本研究探討O-tosylalkylamidoximes與作為1,3-dipolarophile Michael Acceptors的3-dimethylaminopropenones在路易士酸FeCl3催化下進行[3 + 2]合環反應合成2,4-disubstituted imidazoles和2,4,5-trisubstituted imidazoles。
此外，本研究亦探討反應之區域選擇性，製備N-substituted- O-tosylamidoximes此一氮上含烷類取代基之起始物與Michael Acceptors進行反應，純化並透過2-D NMR NOESY鑑定其烷類取代基接在產物imidazole之氮上相對位置，結果推論具高區域選擇性，也藉此暫時推測出其反應機制。

A [3+2] cycloadditon type of process for the iron-catalyzed synthesis of 2,4-disubstituted imidazoles and 2,4,5-trisubstituted imidazoles from O-Tosyl Amide Oximes and 3-dimethylamino-1-propenone as a 1,3-dipolarophile Michael acceptor has been achieved. In order to explore the reaction mechanism and regiochemistry, we synthesized N-substituted-O-tosyl amide oximes as a starting material then the study clarified the regioselectivity and the scope was explored with many substrates. Moreover, the substituted imidazole derivatives are valuable in treatment of many systemic fungal infections.

[1]. Annie Tam, Lan S. Armstrong, and Thomas E. La Cruz, Org. Lett. 2013, 15, 3586-3589.
[2]. Jean-Marie Stutzmann, Georg Andrees Bohme, Alain Bioreau, Dominique Damour, Marc Williams Debono, Arielle Genevois-Borella, Assunta Imperato, Patrick Jimonet, Jeremy Pratt, John C. R. Randle, Yves Ribeill, Marc Vuilhorgne and Serge Mignani. Bioorg. Med. Chem. Lett. 2000, 10, 1133-1137.
[3]. John J. Baldwin, Marcia E. Christy, George H. Denny, Charless N. Habecker, Mark B. Freedman, Paulette A. Lyle, Gerald S. Ponticello, Sandor L. Varga, Dennis M. Gross, and Charless S. Sweet. J. Med. Chem., 1986, 29(6), 1065-1080.
[4]. Shu Liu, Padmavathy Nandha Premnath, Joshua K. Bolger, Tracy L. Perkins, Lindsay O. Kirkland, George Kontopidis, and Campbell McInnes. J. Med. Chem., 2013, 56(4), 1065-1080.
[5]. Robert C. Reid, Mei-Kwan Yau, Ranee Singh,† Johan K. Hamidon, Junxian Lim, Martin J. Stoermer, and David P. Fairlie, J. Med. Chem. 2014, 57, 8459−8470.
[6]. Thierry Canton, Georg Andrees Bohme, Alain Boireau, Franc¸ Oise Bordier, Serge Mignani, Patrick Jimonet, Ghafoor Jahn, Mohammad Alavijeh, James Stygall, Simon Roberts, Clive Brealey, Marc Vuilhorgne, Marc-William Debono, Sylvain Le Guern, Michel Laville, Dominique Briet, Michel Roux, Jean-Marie Stutzmann, and Jeremy Pratt, J Pharmacol Exp Ther. 2001, 299(1), 314-322.
[7]. Kavitha Sudheendran, Dietmar Schmidt, Wolfgang Frey, Jurgen Corrad, Uwe Beifuss*, Tetrahedron, 2014, 70, 1635-1645.
[8]. Kristina Nadrah, Marija Sollner Dolenc, Synlett. 2007, 8, 1257–1258.
[9]. Chia-Chi Lin, Tsung-Han Hsieh, Pen-Yuan Liao, Zhen-Yuan Liao, Chih-Wei Chang, Yu-Chiao Shih, Wen-Hsiung Yeh, and Tun-Cheng Chien, Org. Lett. 2014, 16, 892−895.
[10]. Dinesh Kumar, Damodara N. Kommi, Pradeep Chopra, Md Imam Ansari, and Asit K. Chakraborti, Eur. J. Org. Chem, 2012, 6407-6413.
{[11]~[16]}: 鐵催化使用配體的常見反應，含Grignard試劑的Kumada coupling、含organozincs的Negishi coupling和含organoboron的Suzuki coupling反應之reference
[11]. Sherry, B. D.; Fürstner, A. Acc. Chem. Res. 2008, 41, 1500.
[12]. Czaplik, W. M.; Mayer, M.; Cvengros, J.; von Wangelin, A. J. ChemSusChem 2009, 2, 396.
[13]. Jana, R.; Pathak, T. P.; Sigman, M. S. Chem. Rev. 2011, 111, 1417
[14]. Bauer, I.; Knölker, H.-J.. Chem. Rev. 2015, 115, 3170.
[15]. Bedford, R. B. Acc. Chem. Res. 2015, 48, 1485.
[16]. Cassani, C.; Bergonzini, G.; Wallentin, C.-J. ACS Catal. 2016, 6, 1640.
[17]. 本實驗室謝宗翰學長的論文，”Amidoxime在合成上的應用”，2012年。
[18]. Conrad J. Kowalski, Kevin W. Fields, J. Org. Chem. 1981, 46, 197-201。
[19]. Petr Simunek, Valerio Bertolasi, Antonín Lyckac and Vladimír Macháceka, Org. Biomol. Chem., 2003, 1, 3250–3256.
[20]. Nitin A. Randive, Varun Kumar, Vipin A. Nair, Monatsh Chem. 2010, 141, 1329–1332.
[21]. Yang Tan, Khashayar Ghandi, Synthetic Metals, 2013, 175,183-191.
[22]. Ned D. Heindel , Tetrahedron Lett. 1971, 18, 1439-1440.
[23]. Mathieu Toumi, Marion Barbazanges, Sebastian H. B. Kroll, Hetal Patel, Ali Simak, R. Charles Coombes, Anthony G. M. Barrett, Tetrahedron Lett. 2010, 51, 6126-6128.
[24]. Jihui Li and Luc Neuville, Org. Lett. 2013, 15, 1752-1755.
[25]. Yuelu Zhu, Cheng Li, Jidong Zhang, Mengyao She, Wei Sun, Kerou Wan, Yaqi Wang, Bin Yin, Ping Liu, and Jianli Li, Org. Lett. 2015, 17, 3872−3875