本論文共敘述三部份之研究，第一部份運用相對低毒性或非毒性之催化劑、且具有低成本與耐藥性之特質，其適合操作在多步驟之反應程序上；如碘（iodine）、無水（三價）氯化鐵（anhydrous iron (III) chloride）、硝酸銨鈰（ceric (IV) ammonium nitrate, CAN）與有機鹵化物（organohalide）等。在此，我們運用這些不同催化劑與特性，催化苯硒醇（benzeneselenol）∕硫醇（thiol）與α,β−不飽和羰基化合物（α,β-unsaturated carbonyl compounds）的1,4−共軛加成反應，在適量催化與溫和反應條件下可獲得相對高產率之β−硫橋羰基化物（β-sulfido carbonyl compounds）。尤其是在催化烯烴酮（enones）化物時展現良好之反應性，因此縮短了反應時間並且增加產率。當反應過程使用高氧化試劑之催化劑，如碘與無水氯化鐵逕行離子性催化反應，將有助於避免使用酸（acid）或鹼（base）之催化。而不同於離子性催化劑行為的單電子氧化試劑，推論其扮演促進劑（promoter）之角色而誘發此反應進行自由基（radical）路徑，特別是硝酸銨鈰催化劑的角色，除具有高度的氧化特性可進行離子性催化反應外，亦喜與硫醇化物進行單電子轉移（single electron transfer, SET）程序，經由硫醇自由基陽離子（radical cation）轉而獲得硫基自由基（thiyl radical），可同時進行自由基反應。
此外，我們成功發展僅以溶劑（solvent）為媒介，控制硫醇與β−硝基苯乙烯（β-nitrostyrenes）或共軛硝基化物分別進行加成與取代反應，可具有良好之位向選擇性（regioselectivity）進而合成硝基硫化物（nitro sulfide）與乙烯基硫化物（vinyl sulfide），此二者硫化物具有廣泛的應用價值在有機合成的中間產物。此類方法不同於以往文獻報導，使用多種催化方法或多種過度金屬（transition metal-catalyzed）的配位耦合以獲得乙烯基硫化物；或是使用酸、鹼或氧化試劑催化獲得硝基硫化物。推論其反應決定因素在於熱力控制（thermodynamic control）與自解催化（autocatalysis）行為，對於相關研究與選擇性控制均有詳細探討。
在論文第二部份，我們使用高活性的碘試劑作為新奇催化劑，用以催化苯乙烯（styrenes）系列物與芳香烴環化物（arenes）進行烴−芳香基（hydroarylation）加成反應，可獲得中、高產率的1,1−二芳香基烷烴（1,1-diarylalkanes）主要產物。碘化物在有機合成上除了被廣泛應用在多形態的官能基（functional groups）外，近期亦被開發應用在合成催化用途。因其具有低成本、操作簡易與較少毒性之特性。同時，Friedel-Crafts烷烴化反應（alkylation）發展一百二十五年後至今，在有機合成之研究與應用仍是非常熱門的課題，其應用領域廣泛且實用性高，仍有多數研究將其印證在複雜分子的合成上。在此，我們首次嘗試使用非金屬鹽氧化試劑或是強質子酸催化這類反應，整體反應屬於溫和且易於操作之條件可催化多種取代基質（substituted substrates）進行反應，依然保有合成價值性高的1,1−二芳香基烷烴。
在論文最後部分，探討一系列新型CB1類大麻素受體拮抗劑之抗肥胖藥物的開發研究，以Rimonabant（R141716A, Acomplia™）作為先導化合物進行pyrazole-C5位置的官能基修飾，依生物等同性概念成功引入雜異原子芳香烴環與各式不同炔基取代之新型化合物並顯現高度之CB1受體親和力、功能活性與CB2/1選擇性。此類新穎化合物在體外生物活性（in vitro）分析中也證明CB1受體與pyrazole-C5取代基結合位置應為具疏水性或芳香烴環基團（aromatic residues）的一組蛋白系列，可影響配位子與受體的交互作用與內在性質（intrinsic property）。在探討一系列pyrazole-C5化合物之結構與活性關係（SAR）過程中，也嘗試改變pyrazole-C3位置的carboxamide與pyrazole-C4位置的官能基，發現具高度CB1親和力與CB2/1選擇性的化合物如29, 31−35, 37, 45, 47−48, 54, 55與57−60等，將適合針對減重機制與抗肥胖藥物的特性進一步深入研究動物體內活性（in vivo efficacy）、藥物動力學（pharmacokinetics）及毒理試驗（toxicology）期能獲得具有潛力治療肥胖症的先導藥物或候選藥物。

Abstract

In the first part of this dissertation, we have focused on these use of relatively low or nontoxic reagents, inexpensive reagents, and high tolerance of different functional groups make iodine, anhydrous iron(III) chloride, ceric (IV) ammonium nitrate (CAN) and organohalide suitable for carrying out multistep synthetic sequences. In particular, we have realized a 1,4-conjugated addition of benzeneselenol/thiol to α,β-unsaturated carbonyl compounds mediated by a catalytic amount (10 mol%) of different catalysts obtaining the desired β-sulfido carbonyl compounds in good to excellent yields with absolute 1,4-selectivity under mild and neutral conditions. The enones show enhanced reactivity in these catalysts, thereby reducing reaction times and improving the yields significantly. These use of iodine and anhydrous iron(III) chloride helps to avoid the use of either acid or base catalysts for this conversion. A plausible mechanism has been proposed for the role of CAN, both as a promoter in free radical chain addition as well as a catalyst in the conjugate addition process especially. The use of a strong oxidizing agent such as CAN could easily form a strong coordinate bond with the carbonyl oxygen of the α,β-unsaturated ketone, which in turn increases the electrophilicity of the β-carbon in assisting the conjugate addition reaction to carry out under mild conditions with short reaction times.

Furthermore, we have documented the first successful example of regioselective control in solvent-mediated multiple addition and substitution of thiols to β-nitrostyrenes. These nitro sulfide and vinyl sulfide products could be efficiently synthesized. It’s different from transition metal-catalyzed synthetic methods and/or acid/base catalysts, which have been developed for the preparation of sulfido compounds of various types. Reaction-dependent thermodynamic and autocatalysis mechanisms are suggested. Details regarding the substrate scope and selectivity of this reaction are discussed.

In the second part is focused on Iodine mediates the hydroarylation of styrenes with arenes and heteroarenes to afford 1,1-diarylalkanes in good to high yields. Simple iodine has broad transformation ability of functional groups and can be used widely in organic synthesis. The advantages of iodine are operational simplicity, low cost, and less toxicity. After more than 125 years, the Friedel-Crafts alkylation is still one of the most studied and most utilized reactions in organic synthesis. The great versatility in scope and applicability continues to justify its crucial role in the synthesis of more and more complex molecules. Herein we developed the mild reaction conditions, operational simplicity, and practicability, as well as the applicability to differently substituted substrates, render this transformation an attractive approach to the valuable 1,1-diarylalkanes.

Finally, a novel series of alkynylthiophenes as potent and selective CB1 cannabinoid receptor antagonists has been developed.
