本論文第一部分是我們開發一個簡單、溫和的方法，以鄰胺基苯甲酸甲酯與具有不同取代基的苯氰胺，在酸性催化條件下即可具有區位選擇性地製備三位氮上取代及二位胺基氮上取代之2-胺基喹唑啉酮。採用對甲苯磺酸作為促進試劑，可使反應形成主要為三位氮上取代的2-胺基喹唑啉酮產物。此外，三位氮上取代產物可經強鹼條件進行Dimroth重排反應，即生成二位胺基氮上取代的2-胺基喹唑啉酮產物。
若是在2-胺基喹唑啉酮的苯環取代基上引進鄰位溴，則可進一步以銅催化的方式形成新的碳氮鍵，使分子內環化生成新的四環結構─苯并咪唑并喹唑啉酮。而這類化合物已被發現有免疫抑制和抗腫瘤的生物活性。
第二部分是以肉桂腈合成2-胺基咪唑衍生物。以肉桂腈與羥胺反應得到之醯胺肟與磺醯化試劑進行Tiemann重排反應得到對應的苯乙烯氰胺，再與羥胺進行一次加成反應後形成羥基胍，接著再與磺醯化試劑反應形成好的離去基後與原先存在的碳碳雙鍵進行芳香環親電子性加成反應，即可進行環化而製備2-胺基咪唑。

In the first part of the thesis, we developed a simple and mild method to synthesize 3-aryl-2-amino- and 2-arylamino-quinazolin-4-ones from methyl 2-aminobenzoates with various aryl cyanamides under the catalysis of acids. We used 4-toluenesulfonic acid monohydrate as the promoting acid to give 3-substituted 2-aminoquinazolin-4-ones with good regioselectivity. Besides, the 2-arylamino-substituted quinazolin-4-ones can be obtained from 3-substituted 2-aminoquinazolin-4-ones by Dimroth rearrangement, which was proceeded under strong basic condition.
If the aryl substitutents on 2-aminoquinazolin-4-ones possessed ortho-bromo substitutent, the intramolecular Copper(I)-catalyzed C-N bond formation can afford the tetracyclic benzimidazo[2,1-b]quinazolin-12-one derivatives. The tetracyclic heterocyclic skeleton has attracted much attention for its application as potential immunosuppressors and anti-tumor agents.
The second part is the synthesis of 2-aminoimidazoles from cinnamonitriles. The cinnamonitriles were reacted with hydroxylamine to form the corresponding carboxamidoximes, which then underwent Tiemann rearrangement reaction to afford corresponding of N-phenylethylene-N-arylsulfonylcyanamides. The N-phenylethylene-N-arylsulfonylcyanamides were reacted with hydroxylamine again to form the corresponding N-phenylethylene-N-arylsulfonyl-N’-hydroxyguanidines. Sulfonylation of the above N’-hydroxyguanidines afforded 2-aminoimidazole derivatives via intramolecular electrophilic addition.

參考文獻

1. Ochiai, T. and Ishida, R. Jpn. J. Pharmacol. 1982, 32, 427.
2. Jackman, G. B.; Petrow, V. and Stephenson, O. J. Pharm. Pharmacol. 1960, 12, 529.
3. Widemann, B. C.; Balis, F. M.; Godwin, K. S.; McCully, C. and Adamson, P. C. Cancer. Chemoth. Pharm. 1999, 44, 439.
4. Tanaka, Y.; Sawamoto, T.; Suzuki, A. and Kimura, T. Drug. Metab. Dispos. 1993, 21, 677.
5. Wilson, R. S.; May, E. L. and Dewey, W. L. J. Med. Chem. 1970, 13, 886.
6. Dickinson, R. P.; Bell, A. W.; Hitchcock, C. A.; Narayana-Swami, S.; Ray, S. J.; Richardson, K. and Troke, P. F. Bioorg. Med. Chem. Lett. 1996, 6, 2031.
7. Bartroli, J.; Turmo, E.; Alguero, M.; Boncompte, E.; Vericat, M. L.; Conte, L.; Ramis, J.; Merlos, M.; Garcia-Rafanell, J. and Forn, J. J. Med. Chem. 1998, 41, 1869.
8. Aly, M. M.; Mohamed, Y. A.; El-Bayouki, K. A. M.; Basyouni, W. M. and Abbas, S. Y. Eur. J. Med. Chem. 2010, 45, 3365.
9. Meyyanathan, S. N.; Ramu, M. and Suresh, B. Med. Chem. Res. 2010, 19, 993.
10. Welch, W. M.; Ewing, F. E.; Huang, J.; Menniti, F. S.; Pagnozzi, M. J.; Kelly, K.; Seymour, P. A.; Guanowsky, V.; Guhan, S.; Guinn, M. R.; Critchett, D.; Lazzaro, J.; Ganong, A. H.; Devries, K. M.; Staigers, T. L. and Chenard, B. L. Bioorg. Med. Chem. Lett. 2001, 11, 177.
