摘要
胍 (guanidines) 是一種具藥理活性的分子, 其主要可做為 NMDA receptor ion channel site ligands。 而氰胺 (cyanamides RR’N–C N) 則是合成胍的前驅物，且氰胺也是一種眾所周知的抗腫瘤 (tumor inhibitors) 藥物。雖然合成氰胺有許多方法，例如:使用氣體氯化氰或溴化氰，在相關胺類化合物催化下合成氰胺。 雖然合成條件還算簡易，但產率皆不高，合成後仍需經繁瑣的純化過程，因此無法商業化量產。本論文研究主要是開發合成氰胺的新方法，利用商業化且具立體障礙的鹼— sodium bis(trimethylsiyl)amide[NaN(SiMe3)2] 化合物和異氰酸酯進行反應，合成高產率且具有藥理活性的氰胺(RR’N–C N) 類化合物，此一新合成方法將可應用於 aliphatic isocyanates, aromatic isocyanates, diisocyanates, 及 acyl isocyanates。

Abstract
Cyanamides (RR’N–C≡N) are known as tumor inhibitors; they are also intermediates in the synthesis of herbicides, and are important precursors in the synthesis of N-alkyl or N-aryl imides. The –C≡N group can be easily removed from a cyanamide, and hence it can be used as a protecting group in the syntheses of secondary and tertiary amines. On the other hand, transformation of cyanamides leads to different classes of organic compounds
such as ureas, carbamates, heterocycles. Due to the widely applications of cyanamides, many of reagents are developed as a cyano cation (CN+) agent to synthesize the cyanamide products, including 2-chlorobenyl thiocyanate, 1-cyanoimidazole, 1-cyanobenzotriiazole, and tosyl cyanide. Most of cyano cation reagents and cyanamides are prepared by the interaction of gaseous cyanogen chloride or cyanogen bromide with amines and with imide salts. Although their syntheses are straightforward, they do not produce quantitative yields and require tedious purification procedures. Herein, we report a ‘one-flask’ transformation method of isocyanates to cyanamides using the commercially available alkali amide NaN(SiMe3)2. This efficiency and convenience method can be applied in aliphatic isocyanates, aromatic isocyanates, aryl isocyanates, and diisocyanates.

(1)　(a) Gilman, A. G.; Goodman, L. S.; Rall, T. W.; Murad, F. Goodman and 　　　　　Gilman’s The Pharmacological Basis of Therapeutics, 7th ed.; Pergamon 　　　　Press: New York, 1990, 899. (b) Saneyoshi, M.; Tokuzen, R.; Maeda, M.; 　　　　Fukuoka, F. Chem. Pharm. Bull. 1968, 16, 505.
(2)　(a) Hu, L. Y.; Guo, J.; Magar, S. S.; Fischer, J. B.; Burke-Howie, K. J.; 　　　Durant, G. J. J. Med. Chem. 1997, 40, 4281. (b) Robinson, J. R.; Brown, 　　　W. H. Can. J. Chem. 1951, 29, 1069.
(3)　Stephens, R. W.; Domeier, L. A.; Todd, M. G.; Nelson, V.A. Tetrahedron 　　　 Lett. 1992, 33, 733.
(4)　(a) Donetti, A.; Omodei-Sale, A.; Mantegani, A. Tetrahedron Lett. 1969, 　　　 39, 3327. (b) Pala, G.; Mantegani, A.; Zugna, E. Tetrahedron 1970, 26, 　　 1275.
(5)　Currie, A. C.; Newbold, G. T.; Spring, F. S. J. Chem. Soc. 1961, 4693.
(6)　Nickon, A.; Fieser, L. F. J. Am. Soc. Chem. 1952, 74, 5566.
(7)　(a) La Mattina, J. L. J. Heterocycl. Chem. 1983, 20, 533.(b) Rastogi, R.; 　　 Sharma, S. Synthesis 1983, 861. (c) Weiss, A.; Winkler, B.; Müller, O. 　　 Synthesis, 1980, 1000.
(8)　Jia, Q.; Cai, T.; Huang, M.; Li, H.; Xian, M.; Poulos, T. L.; Wang, P. G. 　　 J. Med. Chem. 2003, 46, 2271.
(9)　Li, H.; Shimizu, H.; Flinspach, M.; Jamal, J.; Yang, W.; Xian, M.; Gai, 　　　 T.; Wen, E. Z.; Jia, Q.; Wang, P. G.; Poulos, T. S. Biochemistry 2002, 　　 41, 13868.
(10) Pilyugin, V. S.; Mikhailyuk, A. N.; Kosareva, V. M. Russ. J. Org. Chem. 　　　 2002, 38, 1782.