Replacing the conventional pyrazole 5-aryl substituent of rimonabant with the 2-thienyl moiety appended with an appropriate alkynyl unit, a novel class of 5-(5-alkynyl-2-thienyl)pyrazole derivatives, behaving as highly potent CB1 receptor antagonists with good CB2/1 selectivity, was discovered. Also disclosed was the finding that a subtle structural modification of these newly developed alkynylthiophenes could result in a distinct difference in the intrinsic property, as demonstrated by compounds 29, and its methylated structural isomers 32 and 35, serving as a neutral antagonist, partial agonist and inverse agonist, respectively. Moreover, closer examination on a variety of alkynyl side chains attached on the C-5 thiophene moiety revealed that 1-hexynyl substituent appeared to be the optimum linker to bestow currently designed compounds (e.g., 45–47) with the most potent CB1 binding affinity, functional activity and excellent selectivity. Current SAR studies suggested that around the pyrazole 5-position of the rimonabant-mimicking molecules, a deep and flat crevice surrounded by a sequence of hydrophobic/aromatic residues should exist in the CB1 receptor binding site.

1. Cremlyn, R. J. An Introduction to Organosulfur Chemistry; John Wiley & Sons: Chischester, 1996.
2. Fujita, E.; Nagao, Y. J. Bioorg. Chem. 1977, 6, 287.
3. (a) Fluharty, A. L. in The Chemistry of the Thiol Group; Patai, S., Ed.; Wiely: New York, 1974; Part 2, pp 589. (b) Trost, B. M.; Keeley, D. E. J. Org. Chem. 1975, 40, 2013.
4. (a) Julia, M.; Badet, B. Bull. Soc. Chim. Fr. 1975, 1363. (b) Shono, T.; Matsumura, Y.; Kashimura, S.; Hatanaka, K. J. Am. Chem. Soc. 1979, 101, 4752. (c) Chang, Y.-H.; Pinnick, H. W. J. Org. Chem. 1978, 43, 373.
5. Cohen, T.; Mura, A. J., Jr.; Shull, D. W.; Fogel, E. R.; Ruffner, R. J.; Falck, J. R. J.Org.Chem. 1976, 41, 3218.
6. Bakuzia, P.; Bakuzis, M. L. F. J.Org.Chem. 1981, 46, 235.
7. (a) Bergman, E. D.; Ginsberg, D.; Rappo, R. Org. React. 1959, 10, 179. (b) Oare, D. A.; Heathcock, C. A. In Topics in Stereochemistry; Eliel, E. L., Wilen, S. H., Eds.; Wiley: New York, 1989; Vol. 9, pp 277.
8. (a) Zhu, S.; Cohen, T. Tetrahedron 1997, 53, 17607. (b) Hiemstra, H.; Wiberg, H. J. Am. Chem. Soc. 1981, 103, 417. (c) Suzuki, K.; Ikekawa, A.; Mukaiyama, T. Bull. Soc. Chem. Jpn. 1982, 55, 3277. (d) Yamashita, H.; Mukaiyama, T. Chem. Lett. 1985, 363. (f) Emori, E.; Arai, T.; Sasai, H.; Shibasaki, M. J. Am. Chem. Soc. 1998, 120, 4043.
9. Kobyashi, S.; Ogawa, C.; Kawamura, M.; Sugiura, M. Synlett. 2001, 983.
10. Bandini, M.; Cozzi, P. G.; Giacomini, M.; Melchiorre, P.; Selva, S.; Umani-Ronchi, A. J. Org. Chem. 2002, 67, 3700.
11. Ranu, B. C.; Dey, S. S.; Samanta, S. ARKIVOC, Issue: iii 2005, 44.
12. Srivastava, N.; Banik, B. K. J. Org. Chem. 2003, 68, 2109.
13. Alam, M. M.; Varala, R.; Adapa, S. R. Tetrahedron Lett. 2003, 44, 5115.
14. Garg, S. K.; Kumar, R.; Chakraborti, A. K. Tetrahedron Lett. 2005, 46, 1721.
15. Garg, S. K.; Kumar, R.; Chakraborti, A. K. Synlett. 2005, 1370.
16. Khatik,G. L.; Kumar, R.; Chakraborti, A. K. Org. Lett. 2006, 8, 2433.
17. (a) Shinde, P. D.; Mahajan, V. A.; Borate, H. B.; Tillu, V. H.; Bal, R.; Chandwadkar, A.; Wakharkar, R. D. J. Mol. Cata. A Chem. 2004, 216, 115. (b) Sreekumar, R.; Rugmini, P.; Padmakumar, R. Tetrahedron Lett. 1997, 38, 6557.
18. Wabnitz, T. C.; Yu, J.-Q.; Spencer, J. B. Synlett 2003, 1070.
19. (a) Yadav, J. S.; Reddy, B. V. S.; Baishya, G. J. Org.Chem. 2003, 68, 7098. (b) Ranu, B. C.; Dey, S. S.; Hajra, A. Tetrahedron 2003, 59, 2417. (c) Ranu, B. C.; Dey, S. S. Tetrahedron 2004, 60, 4183.
20. (a) Harris, J. F.; Stacey, F. W. Organic Reactions; Roger Adams, 1963; vol.13, chap.4. (b) Oswald, A. A. J. Org. Chem. 1961, 26, 842. (c) Bredereck, Wagner, Kottenhahn, Chem. Ber. 1960, 98, 2415. (d) Harman. Chemical abstracts 1950, 44, 8942. (h) Oswald, A. A.; Noel, F. J. Org. Chem. 1961, 26, 3948.
21. (a) Kharasch, M. S.; Fuchs, C. F. J. Org. Chem. 1948, 13, 97. (b) Griesbaum, K. Angew. Chem. Int. Ed. Engl. 1970, 9, 27. (c) Kharasch, M. S.; Nudenberg, W.; Mantell, G. J. J. Org. Chem. 1954, 16, 524.
22. Togo, H.; Iida, S. Synlett. 2006, 2159.
23. For reviews on CAN-mediated reactions, see: (a) Ho, T. L. Ceric ion oxidation in organic chemistry. Synthesis 1973, 347. (b) Ho, T. L. Organic Synthesis by Oxidation with Metal Compounds; Plenum Press: New York, 1986. (c) Imamoto, T. Lanthanide Reagents in Organic Synthesis; Academic Press: London, 1994; p 119. (d) Nair, V.; Mathew, J.; Prabhakaran, J. Chem. Soc. Rev. 1997, 127. (e) Hwu, J. R.; King, K.-Y. Curr. Sci. 2001, 8, 1043.
24. Molander, G. A. Chem. Rev. 1992, 92, 29.
25. (a) Heiba, E. I.; Dessau, R. M. J. Am. Chem. Soc. 1972, 94, 2888. (b) Heiba, E. I.; Dessau, R. M. J. Am. Chem. Soc. 1971, 93, 995. (c) Heiba, I.; Dessau, R. M.; Rodewald, P. G. J. Am. Chem. Soc. 1974, 96, 7977. (d) Heiba, E. I.; Dessau, R. M. J. Am. Chem. Soc. 1971, 93, 524.
26. Renaud, P. In Radical in Organic Synthesis; Sibi, M. P., Ed.; Wiley: New York, 2001; Vol. 1, pp 219
27. Nair, V.; Augustine, A. Organic Lett. 2003, 5, 543.
28. (a) Freeman, F. Chem. Rev. 1984, 64, 117. (b) Folkins, P. L.; Harpp, D. N. J. Am. Chem. Soc. 1991, 113, 8998. (c) Gu, D.; Harpp, D. N. Tetrahedron Lett. 1993, 34, 67. (d) Ho, T. L. Synthesis 1972, 561.