11. Miller, S. C. and Mitchison, T. J. ChemBioChem. 2004, 5, 1010.
12. DeRuiter, J.; Brubaker, A. N.; Millen, J. and Riley, T. N. J. Med. Chem. 1986, 29, 627.
13. Padia, J. K.; Field, M.; Hinton, J.; Meecham, K.; Pablo, J.; Pinnock, R.; Roth, B. D.; Singh, L.; Suman-Chauhan, N.; Trivedi, B. K. and Webdale, L. J. Med. Chem. 1998, 41, 1042.
14. Selvam, T. P. and Kumar, P. V. Research in Pharmacy. 2011, 1, 1.
15. Lunn, W. H. W.; Harper, R. W. and Stone, R. L. J. Med. Chem. 1971, 14, 1069.
16. Lange, N. A. and Sheibley, F. E. J. Am. Chem. Soc. 1932, 54, 1994.
17. Curd, F. H. S.; Landquist, J. K. and Rose, F. L. J. Chem. Soc. 1947, 775.
18. Garratt, P. J.; Hobbs, C. J. and Wrigglesworth, R. J. Org. Chem. 1989, 54, 1062.
19. Ram, V. J. and Srimal, R. C. J. Prakt. Chem. 1990, 5, 629.
20. 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. and Botyanszki, J. J. Med. Chem. 2014, 57, 2091.
21. Grout, R. J. and Partridge, M. W. J. Chem. Soc. 1960, 3540.
22. Taylor, E. C. and Ravindranathan, R. V. J. Org. Chem. 1962, 27, 2622.
23. Maguire, J. H. and McKee, R. L. J. Org. Chem. 1974, 39, 3434.
24. Nakao, H. and Sunagawa, G. Chem. Pharm. Bull. 1965, 13, 465.
25. Kundu, B.; Partani, P.; Duggineni, S. and Sawant, D. J. Comb. Chem. 2005, 7, 909.
26. Yin, P.; Liu, N.; Deng, Y.-X.; Chen, Y.; Deng, Y. and He, L. J. Org. Chem. 2012, 77, 2649.
27. Padia, J. K.; Chilvers, H.; Daum, P.; Pinnock, R.; Suman-Chauhan, N.; Webdale, L. and Trivedi, B. K. Bioorg. Med. Chem. Lett. 1997, 7, 805
28. Chao, Q.; Deng, L.; Shih, H.; Leoni, L. M.; Genini, D.; Carson, D. A. and Cottam, H. B. J. Med. Chem. 1999, 42, 3860.
29. Ji, F.; Lv, M.-F.; Yi, W.-B. and Cai, C. Org. Biomol. Chem. 2014, 12, 5766.
30. Lin, C.-C.; Hsieh, T.-H.; Liao, P.-Y.; Liao, Z.-Y.; Chang, C.-W.; Shih, Y.-C.; Yeh, W.-H. and Chien, T.-C. Org. Lett. 2014, 16, 892.
31. Townsend, L. B. Heterocycles. 2004, 63, 2475.
32. Shikhaliev, K. S.; Shestakov, A. S.; Medvedeva, S. M. and Gusakova, N. V. Russ. Chem. Bull. 2008, 57, 170.
33. Carpenter, R. D.; Lam, K. S. and Kurth, M. J. J. Org. Chem. 2007, 72, 284.
34. Bleda, J. A.; Fresneda, P. M.; Orenes, R. and Molina, P. Eur. J. Org. Chem. 2009, 2490.
35. Yang, D.; Wang, Y.; Yang, H.; Liu, T. and Fu, H. Adv. Synth. Catal. 2012, 354, 477.
36. Anbarasan, P.; Neumann, H. and Beller, M. Chem. Eur. J. 2011, 17, 4217.
37. Yoshida, S.; Hatakeyama, Y.; Johmoto, K.; Uekusa, H. and Hosoya, T. J. Am. Chem. Soc. 2014, 136, 13590.
38. Yang, W.; Chen, J.; Huang, X.; Ding, J.; Liu, M. and Wu, H. Org. Lett. 2014, 16, 5418.
39. Ife, R. J.; Brown, T. H.; Blurton, P.; Keeling, D. J.; Leach, C. A.; Meeson, M. L.; Parsons, M. E. and Theobald, C. J. J. Med. Chem. 1995, 38, 2763.
40. Congiu, C.; Cocco, M. T. and Onnis, V. Bioorg. Med. Chem. Lett. 2008, 18, 989.
41. Katritzky, A. R. and Rees, C. W. (1984) Comprehensive Heterocyclic Chemistry 5 (1nd ed., p. 469). Pergamon Press.
42. Venkatesan, A. M.; Agarwal, A.; Abe, T.; Ushirogochi, H. O.; Santos, D.; Francisco, Z. L.; Lin, Y. I.; Peterson, P. J.; Yang, Y.; Weiss, W. J.; Shales, D. M. and Mansour, T. S. Bioorg. Med. Chem. 2008, 16, 1890.