(11) Cai, T.; Xian, M.; Wang, P. G. Bioorg. Med. Chem. Lett. 2002, 12, 1507.
(12) Wheland, R. C.; Martin, E. L. J. Org. Chem. 1975, 40, 3101.
(13) Wu, Y.-Q.; Limburg, D. C.; Wilkinson, D. E.; Hamilton, G. S. Org. Lett. 　　　 2000, 2, 795.
(14) (a) Van Leusen, A. M.; Jagt, J. C. Tetrahedron Lett. 1970, 12, 967. (b) 　　　 Hughes, T. V.; Hammond, S. D.; Cava, M. P. J. Org. Chem. 1998, 63, 401.
(15) Davis, W. A.; Cava, M. P. J. Org. Chem. 1983, 48, 2774.
(16) Jia, Q.; Cai, T.; Hung, M.; Li, H.; Xing, M. J. Med. Chem. 2003, 46, 2741.
(17) Wieloch, T. Science, 1985, 230, 681
(18) Seltzer Z, Cohn S, Ginzburg R and Beilin B. Modulation of neuropathic 　　　　 pain behavior in rats by spinal disinhibition and NMDA receptor blockade 　　 of injury discharge. Pain 45, 69-75, 1991.
(19) Davies SN, Lodge D. Evidence for involvement of N-methyl-D-asparate 　　　　　 receptors in "wind-up" of class 2 neurones in the dorsal horn of the rat. 　　 Brain Res. 424, 402-406, 1987.
(20) Backonja M, Arndt G, Gombar KA, Check B and Zimmermann M. Response of 　　　　 chronic neuropathic pain syndromes to ketamine: a preliminary study. Pain 　　 56, 51-57, 1994.
(21) Greenhill, J. L.; Lue, P. In Progress in Medicinal Chemistry, Ellis, G. 　　　 P.; Luscombe, D. K. Eds.; Elsevier Science: New York, 1993, Vol. 30, 　　　　 Chapter 5.
(22) Paquette, L. A. In Encyclopedia of Reagents for Organic Synthesis; Wiley: 　　 Chichester, UK, 1995, 4564.
(23) Chow, S.; Wen, K.; Sanghvi, Y. S.; Theodorakis, E. A. Bioorg. Med. Chem. 　　 Lett. 2003, 13, 1631.
(24) Hwu, J. R.; Hsu, C. H.; Wong, F. F.; Chung, C.-S.; Hakimelahi, G. H. 　　　　 Synthesis 1998, 32
(25) Hwu, J. R.; Das, A. R.; Yang, C. W.; Huang, J.-J.; Hsu, M.-H. Org. Lett. 　　 2005, 7, 3211.
(26) Marinescu, L.; Thinggaard, J.; Thomsen, I. B.; Bols, M. J. Org. Chem. 　　　　 2003, 68, 9453.
(27) Bakunov, S. A.; Rukavishnikov, A. V.; Tkachev, A. V. Synthesis 2000, 8, 　　　 1148.
(28) Kamijo, S.; Jin, T; Yamamoto, Y. Angew. Chem. 2002, 114, 1858.
(29) Capps, H. H.; Dehn, W. M. J. Am. Chem. Soc. 1932, 54, 4301.
(30) Renodon-Cornière, A.; Dijols, S.; Perollier, C.; Lefevre-Groboillot, D.; 　　 Boucher, J.-L.; Attias, R.; Sari, M.-A.; Stuehr, D.; Mansuy, D. J. Med. 　　　 Chem. 2002, 45, 944.
(31) Castro, J. L.; Ball, R. G.; Broughton, H. B.; Russel, M. G. N.; Rathbone, 　　 D.; Watt, A. P.; Baker, R.; Chapman, K. L.; Fletcher, A. E.; Patel, S.; 　　　 Smith, A. J.; Marshall, G. R.; Ryecroft, W.; Matassa, V. G. J. Med. Chem. 　　 1996, 39, 842.
(32) Gaponik, P. N.; Karavai, V. P.; Davshko, I. E.; Degtyarik, M. M.; 　　　　　　 Bogatikov, A. N. Chem. Heterocycl. Compd. 1990, 26, 1274.
(33) Moryashova, S. I.; Salamandra, L. K.; Fedorov, A. E.; Rodinovskaya, L. 　　　 A.; Shestopalov, A. M.; Semenov, V. V. Russ. Chem. Bl. 1998, 47, 357.
(34) Hartke, K.; Palou,E.; CHBEAM; Chem. Ber. 1966, 99, 3155.
(35) Kwon, C. -H.; Nagasawa, H. T. J. Org. Chem. 1990, 55, 3403.