29. (a) Christoffers, J. Chem. Commun. 1997, 943. (b) Christoffers, J. J. Chem. Soc., Perkin Trans. 1 1997, 3141.
30. (a) Watahiki, T.; Oriyama, T. Tetrahedron Lett. 2002, 43, 8959. (b) Watahiki, T.; Akabane, Y.; Mori, S.; Oriyama, T. Org. Lett. 2003, 5, 3045. (c) Durandetti, M.; Meignein, C.; Perichon, J. J. Org. Chem. 2003, 68, 3121.
31. (a) Molander, G. A.; Etter, J. B. Tetrahedron Lett. 1984, 25, 3281. (b) Molander, G. A.; Etter, J. B. J. Org. Chem. 1986, 51, 1778. (c) Molander, G. A.; McKie, J. A. J. Org. Chem. 1991, 56, 4112. (d) Molander, G. A.; McKie, J. A. J. Org. Chem., 1993, 58, 7216. (e) Molander, G. A.; Shakya, S. R. J. Org. Chem. 1994, 59, 3445.
32. (a) Olah, G. A.; Kobayashi, S.; Tashiro, M. J. Am. Chem. Soc. 1972, 94, 7448. (b) For a review on iron-catalyzed Friedel-Craft acylations, see: Pearsons, D. E.; Buehler, C. A. Synthesis 1972, 533. (c) Effenberger, F.; Steegmuller, D. Chem. Ber. 1988, 121, 117. (d) Desmurs, J. R.; Dubac, J.; Laporterie, A.; Laporte, C.; Marquie, J. PCT Int. Appl. WO 9840339 (Rhodia Chimie, Fr.); (e) Laporte, C.; Marquie, J.; Laporterie, A.; Desmurs, J. R.; Dubac, J. C. R. Acad. Sci. Paris, t. 2, Ser. IIc 1999, 455. (f) Marquie, J.; Laporte, C.; Laporterie, A.; Dubac, J.; Desmurs, J. R.; Roques, N. Ind. Eng. Chem. Res. 2000, 39, 1124. (g) Marquie, J.; Laporterie, A.; Dubac, J.; Roques, N.; Desmurs, J.-R. J. Org. Chem. 2001, 66, 421. (h) Choudary, B. M.; Chowdari, N. S.; Kantam, M. L.; Kannan, R. Tetrahedron Lett. 1999, 40, 2859. (i) Tanemura, K.; Suzuki, T.; Nishida, Y.; Satsumabayashi, K.; Horaguchi, T. Chem. Lett. 2003, 32, 932. (j) Jovel, I.; Mertins, K.; Kischel, J.; Zapf, A.; Beller, M. Angew. Chem., Int. Ed. 2005, 44, 3913. (l) Kischel, J.; Jovel, I.; Mertins, K.; Zapf, A.; Beller, M. Org. Lett. 2006, 8, 19. (m) Li, R.; Wang, S. R.; Lu, W. Org. Lett. 2007, 9, 2219.
33. (a) Friedel-Crafts and Related Reactions; Olah, G. A., Ed.; Wiley-Interscience: New York, 1963-1965; Vol. I-IV; (b) Friedel-Crafts Chemistry; Olah, G. A., Ed.; Wiley: New York, 1973. (c) Heaney, H. in Comprehensive Organic Synthesis; Trost, B. M., Ed.; Pergamon Press: Oxford, 1991; Vol. 2, p 733.
34. Karjala, S. A.; McElvain, S. M. J. Am. Chem. Soc. 1993, 55, 2966.
35. Free Radicals in Organic Chemistry; Fossey, J.; Lefort, D.; Sorba, J., Ed.; Wiely: New York, 1995; pp. 109.
36. (a) Jung, M. E.; Gervoy, J. J. Am. Chem. Soc. 1991, 113, 224. (b) Jung, M. E.; Trifunovich, I. D.; Lensen, N. Tetrahedron Lett. 1992, 33, 6719.
37. (a) Russell, G. A.; Li, C.; Chen, P. J. Am. Chem. Soc. 1996, 118, 9831. (b) Curran, D. P.; Tamine, J. J. Org. Chem. 1991, 56, 2746. (c) Franz, J. A.; Bushaw, B. A.; Alnajjar, M. S. J. Am. Chem. Soc. 1989, 111, 268. (d) Free Radical in Organic Chemistry; Fossey, J.; Lefort, D.; Sorba, J., Ed.; Wiely: New York, 1995; pp 80 & pp 99.
38. (a) Levander, O. A. Selenium. In Trace Elements in Human and Animal Nutrition; Mertz, W. Ed.; Academic Press: Orlando, 1986, vol. 2, p 209. (b) Levander, O. A. A. Rev. Nutr. 1987, 7, 227. (c) Neve, J. Biological Functions of Selenium. In Selenium in Medicine and Biology; Neve, J., Favier, A., Eds.; W. de Gruyter: Berlin, 1988; pp 97. (d) Selenium in Biology and Human Health; Burk, R. F., Ed.; Springer-Verlag: New York, 1994. (e) Ganther, H. E. Carcinogenesis 1999, 20, 1657. (f) Mugesh, G.; du Mont, W.-W.; Sies, H. Chem. Rev. 2001, 101, 2125.
39. (a) Flohé, L.; Günzler, E. A.; Schock, H. H. FEBS Lett. 1973, 32, 132. (b) Rotruck, J. T.; Pope, A. L.; Ganther, H. E.; Swanson, A. B.; Hafeman, D. G.; Hoekstra, W. G. Science 1973, 179, 588.
40. (a) Perkins, M. J.; Smith, B. V.; Turner, E. S. J. Chem. Soc. Chem. Commun. 1980, 20, 977. (b) Akiyama, R.; Kobayashi, S. J. Am. Chem. Soc. 2003, 125, 3412.
41. Clarembeau, M.; Cravador, A.; Dumont, W.; Hevesi, L; Krief, A. Tetrahedron. 1985, 41, 4793.
42. Gilman, H.; Cason, L. F. J. Am. Chem. Soc. 1951, 73, 1074.
43. (a) Corey, E. J.; Estreicher, H. J. Am. Chem. Soc. 1978, 100. 6294. (b) Seebach, D.; Colvin, E. W.; Weller, T. Chimia 1979, 33, 1. (c) Barrett, A. G. M.; Graboski, G. G. Chem. Rev. 1986, 86, 751. (d) Rosini, G.; Ballini, R. Synthesis 1988, 833. (e) Kabalka, G. W.; Guindi, L. H. M.; Varma, R. S. Tetrahedron 1990, 46, 7443. (f) Lewis, R. J.; Moodie, R. B. J. Chem. Soc., Perkin Trans. 2 1997, 563. (g) Adams, J. P.; Paterson, J. R. J. Chem. Soc., Perkin Trans. 1 1999, 749. (h) Adams, J. P.; Paterson, J. R. J. Chem. Soc., Perkin Trans. 1 2000, 3695. (i) Perekalin, V. V.; Lipina, E. S.; Berestovitskaya, V. M.; Efremov, D. A. Nitroalkenes, Conjugated Nitro Compounds; Wiley & Sons, Ltd.: Chichester, 1994. (j) Olah, G. A.; Malhotra, R.; Narang, S. C. Nitration: Methods and Mechanisms; VCH: New York, 1989.
44. (a) Buckley, G. D. J. Chem. Soc. 1947, 1494. (b) Buckley, G. D.; Ellery, E. J. J. Chem. Soc. 1947, 1497. (c) Ashwood, M. S.; Bell, L. A.; Houghton, P. G.; Wright, S. H. B. Synthesis 1988, 379.
