 1512; (d) Hess, H. J.; Cronin, T. H.; Scriabine, A. J. Med. Chem. 1968, 11, 130; (e) Chao, Q.; Deng, L.; Shih, H.; Leoni, L. M.; Genini, D.; Carson, D. A.; Cottam, H. B. J. Med. Chem. 1999, 42, 3860.