43. Nakamura, T.; Kakinuma, H.; Umemiya, H.; Amada, H.; Miyata, N.; Taniguchi, K.; Bando, K. and Sato, M. Bioorg. Med. Chem. Lett. 2004, 14, 333.
44. Roman, G.; Riley, J. G.; Vlahakis, J. Z.; Kinobe, R. T.; Brien, J. F.; Nakatsu, K. and Szarek, W. A. Bioorg. Med. Chem. 2007, 15, 3225.
45. Bbizhayev, M. A. Life Sci. 2006, 78, 2343.
46. Adams, J. L.; Boehm, J. C.; Gallagher, T. F.; Kassis, S.; Webb, E. F.; Hall, R.; Sorenson, M.; Garigipati, R.; Griswold, D. E. and Lee, J. C. Bioorg. Med. Chem. Lett. 2001, 11, 2867.
47. Steenackers, H. P. L.; Ermolat’ev, D. S.; Savaliya, B.; Weerdt, A. D.; Coster, D. D.; Shah, A.; Eycken, E. V. V.; Vos, D. E. D.; Vanderleyden, J. and Keersmaecker, S. C. J. D. J. Med. Chem. 2011, 54, 472.
48. Li, W.-T.; Hwang, D.-R.; Song, J.-S.; Chen, C.-P.; Chuu, J.-J.; Hu, C.-B.; Lin, H.-L.; and Chen, C.-T. J. Med. Chem. 2010, 53, 2409.
49. Rogers, S. A. and Melander, C. Angew. Chem. Int. Ed. 2008, 47, 5229.
50. Chiriano, G.; Simone, A. D.; Mancini, F.; Perez, D. I. and Roberti, M. Eur. J. Med. Chem. 2012, 48, 206.
51. Ilies, M.; Costanzo, L. D.; North, M. L.; Scott, J. A. and Christianson, D. W. J. Med. Chem. 2010, 53, 4266.
52. Zidar, N.; Montalvão, S.; Hodnik, Ž.; Nawrot, D. A.; Žula, A.; Ilaš, J.; Kikelj, D.; Tammela, P. and Mašič, L. P. Mar. Drugs. 2014, 12, 940.
53. Molina, P.; Fresneda, P. M. and Sanz, M. A. J. Org. Chem. 1999, 64, 2540.
54. Li, W.-T.; Hwang, D.-R.; Song, J.-S.; Chen, C.-P.; Chuu, J.-J.; Hu, C.-B.; Lin, H.-L.; Huang, C.-L.; Huang, C.-Y.; Tseng, H.-Y.; Lin, C.-C.; Chen, T.-W.; Lin, C.-H.; Wang, H.-S.; Shen, C.-C.; Chang, C.-M.; Chao, Y.-S. and Chen, C.-T. J. Med. Chem. 2010, 53, 2409.
55. Zhang, L.; Sathunuru, R.; Caridha, D.; Pybus, B.; O’Neil, M. T.; Kozar, M. P. and Lin, A. J. J. Med. Chem. 2011, 54, 6634.
56. Harris, T. L.; Worthington, R. J. and Melander, C. Bioorg. Med. Chem. Lett. 2011, 21, 4516.
57. Boehm, J. C.; Gleason, J. G.; Pendrak, I.; Sarau, H. M.; Schmidt, D. B.; Foley, J. J. and Kingsbury, W. D. J. Med. Chem. 1993, 36, 3333.
58. Lu, Y.; Chen, J.; Wang, J.; Li, C.-M.; Ahn, S.; Barrett, C. M.; Dalton, J. T.; Li, W. and Miller, D. D. J. Med. Chem. 2014, 57, 7355.
59. Molina, P.; Fresneda, P. M. and Sanz, M. A. J. Org. Chem. 1999, 64, 2540.
60. Zhang, Y. J. Labelled. Compd. Rad. 2002, 45, 1055.
61. Ermolat’ev, D. S. and Eycken, E. V. V. D. J. Org. Chem. 2008, 73, 6691.
62. Lovely, C. J.; Du, H.; Sivappa, R.; Bhandari, M. R.; He, Y. and Dias, H. V. R. J. Org. Chem. 2007, 72, 3741.
63. Yamamoto, Y.; Tsuritani, T. and Mase, T. Tetrahedron Lett. 2008, 49, 876.
64. Gerfaud, T.; Wei, H. L.; Neuville, L. and Zhu, J. Org. Lett. 2011, 13, 6172.
65. Sharghi, H. and Sarvari, M. H. Synthesis. 2003, 2, 243.