45. (a) Bedford, C. D.; Nielsen, A. T. J. Org. Chem. 1978, 43, 2460. (b) Hayama, T.; Tomoda, S.; Takeuchi, Y.; Nomura, Y. Tetrahedron Lett. 1983, 24, 2795. (c) Seebach, D.; Knochel, P. Helv. Chim. Acta 1984, 67, 261. (d) Seebach, D.; Giorgio, C.; Knochel, P. Tetrahedron 1985, 41, 4861. (e) Hanson, A. T.; Nillson, M. Tetrahedron 1982, 38, 389. (f) Stiver, S.; Yates, P. J. Chem. Soc., Chem. Commun. 1983, 50.
46. (a). Retherford, C.; Yeh, M.-C. P.; Schipor, I.; Chen, H. G.; Knochel, P. J. Org. Chem. 1989, 54, 5200. (b) Retherford, C.; Knochel, P. Tetrahedron Lett. 1991, 32, 441. (c) Jubert, C.; Knochel, P. J. Org. Chem. 1992, 57, 5425. (d) Jubert, C.; Knochel, P. J. Org. Chem. 1992, 57, 5431.
47. (a) Yao, C.-F.; Chen, W.-C.; Lin, Y.-M. Tetrahedron Lett. 1996, 37, 6339. (b) Yao, C.-F.; Kao, K.-H.; Liu, J.-T.; Chu, C.-M.; Wang, Y.; Chen,W.-C.; Lin, Y.-M.; Lin, W.-W.; Yan, M.-C.; Liu, J.-Y.; Chuang, M.-C.; Shiue, J.-L. Tetrahedron 1998, 54, 791. (c) Yan, M.-C.; Tu, Z.; Lin, C.; Yao, C.-F. Tetrahedron Lett, 2002, 43, 7991.
48. (a) Yao, C.-F.; Yang, C.-S.; Fang, H.-Y. Tetrahedron Lett. 1997, 38, 6419. (b) Kao, K.-H.; Yang, C.-S.; Liu, J.-T; Lin, W.-W.; Fang, H.-Y.; Yao, C.-F.; Chen. C. Tetrahedron 1998, 54, 13997. (c) Yan, M.-C.; Liu, J.-Y.; Lin, W.-W.; Kao, K.-H.; Liu, J.-T; Jang, J.-J.; Yao, C.-F. Tetrahedron 1999, 55, 12493. (d) Tu, Z.; Jang, Y.; Lin, C.; Liu, J.-T.; Hsu, J.; Sastry, M. N. V. N.; Yao, C.-F. Tetrahedron 2005, 61, 10541. (e) Gao, S.; Tu, Z.; Kuo, C.-W.; Liu, J.-T.; Chu, C.-M.; Yao, C.-F. Organic & Biomolecular Chemistry 2006, 4, 2851. (f) Liu, J.-T; Lin, W.-W.; Jang, J.-J.; Liu, J.-Y.; Yan, M.-C.; Hung, C.; Kao, K.-H.; Wang, Y.; Yao, C.-F. Tetrahedron 1999, 55, 7115.
49. (a) Yao, C.-F.; Chu , C.-M.; Liu, J.-T. J. Org. Chem. 1998, 63, 719. (b) Chu, C.-M.; Liu, J.-T.; Lin, W.-W.; Yao, C.-F. J. Chem. Soc. Perkin Trans. 1 1999, 47. (c) Liu, J.-Y.; Liu, J.-T; Yao, C.-F. Tetrahedron Lett. 2001, 42, 3613. (d) Liu, J.-T.; Jang, Y.-J.; Shih, Y.-K.; Hu, S.-R.; Chou, C.-M.; Yao, C.-F. J. Org. Chem. 2001, 66, 6021.
50. (a) Jang, Y-J.; Shih, Y.-K.; Liu, J.-Y.; Kuo, W.-Y.; Yao, C.-F. Chem. Eur. J. 2003, 9, 2123. (b) Jang, Y.-J.; Yan, M.-C.; Wu, J.; Lin, Y.-F.; Yao, C.-F. J. Org. Chem. 2004, 69, 3961. (c) Jang, Y.-J.; Wu, J.; Lin, Y.-F.; Yao, C.-F. Tetrahedron 2004, 60, 6565.
51. (a) Cason, L. F.; Wanser, C. C. J. Am. Chem. Soc. 1951, 73, 142. (b) Ménand, M..; Dalla, V. Syn. Lett. 2005, 95.
52. 王界傑，利用Baylis-Hillman反應產物製備噁唑類化合物以及利用自由基反應製備乙烯硫化物，國立台灣師範大學化學研究所碩士論文，中華民國九十四年六月，pp. 117.
53. (a) Gschwend, H. W.; Rodriguez, H. R. Org. React. 1979, 26, 32. (b) Oshima, K.; Shimoji, K.; Takahashi, H.; Yamamoto, H.; Nozaki, H. J. Am. Chem. Soc. 1973, 95, 2694; (c) Takeda, T.; Furukawa, H.; Fujimori, M.; Suzuki, K.; Fujiwara, T. Bull. Chem. Soc. Jpn. 1984, 57, 1863.
54. (a) Cookson, R. C.; Persons, P. J. J. Chem. Soc., Chem. Commun. 1976, 990. (b) Takeda, T.; Fujiwara, T. Chem. Lett. 1982, 11, 1113. (c) Morris, T. H.; Smith, E. H.; Walsh, R. Chem. Commun. 1987, 964. (d) Magnus, P.; Quagliato, D. J. Org. Chem. 1985, 50, 1621. (e) Mizuno, H.; Domon, K.; Masuya, K.; Tanino, K.; Kuwajima, I. J. Org. Chem. 1999, 64, 2648. (f) Domon, K. M. K.; Tanino, K.; Kuwajima, I. Synlett 1996, 157.
55. (a) Trost, B. M.; Vladuchick, W. C.; Bridges, A. J. J. Am. Chem. Soc. 1980, 102, 3548. (b) Blatcher, P.; Grayson, J. I.; Warren, S. J. Chem. Soc., Chem. Commun. 1978, 657. (c) Cohen, T.; Mura, A. J., Jr.; Shull, D. W.; Fogel, E. R.; Ruffner, R. J.; Falck, J. R. J. Org. Chem. 1976, 41, 3218. (d) Gundermann, K. D.; Holmanon, D. Angew. Chem., Int. Ed. Engl. 1966, 5, 668. (e) Hopkins, P. B.; Fuchs, P. L. J. Org. Chem. 1978, 43, 1208. (f) Takeda, T.; Fujii, T.; Morita, K.; Fujiwara, T. Chem. Lett. 1986, 15, 1311. (g) Narasaka, K.; Hayashi, Y.; Shimadzu, H.; Niihata, S. J. Am. Chem. Soc. 1992, 114, 8869. (h) Takeda, T.; Fujiwara, T. Synlett 1996, 481.
