設計暨合成雙（苯并夫喃-1,3-異環）化合物作為新型抗屈公熱及黃熱病毒之試劑

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研究生：	尼特許 Gupta, Nitesh Kumar
論文名稱：	設計暨合成雙（苯并夫喃-1,3-異環）化合物作為新型抗屈公熱及黃熱病毒之試劑 Design and Syntheses of Bis(benzofuran-1,3-heterocycles)s as New Agents against Chikungunya and Yellow Fever Viruses
指導教授：	胡紀如 Hwu, Jih-Ru
口試委員:	陳貴通 Tan, Kui-Thong 張家靖 Chang, Chia-Ching 蔡淑貞 Tsay, Shwu-Chen 許銘華 Hsu, Ming-Hua
學位類別：	博士 Doctor
系所名稱：	理學院 - 化學系 Department of Chemistry
論文出版年：	2017
畢業學年度：	106
語文別：	英文
論文頁數：	283
中文關鍵詞：	屈公熱、黃熱、抗病毒、苯并夫喃、異環化合物、蘇拉明
外文關鍵詞：	Chikungunya, Yellow Fever, Antiviral, Benzofuran, Heterocycles, Suramin
相關次數：	點閱：2 下載：0
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過去數十年間，，已觀察到許多新型病毒（RNA病毒及新興病毒）散佈至世界各地，，形成未知的疾病。其中屈公熱病毒 (Chikungunya Virus, CHIKV) 及黃熱熱病毒為最典型例子。這兩種病毒主要透過蚊子傳播，，屈公熱病毒曾在非洲、亞洲及中南美洲爆發大規模之感染，，然而截至今日卻沒有任何具顯著效果之抗病毒藥物。此外，黃熱病 (yellow fever)為，一種由黃熱病毒所引起之急性出血疾病，, 儘管已有安全可靠之疫苗，，但仍然缺乏治療且抑制該病毒之藥物。此病毒主要流行於熱帶地區，，涵蓋非洲及中南美洲47個國家，，總計9億人口處於可能感染之範圍。
緣此，我們根據suramin類化合物之結構特性設計並合成出了多種新型雙綴合物數種不同類型之新型雙分子化合物，包括其分屬bis(benzofuran–1,3-thiazolidin-4-one)s， bis(benzofuran–1,3-thiazinan-4-one)s，bis(benzofuran–1,3-imidazolidn-4-one)s，bis(benzofuran–benzofuran)s，bis(benzofuran–1,3-oxazolidin-4-one)s及 bis(benzofuran–imidazoline) 6個家族。並並測試以上雙分子化合物其抑制屈公熱病毒之活性。前述化合物其結構在5員環及6員環中之異原子分別為1,3-N,S, 1,3-N,N, 及1,3-N,O。研究時以我們利用組合化學概念為基礎，利用化學合成法修飾含氮五或六員環上之數種不同取代基，並建立活性化合物之結構活性關係資料庫，並據以探討其結構活性關係時。其中主要的置換之取代基為alkyl，cycloalkyl，arylalkyl，heteroaromatic 及 substituted aryl等。其中芳香環取代基其上可進一步修飾接上上推電子基或拉電子基，雙分子化合物之中心則以亞甲基關節則作為雙綴合物的中心連接。所有以上合成化合物之結構均透過光譜之鑑定（NMR，IR及Mass）。
所有新型雙分子化合物雙綴合化合物皆已經過抗屈公熱測試、抗YFV測試及、細胞生長抑制測試及結構活性關係之鑑定。在cpe還原測定中，於Vetro E6細胞中，雙分子化合物雙綴合物2p，2q， 2t，3p，3q，及 3s之活性數據結果極佳。之於Vetro E6細胞中抗屈公熱病毒活性測試結果極佳，之活性達到EC50介於為1.9至2.7mM 之間，SI值大於介於755或更高。根據抗屈公熱病毒的活性測試之結果，可以知如使用道六員圓環的thiazinanone ring，其活性可能比使用五員圓環的thiazolidinone ring更還要好。一些該等新型雙分子化合物雙綴合物也發現具有抑制Huh-7細胞中YFV strain 17D的效果。其中化合物3u，4e，4n及5k可抑制YFV strain 17D 時，其最佳達到EC50為最低至3.54μM，及SI值最高至為15.3。根據抗YFV黃熱病毒之測試數據，bis(benzofuran-1,3-N,N-heterocycle)s化合物（如化合物4及5）比其他化合物更具有潛力極佳。此外，針對其結構、親油性及抗屈公熱病毒之活性分析可成功推導出21種構效分析及guidelines準則等。
論文中兩個主要研究主題，於化學合成方面，即設計合成新型bis(benzofuran-heterocycle)類之各種雙分子化合物，成果豐碩。於生醫醫藥方面，合成出之化合物具極佳之抗屈公熱病毒及抗黃熱病毒之活性，結果不凡。論文中提及之方法及概念，期可增加全球有機合成及藥物化學相關領域之競合力，於將來研發新型新興病毒之抗病毒藥物時做出貢獻。

Over the past decades, it has been observed that number of new viruses ("RNA viruses and emerging viruses") and other pathogens have spread worldwide, introducing since then unknown diseases into previously unaffected regions. Chikungunya virus (CHIKV) and Yellow fever virus are the best examples of emerging RNA viruses which continuous to cause outbreaks throughout the world. Yellow fever and Chikungunya viruses are transmitted through mosquitoes. There are currently still no approved antiviral drugs to treat or prevent chikungunya virus (CHIKV) infections despite the fact that this arbovirus continues to cause outbreaks in Africa, Asia, and South- and Central-America. Being an acute viral hemorrhagic disease, yellow fever can be prevented by an effective, safe, and reliable vaccine, but cannot be eliminated completely. Unfortunately, there is no antiviral drug available to cure yellow fever. This disease is endemic in tropical areas with a combined population of over 900 million people; most of them are in 47 countries in Africa, Central and South America.
Thus, novel bis-conjugated compounds namely, bis(benzofuran–1,3-thiazolidin-4-one)s, bis(benzofuran–1,3-thiazinan-4-one)s, bis(benzofuran–1,3-imidazolidn-4-one)s, bis(benzofuran–benzofuran)s, bis(benzofuran–1,3-oxazolidin-4-one)s, and bis(benzofuran–imidazoline) were designed based on the structural features of suramin. These new bis-conjugated compounds were synthesized and tested against CHIKV. The hetero atoms in the five- and six-membered rings were 1,3-N,S, 1,3-N,N, and 1,3-N,O. Establishment of structure-activity relationship was done on the basis of chemically synthesized new compounds, in which nitrogen containing five- and six-membered ring were allowed to possess various substituents such as alkyl, cycloalkyl, arylalkyl, heteroaromatic and substituted aryl. The aryl group was allowed to possess different electron donating and electron withdrawing substituents. The methylene joint forms the center of all new bis-cojugates. The structures of all chemically synthesized compounds were confirmed by spectroscopically (NMR, Mass, and IR).
The anti-CHIKV assay, anti-YFV assay, cytostatic determination assays were performed and the structure−activity relationship was established for these new bis-conjugated compounds. In CPE reduction assays, most appealing results were associated with bis-conjugates 2p, 2q, 2t, 3p, 3q, and 3s which inhibited CHIKV replication in Vero E6 cells with EC50 in the range of 1.9 to 2.7 M and selectivity index values of ~75 or higher. Based on the anti-CHIKV activities of the tested compounds, the six-membered thiazinanone ring could be considered superior to the five-membered thiazolidinone ring. Several new bis-conjugated compounds were found to inhibit YFV strain 17D (Stamaril) on Huh-7 cells. The most appealing results were associated with conjugates 3u, 4e, 4n, and 5k which inhibited YFV strain 17D at minimum EC50 of 3.54 μM and maximum selective index value of 15.3. From the anti-YFV assay data we can say that among all the classes, bis(benzofuran-1,3-N,N-heterocycle)s i.e. conjugate 4 and 5 was found to be more potent than other conjugated libraries. Moreover, 22 guidelines were deduced from the analysis of their structures, lipophilicity, anti-CHIKV and anti-YFV activity.