56. Trost, B. M.; Lavoie, A. C. J. Am. Chem. Soc. 1983, 105, 5075.
57. (a) Sader, H. S.; Johnson, D. M.; Jones, R. N. Antimicrob. Agents Chemother. 2004, 48, 53. (b) Johannesson, P.; Lindeberg, G.; Johansson, A.; Nikiforovich, G. V.; Gogoll, A.; Synnergren, B.; Le Greves, M.; Nyberg, F.; Karlen, A.; Hallberg, A. J. Med. Chem. 2002, 45, 1767. (c) Ceruti, M.; Balliano, G.; Rocco, F.; Milla, P.; Arpicco, S.; Cattel, L.; Viola, F. Lipids 2001, 36, 629. (d) Marcantoni, E.; Massaccesi, M.; Petrini, M.; Bartoli, G.; Bellucci, M. C.; Bosco, M.; Sambri, L. J. Org. Chem. 2000, 65, 4553. (e) Lam, H. W.; Cooke, P. A.; Pattenden, G.; Bandaranayake, W. M.; Wickramasinghe, W. A. J. Chem. Soc., Perkin Trans. 1 1999, 847. (f) Morimoto, K.; Tsuji, K.; Iio, T.; Miyata, N.; Uchida, A.; Osawa, R.; Kitsutaka, H.; Takahashi, A. Carcinogenesis 1991, 12, 703.
58. (a) Weizevich, P. J.; Turner, L. B.; Frolich, P. K. Ind. Eng. Chem. 1933, 25, 295. (b) Bernstein, S.; Dorfmann, L. J. Am. Chem. Soc. 1946, 68, 1152. (c) Rosenkranz, G.; Kaufmann, S.; Romo, J. J. Am. Chem. Soc. 1949, 71, 3689. (d) Ralls, J. D.; Dodson, R. M.; Riegel, B. J. Am. Chem. Soc. 1949, 71, 3320. (e) Campaigne, E.; Leal, J. R. J. Am. Chem. Soc. 1954, 76, 1272. (f) Campaigne, E.; Mose, R. D. J. Am. Chem. Soc. 1954, 76, 1269. (g) Mukaiyama, T.; Saigo, K. Chem. Lett. 1973, 479.
59. Tanigawa, Y. unpublished work in these laboratories. Also see Trost, B. M.; Bridges, A. J. Org. Chem. 1975, 40, 2014.
60. (a) Ichinose, Y.; Wakamatsu, K.; Nozaki, K.; Birbaum, J. L.; Oshima, K.; Utimoto, K. Chem. Lett. 1987, 1647. (b) Benati, L.; Montevecchi, P. C.; Spagnolo, P. J. Chem. Soc., Perkin Trans. 1 1991, 2103. (c) Benati, L.; Capella, L.; Montevecchi, P. C.; Spagnolo, P. J. Chem. Soc., Perkin Trans. 1 1995, 1035. (d) Beauchemin, A.; Gareau, Y. Phosphorus, Sulfur Silicon Relat. Elem. 1998, 139, 187.
61. (a) Mcdonald, J. W.; Corbin, J. L.; Newton, W. E. Inorg. Chem. 1976, 15, 2056. (b) Kuniyasu, H.; Ogawa, A.; Sato, K. I.; Ryu, I.; Kambe, N.; Sonoda, N. J. Am. Chem. Soc. 1992, 114, 5902. (c) Ogawa, A.; Ikeda, T.; Kimura, K.; Hirao, T. J. Am. Chem. Soc. 1999, 121, 5108. (d) Backvall, J. E.; Ericsson, A. J. Org. Chem. 1994, 59, 5850. (e) Koelle, U.; Rietmann, C.; Tjoe, J.; Wagner, T.; Englert, U. Organometallics 1995, 14, 703. (f) Sugoh, K.; Kuniyasu, H.; Sugae, T.; Ohtaka, A.; Takai, Y.; Tanaka, A.; Machino, C.; Kambe, N.; Kurosawa, H. J. Am. Chem. Soc. 2001, 123, 5108.
62. (a) Murahashi, S.; Yamamura, M.; Yanagisawa, K.; Mita, N.; Kondo, K. J. Org. Chem. 1979, 44, 2408. (b) Foa, M.; Santi, R.; Garavaglia, F. J. Organomet. Chem. 1981, 206, C29 (c) Baranano, D.; Mann, G.; Hartwig, J. F. Curr. Org. Chem. 1997, 1, 287. (d) Rane, A. M.; Miranda, E. I.; Soderquist, J. A. Tetrahedron Lett. 1994, 35, 3225. (e) Li, G. Y. J. Org. Chem. 2002, 67, 3643. (f) Bates, C. G.; Saejueng, P.; Doherty, M. Q.; Venkataraman, D. Org. Lett. 2004, 6, 5005. (g) Commercon, A.; Normant, J.; Villieras, J. J. Organomet. Chem. 1975, 93, 415. (h) Yatsumonji Y., Okada O., Tsubouchi A., Takeda T. Tetrahedron 2006, 62, 9981. (i) Carpita, A.; Rossi, R.; Scamuzzi, B. Tetrahedron Lett. 1989, 30, 2699. (j) Martı´nez, A. G.; Barcina, J. O.; de Fresno Cerezo, A.; Subramanian, L. R. Synlett 1994, 561. (k) Cristau, H. J.; Chabaud, B.; Labaudiniere, R.; Christol, H. J. Org. Chem. 1986, 51, 875.
63. (a) Zincke. Ber. 1869, 2, 737. (b) Zincke. Ann. 1871, 169, 367. (c) Zincke. Ber. 1871, 4, 298. (d) Zincke. Ber. 1872, 161, 93.
64. (a) Grucarevic and Merz. Ber. 1873, 6, 1240. (b) Piccard. Ber. 1874, 7, 1785.
65. Doebner and Stackman. Ber. 1876, 9, 1918.
66. (a) Friedel and Crafts. Compt. rend. 1877, 84, 1392. (b) Friedel and Crafts. Compt. rend. 1877, 84, 1450. (c) Friedel andCrafts. Compt. rend. 1877, 86, 74.
67. Crafts. J. Chem. Soc. 1900, 77, 993 & 1006.
68. Friedel; Crafts and Ador. Ber. 1877, 10, 1854.
69. Friedel andCrafts. Compt. rend. 1877, 84, 1450.
70. (a) Pearson, D. E.; Buehler, C. A. Synthesis 1972, 533. (b) Desmurs, J.-R.; Labrouillere, M.; Dubac, J.; Laporterie, A.; Gaspard, H.; Metz, F. Ind. Chem. Library 1996, 8, 15. (c) Spagnol, M.; Gilbert, L.; Alby, D. Ind. Chem. Library 1996, 8, 29. (d) Kozhevnikov, I. V. Appl. Cat. A 2003, 256, 3. (e) Hachiya, I.; Moriwaki, M.; Kobayashi, S. Bull. Chem. Soc. Jpn. 1995, 68, 2053. (f) Hachiya, I.; Moriwaki, M.; Kobayashi, S. Tetrahedron Lett. 1995, 36, 409. (g) Ranu, B. C.; Ghosh, K.; Jana, U. J. Org. Chem. 1996, 61, 9546. (h) Smyth, T. P.; Corby, B. W. J. Org. Chem. 1998, 63, 8946. (i) Nakano, H.; Kitazume, T. Green Chem. 1999, 1, 179. (j) Le Roux, C.; Dubac, J. Synlett 2002, 181. (k) Ross, J.; Xiao, J. Green Chem. 2002, 4, 129. (l) Gmouh, S.; Yang, H.; Vaultier, M. Org. Lett. 2003, 5, 2219.
71. Sartori, G.; Maggi, R. Chem. Rev. 2006, 106, 1077.
72. Kürti, L.; Czakó, B. Strategic Applications of Named Reactions in Organic Syntyesis; Elsevier Inc.: UK, 2005; pp. 176 & 178.
73. (a) Spagnol, M.; Gilbert, L.; Alby, D. 1996, 8, 29. (b) Ghorpade, S. P.; Darshane, V. S.; Dixit, S. G. Appl. Cat. A 1998, 166, 135. (c) Sukumar, R.; Sabu, K. R.; Bindu, L. V.; Lalithambika, M. Surf. Sci. Catal. 1998, 113, 557. (d) Kumarraja, M.; Pitchumani, K. Synth. Commun. 2003, 33, 105. (e) Nakano, H.; Kitazume, T. Green Chem. 1999, 1, 179. (f) Clark, J. H.; Kybett, A. P.; Macquarrie, D. J.; Barlow, S. J.; Landon, P. J. Chem. Soc., Chem. Commun. 1989, 1353. (g) Cativiela, C.; Garcia, J. I.; Garcia-Matres, M.; Mayoral, J. A.; Figueras, F.; Fraile, J. M., Cseri, T.; Chiche, B. Appl. Cat. A 1995, 123, 273. (h) Retey, J. Naturwissenschaften 1996, 83, 439.
74. (a) Branchadell, V.; Oliva, A.; Bertran, J. J. Mol. Catal. 1988, 44, 285. (b) Branchadell, V.; Oliva, A.; Bertran, J. J. Chem. Soc., Perkin Trans. 2 1989, 1091. (c) Brown, H. C.; Grayson, M. J. Am. Chem. Soc. 1953, 75, 6285. (d) Brown, H. C.; Jungk, H. J. Am. Chem. Soc. 1955, 77, 5584. (e) Brown, H. C.; Jungk, H. J. Am. Chem. Soc. 1955, 77, 5579. (f) DeHaan, F. P.; Delker, G. L.; Covey, W. D.; Ahn, J.; Anisman, M. S.; Brehm, E. C., Chang, J.; Chicz, R. M.; Cowan, R. L. J. Am. Chem. Soc. 1984, 106, 7038. (g) Macknight, E.; McClelland, R. A. Can. J. Chem. 1996, 74, 2518.
75. (a) Dyker, G. Angew. Chem. 1999, 111, 1808; Angew. Chem., Int. Ed 1999, 38, 1698. (b) Dyker, G.; Muth, E.; Hashmi, A. S. K.; Ding, L. Adv. Synth. Catal. 2003, 345, 1247. (c) Liu, J.; Muth, E.; Florke, U.; Henkel, G.; Merz, K.; Sauvageau, J.; Schwalke, E.; Dyker, G. Adv. Synth. Catal. 2006, 348, 456. (d) Muhlthau, F.; Schuster, O.; Bach, T. J. Am. Chem. Soc. 2005, 127, 9348. (e) Tsuchimoto, T.; Ozawa, Y.; Negoro, R.; Shirakawa, E.; Kawakami, Y. Angew. Chem., Int. Ed. 2004, 43, 4231. (f) Sezen, B.; Sames, D. J. Am. Chem. Soc. 2003, 125, 5274 (g) Sezen, B.; Sames, D. Org. Lett. 2003, 5, 3607. (h) Sezen, B.; Sames, D. J. Am. Chem. Soc. 2003, 125, 10580.
76. (a) Murai, S.; Kakiuchi, F.; Sekine, S.; Tanaka, Y.; Kamatami, A.; Sonoda, M.; Chatani, N. Nature 1993, 366, 529. (b) Kakiuchi, F.; Sekine, S.; Tanaka, Y.; Kamatami, A.; Sonoda, M.; Chatani, N.; Murai, S. Bull. Chem. Soc. Jpn. 1995, 68, 62. (c) Kakiuchi, F.; Murai, S. Acc. Chem. Res. 2002, 35, 826. (d) Kakiuchi, F.; Uetsuhara, T.; Tanaka, Y.; Chatani, N.; Murai, S.; J. Mol. Catal. A: Chem. 2002, 182, 511. (e) Guari, Y.; Castellanos, A.; Sabo-Etienne, S.; Chaudret, B. J. Mol. Catal. A: Chem. 2004, 212, 77.
77. (a) Kakiuchi, F.; Yamauchi, M.; Chatani, N.; Murai, S. Chem. Lett. 1996, 111. (b) Jun, C.-H.; Hong, J.-B.; Kim, Y.-H.; Chung, K.-Y. Angew. Chem., Int. Ed. 2000, 39, 3440. (c) Jun, C.-H.; Moon, C. W.; Hong, J.-B.; Lim, S.-G.; Chung, K.-Y.; Kim, Y.-H. Chem. Eur. J. 2002, 8, 485. (d) Lim, Y.-G.; Han, J.-S.; Koo, B. T.; J.-B. Kang, J. Mol. Catal. A: Chem. 2004, 209, 41.
78. (a) Thalji, R. K.; Ahrendt, K. A.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2001, 123, 9692. (b) Ahrend, K. A.; Bergman, R. G.; Ellman, J. A. Org. Lett. 2003, 5, 1301.
79. (a) Shimizu, I.; Meng Khien, K.; Nakajima, M.; Yamamoto, A. Chem. Lett. 1997, 851. (b) Karshtedt, D.; Bell, A. T.; Tilley, T. D. Organometallics 2004, 23, 4169. (c) Bhalla, G.; Oxgaard, J.; Goddard, W. A.; Periana, R. A. Organometallics 2005, 24, 3229.
80. (a) Kakiuchi, F.; Yamamoto, Y.; Chatani, N.; Murai, S. Chem. Lett. 1995, 681. (b) Jia, C. G.; Lu, W. T.; Oyamada, J.; Kitamura, T.; Matsuda, K.; Irie, M. Fujiwara, Y. J. Am. Chem. Soc. 2000, 122, 7252. (c) Kitamura, T.; Yamamoto, K.; Kotani, M.; Oyamada, J.; Jia, C.; Fujiwara, Y. Bull. Chem. Soc. Jpn. 2003, 76, 1889. (d) Reetz, M. T.; Sommer, K. Eur. J. Org. Chem. 2003, 3485.
81. (a) Kischel, J.; Jovel, I.; Mertins, K.; Zapf, A.; Beller, M. Org. Lett. 2006, 8, 19. (b) Rueping, M.; Nachtsheim, B. J.; Scheidt, T. Org. Lett. 2006, 8, 3717. (c) Sun,H.-B.; Li, B,; Hua, R.; Yin, Y. Eur. J. Org. Chem. 2006, 4231. (d) Hajra, S.; Maji, B.; Bar, S. Org. Lett. 2007, 9, 2783.
82. (a) Mallory, F. B.; Mallory, C. W. Org. React. 1984, 30, 1. (b) Yamato, T.; Miyamoto, S.; Hironaka, T.; Miura, Y. Org. Lett. 2005, 7, 3. (c) Nakamura, Y.; Yamazaki, T.; Nishimura, J. Org. Lett. 2005, 7, 3259.
83. (a) Brisbois, R. G.; Wanke, R. A.; Stubbs, K. A.; Stick, R. V. “Iodine Monochloride” Encyclopedia of Reagents for Organic Synthesis; John Wiley & Sons: New York, 2004. (b) Wallingford, V. H.; Krüger, P. A. 5-Iodo-anthranilic Acid. Org. Synth.; Coll. Vol. 2: 1943, pp. 349.
84. Bandini, M.; Melloni, A.; Umani-Ronchi, A. Angew. Chem., Int. Ed. 2004, 43, 550.
85. Ross, R. A. Trends Pharmacol Sci. 2007, 28, 567.
86. Pagotto, U.; Marsicano, G.; Cota, D.; Lutz, B.; Pasquali, R. Endocrine Rev. 2006, 27, 73.
87. Devane, W.; Hanus, L.; Breuer, A. et al. Science 1992, 258, 1946.
88. (a) Mechoulam, R. et al. Biochem. Pharmacol. 1995, 50, 83. (b) Sugiura, T.; Kondo, S.; Sukagawa, A. et al. Biochem. Biophys. Res. Commun. 1995, 215, 89.
89. Fowler, C. Br. J. Pharmacol. 2004, 141, 195. (b) Matias, I.; Bisogno, T.; Marzo, D. V. Int. J. Obes. 2006, 30 (Suppl. 1), S7. (c) Pacher, P.; Batkai, S.; Kunos, G. Pharmacol. Rev. 2006, 58, 389.
90. (a) Alger, B. E. Progress in Neurobiology 2002, 68, 247. (b) Wilson, R.I.; Nicoll, R. A. Science 2002, 296, 678. (c) Freund, T. F.; Katona, I.; Piomelli, D. Physiol. Rev. 2003, 83, 1017.
91. Petitet, F.; Donlan, M.; Michel, A. Chem. Biol. Drug Des. 2006, 67, 252.
92. Lynn, A. B.; Herkenham, M. J. Pharmacol. Exp. Ther. 1993, 268, 1612.
93. (a) Birch, E. A. Lancet 1889, 1, 625. (b) Donovan, M. Dublin Journal of Medical Science 1845, 26, 368. (c) Touw, M. J. Psychoact. Drugs 1981, 13, 23.
94. Osei-Hyiaman, D.; DePetrillo, M.; Pacher, P. et al. J. Clin. Invest. 2005, 115, 1298.
95. Berry, E. M.; Mechoulam, R. Pharmacology & Therapeutics 2002, 95, 185.
96. (a) Lan, R. et al. J. Med. Chem. 1999, 42, 769. (b) Francisco, M. E. I. et al. J. Med. Chem. 2002, 45, 2708. (c) Nakamura-Palacios, E. M. et al. CNS Drug Rev. 1999, 5, 43.
97. For recent reviews, see: (a) Lange, J. H. M.; Kruse, C. G. Drug Disco. Today 2005, 10, 693. (b) Muccioli, G. G.; Lambert, D. M. Expert Opin. Ther. Pat. 2006, 16, 1405. (c) Högenauer, E. K. Expert Opin. Ther. Pat. 2007, 17, 1457.
98. (a) Lange, J. H. M.; vanStuivenberg, H. H.; Coolen, H. K. A. C.; Adolfs, T. J. P.; McCreary, A. C.; Keizer, H. G.; Wals, H. C.; Veerman, W.; Borst, A. J. M.; DeLooff, W.; Verveer, P. C.; Kruse, C. G. J. Med. Chem. 2005, 48, 1823. (b) Plummer, C. W.; Finke, P. E.; Mills, S. G.; Wang, J.; Tong, X.; Doss, G. A.; Fong, T. M.; Lao, J. Z.; Schaeffer, M. T.; Chen, J.; Shen, C. P.; Stribling, D. S.; Shearman, L. P.; Strack, A. M.; Van der Ploeg, L. H. Bioorg. Med. Chem. Lett. 2005, 15, 1441. (c) Tai, C.-L.; Hung, M.-S.; Pawar, V. D.; Tseng, S.-L.; Song, J.-S.; Hsieh, W.-P.; Chiu, H.-H.; Wu, H.-C. Hsieh, M.-T.; Kuo, C.-W.; Hsieh, C.-C.; Tsao, J.-P.; Chao, Y.-S.; Shia, K.-S. Org. Biomol. Chem. 2008, 6, 447.
99. Although a general term “antagonist” is used herein, however, it is understandable that as demonstrated by SR141716A, assessed by the [35S]GTPS and/or cAMP assay(s),[109a-c] many CB1 receptor antagonists behave as inverse agonists. In fact, a more appropriate term “modulator” should be used to describe ligands with unknown intrinsic activity. As for known-function ligands, they are broadly classified as full agonists, partial agonists, (neutral, silent) antagonists and inverse agonists, respectively, as indicated in the literature.[109d-f] However, it should be noted that to determine a ligand’s intrinsic activity is often hard to be performed. (a) Reggio, P.H. Curr. Pharm. Des. 2003, 9, 1607. (b) Meschler, J.P. et al. Biochem. Pharmacol. 2000, 60, 1315.
100. Rinaldi-Carmona, M. et al. J. Pharmacol. Exp. Ther. 2004, 310, 905.
101. (a) Pi-Sunyer, F. X.; Aronne, L. J.; Heshmati, H. M.; Devin, J.; Rosenstock, J. JAMA 2006, 5, 761. (b) Thornton-Jones, Z. D.; Vickers, S. P.; Clifton, P. G. Psychopharmacology (Berlin) 2005, 179, 452. (c) Raynor, H. A.; Niemeier, H. M.; Wing, R. R. Eat. Behav. 2006, 7, 1.
102. (a) Scheen, A. J. Lancet 2006, 368, 1660 (b) Oper, A. Nat. Rev. Drug. Discov. 2007, 6, 334.
103. (a) Cohen, C.; Perrault, G.; Voltz, C.; Steinberg, R.; Soubrie, P. Behav. Pharmacol. 2002, 13, 451. (b) Hungund, B. L.; Basavarajappa, B. S.; Vadasz, C.; Kunos, G.; Rodriguez de Fonseca, F.; Colombo, G.; Serra, S.; Parsons, L.; Koob, G. F. Alcohol. Clin. Exp. Res. 2002, 26, 565.
104. Xia, M.; Liotta, F.; Pan, M.; Wachter, M. P.; Lu, H. WO patent 2007061948.
105. (a) Thornber, C. W. Chem. Soc. Rev. 1979, 8, 563. (b) Moreira, L. M.; Barreiro, E. J. Curr. Med. Chem. 2005, 12, 23. (c) Patani, G. A.; LaVoie, E. J. Chem. Rev. 1996, 96, 3147. (d) Hernandez, M. A.; Rathinavelu, A. Basic Pharmacology: Understanding Drug Action and Reaction. Taylor & Francis Group, 2006, Chapter 3, 68−71. (e) Burger, A. Prog.Drug Res. 1991, 37, 287.
106. Kobayashi, K.; Sugie, A.; Takahashi, M.; Masui, K.; Morl, A. Org. Lett. 2005, 7, 5083.
107. Littke, A. F.; Fu, G. C. Angew. Chem. Int. Ed. 2002, 41, 4176.
108. (a) Shim, J. Y.; Welsh, W. J.; Cartier, E.; Edwards, J. L.; Howlett, A. C. J. Med. Chem. 2002, 45, 1447. (b) Hurst, D. P.; Lynch, D. L.; Barnett-Norris, J.; Hyatt, S. M.; Seltzman, H. H.; Zhong, M.; Song, Z. H.; Nie, J.; Lewis, D.; Reggio, P. H. Mol Pharmacol. 2002, 62, 1274.
109. (a) Govaerts, S. J.; Hermans, E.; Lambert, D. M. Eur. J. Pharm. Sci. 2004, 23, 233. (b) Landsman, R. S.; Burkey, T. H.; Consroe, P.; Roeske, W. R.; Yamamura, H. I. Eur. J. Pharmacol. 1997, 334, R1. (c) Mato, S.; Pazos, A.; Valdizán, E. M. Eur. J. Pharmacol. 2002, 443, 43. (d) Kenakin, T. FESEB J. 2001, 15, 598. (e) de Ligt, R. A.; IJzerman, A. P. Curr. Pharm. Des. 2002, 8, 2333. (f) Salamone, J. D.; McLaughlin, P. J.; Sink, K.; Makriyannis, A.; Parker, L. A. Physio. Behav. 2007, 91, 383 and references therein.
110. Based on the Palczewski’s X-ray structure of bovine rhodopsin,[106,107] molecular modeling studies on 5-alkyl, 5-alkenyl and 5-alkynylthiophene derivatives in the CB1 receptor homology model are currently being carried out in our laboratories. Preliminary results revealed that among various aliphatic substituents on the thiophene ring, the alkynyl group appeared to be the most appropriate choice in the system described above.
111. Hurst, D.; Umejiego, U.; Lynch, D.; Seltzman, H.; Hyatt, S.; Roche, M.; McAllister, S.; Fleischer, D.; Kapur, A.; Abood, M.; Shi, S.; Jones, J.; Lewis, D.; Reggio, P. J. Med. Chem. 2006, 49, 5969 and references therein.
112. Perrin, D. D.; Perrin, D. R. Purification of Laboratory Chemical; 4th. Ed.; Pergamon Press; New York; 1996.
113. Wabnitz, T. C.; Yu, J.-Q.; Spencer, J. B. Chem. Eur. J. 2004, 10, 484.
114. Firouzabadi, H.; Iranpoor, N.; Jafari, A. A. Synlett. 2005, 299.
115. Silva, F. M. D.; Gomes, A. K.; Jones, J. Can. J. Chem. 1999, 77, 624.
116. Flowers, W. T.; Freitas, A. M.; Holt, G.; Purkiss, S. C. J. Chem. Soc. Perkin Trans. 1 1981, 1119.
117. (a) Wabnitz, T. C.; Spencer, J. B. Org. Lett. 2003, 5, 2141. (b) Ranu, B. C.; Mandal, T. Synlett. 2004, 1239.
118. Sabirov, S. S.; Gnevasheva, L. M.; Ismailov, M. I.; Isobaev, M. D. J .Org. Chem. USSR. 1984, 20, 1239.
119. Narasaka,K.; Arai, N.; Okauchi, T. Bull. Chem. Soc. Jpn. 1993, 66, 2995.
120. Nishio, T.; Tokunaga, T.; Omote, Y. Synth. Commun. 1984, 14, 363.
121. (a) Hofslokken, N.; Flock, S.; Skattebol, L. Tetrahedron Lett. 1996, 37, 119. (b) Chan, T.-H.; Brownbridge, P. J. Am. Chem. Soc. 1980, 102, 3534.
122. (a) Fetterly, B. M.; Jana, N. K.; Verkade, J. G. Tetrahedron 2006, 62, 440. (b) Khan, A. T.; Ghosh, S.; Choudhury, L. H. Eur. J. Org. Chem. 2006, 9, 2226. (c) Khatik, G. L.; Kumar, R.; Chakraborti, A. K. Org. Lett. 2006, 8, 2433.
123. Narasaka, K.; Arai, N.; Okauchi, T. Bull. Chem. Soc. Jpn. 1993, 66, 2995.
124. Andrey, O.; Alexakis, A.; Bernardinelli, G. Org. Lett. 2003, 5, 2559.
125. Armarego, W. L. F. J. Chem. Soc. C. 1969, 986.
126. Bordwell, F. G.; Garbisch, Jr., E. W. J. Org. Chem. 1962, 27, 3049.
127. Kotrusz, P.; Toma, S. Molecules 2006, 11, 197.
128. Somanathan, R.; Rivero, I. A.; Aguirre, G.; Ramirez, M.; Hellberg, L. H.; Bakir, F. Synth. Commun. 1996, 26, 1023.
129. (a) Taniguchi, N. J. Org. Chem. 2007, 72, 1241. (b) Annunziata, A.; Galli, C.; Gentili, P.; Guarnieri, A.; Beit-Yannai, M.; Rappoport, Z. Eur. J. Org. Chem.2002, 13, 2136.
130. Zheng, Y.; Du, X.; Bao, W. Tetrahedron Lett. 2006, 47, 1217.
131. Bates, C. G.; Saejueng, P.; Doherty, M. Q.; Venkataraman, D. Org. Lett. 2004, 6, 5005.
132. Ranu, B. C.; Chattopadhyay, K.; Banerjee, S. J. Org. Chem. 2006, 71, 423.
133. Ogawa, A.; Ikeda, T.; Kimura, K.; Hirao, T. J. Am. Chem. Soc. 1999, 121, 5108.
134. Behzadi,; Owen, J. Chem. Soc. Perkin Trans. 1 1973, 2733.
135. Cao, C.; Fraser, L. R.; Love, J. A. J. Am. Chem. Soc. 2005, 127, 17614.
136. Silveira, C. C.; Perin, G.; Braga, A. L.; Dabdoub, M. J.; Jacob, R. G. Tetrahedron. 1999, 55, 7421.
137. Carpita, A.; Rossi, R.; Scamuzzi, B. Tetrahedron Lett. 1989, 30, 2699.
138. Inoue,M. et al. Bull. Chem. Soc. Jpn. 1978, 51, 174.
139. (a) Kopecky, K. R.; Hall, M. C. Can. J. Chem. 1981, 59, 3095. (b) Yamada, F.; Nishiyama, T.; Suzuura, Y.; Yamamura, T. Bull. Chem. Soc. Jpn. 1985, 58, 115.
140. Mertins, K.; Iovel, I.; Kischel, J.; Zapf, A.; Beller, M. Adv. Synth. Catal. 2006, 348, 691.
141. (a) Dieden, R.; Hevesi, L. Synthesis. 1988, 8, 616. (b) Sakakibara, M.; Katsumata, K.; Watanabe, Y.; Toru, T.; Ueno, Y. Synthesis. 1992, 4, 377.
142. (a) Miyoshi, N.; Ishii, H.; Kondo, K.; Murai, S.; Sonoda, N. Synthesis. 1979, 4, 300. (b) Middleton, D. S.; and Simpkins, N. S.; Begley, M. J.; Terrett, N. K. Tetrahedron. 1990, 46, 545.
143. Miyashita, M.; Yoshikoshi, A. Synthesis. 1980, 8, 664.
144. Bouhlel, E.; Hassine, B. B. Synth. Commun. 1992, 22, 2183.
145. (a) Wang, C.; Russell, G. A. J. Org. Chem. 1999, 64, 2066. (b) Serra, A. C.; Corrêa, C.; Silva, M. M. D.; Serra, M. L. C. do Vale. Tetrahedron. 1991, 47, 9463.
146. Felder, C. C.; Joyce, K. E.; Briley, E. M.; Mansouri, J.; Mackie, K.; Blond, O.; Lai, Y.; Ma, A. L. Mol. Pharmacol. 1995, 48, 443.
147. Frang, H.; Mukkala, V. M.; Syysto, R.; Ollikka, P.; Hurskainen, P.; Scheinin, M.; Hemmila, I. Assay Drug Dev. Technol. 2003, 1, 275.