Two major issues have been discussed and solved in this dissertation. These include the design and synthesis of new bis(benzofuran-heterocycle) conjugates and finding anti-CHIKV and anti-YFV leads. By designing and syntheses of these novel anti-CHIKV and -YFV leads, significant contribution has been made in the field of organic and medicinal chemistry, which may be helpful for the researchers around the globe. These results and compounds provide a starting point for further optimization, design, and synthesis of new antiviral agents for these (re)emerging diseases.

Content
Abstract (in English)…………………………………………………………………………… i
Abstract (in Chinese)………………………………………………………………………....... iv
Acknowledgement ………………………………………………………………………..…… vi
Content …………………………………………………………………………………...…... viii
List of Figures ………………………………………………………………………..…… xxxvii
List of Tables ………………………………………………………………………………. xxxix
List of Schemes ………………………………………………………………………………… xl
1. Introduction ………………………………………………………......................................... 1
2. Results ……………………………………………………………………………...……….. 26
2.1 Synthesis of bis(benzofuran–imine)s intermediate 14 ………………………... 26
2.2 Synthesis of novel bis(benzofuran–1,3-thiazolidin-4-one)s conjugates 2 and Their Analogs (1,3-S,N-dimers) …………..…………………………………………… 27
2.3 Synthesis of novel bis(benzofuran–1,3-thiazinan-4-one)s target conjugates 3 and Their Analogs (1,3-S,N-dimers) ……….……………………….…… 28
2.4 Synthesis of 2-(N-methylamino-N-phenyl)acetamide derivatives 19 ……………. 29
2.5 Synthesis of novel bis(benzofuran–1,3-imidazolidin-4-one)s conjugates and Their Analogs 4 (1,3-N,N-dimers) …………...…..………………………………………. 30
2.6 Synthesis of benzofuran-2-carboylate dimer and bisbenzofuroic acid intermediate. 32
2.7 Synthesis of benzofuramide dimer intermediate ……………………….…………. 33
2.8 Synthesis of benzofuran-benzimidazole dimer conjugates and Their Analogs 5 … 34
2.9 Synthesis of bis(benzofuran-benzimidazole) conjugate 5n …………..…………… 36
2.10 Synthesis of novel bis(benzofuran–1,3-oxazolidin-4-one)s conjugates and Their Analogs ……………………………………………………………………………. 37
2.11 5,5'-Methylenebis[2-(4'',5''-dihydo-1H-imidazol-2''-yl)benzofuran] 7.…..………. 38
2.12 Evaluation of Anti−CHIKV Activity ……..……………………………………… 41
2.13 Evaluation of Anti−YFV Activity ………..………………………………………. 43
2.14 Lipophilicity ………………………………………………………………………. 43
3. Discussion …………………………………………………………………………………... 56
3.1 Comparative Studies of Racemic Compound and its Isomers …………..………… 56
3.2 Structural Details and StructureActivity Relationship of Bis(benzofuran-1,3- heterocycle)s cojugates ………...………………………………………………….. 60
3.2a. SAR for Bis-benzofuran Conjugates against Chikungunya virus…………….…..… 59
3.2b. SAR for Bis-benzofuran Conjugates against Yellow Fever virus……………….… 63
4. Conclusion …………………………………………………………………………………... 68
5. Experimentals ………………………………………………………………………………. 69
Materials and methods….………………………...………………………………… 69
5,5'-Methylenebis(salicylaldehyde) (9)…………………………………………….. 71
5,5'-Methylenebis[2-(2'',2''-diethoxy)ethoxy]benzaldehyde (11)………………...… 72
5,5'-Methylenebis(benzofuran-2-carbaldehyde) (12)…………………………...….. 73
Standard Procedure 1 for the Preparation of Bisimines (14)………………….……. 73
5,5'-Methylenebis[N-(benzofuran-2-yl)(methylidene)aniline] (14a)……………..... 74
5,5'-Methylenebis[N-(benzofuran-2-yl)methylidene-4-methylaniline] (14b)…….... 74
5,5'-Methylenebis[N-(benzofuran-2-yl)methylidene-3,5-dimethylaniline] (14c)...… 75
5,5'-Methylenebis[N-(benzofuran-2-yl)methylidene-4-methoxyaniline] (14d)…….. 76
5,5'-Methylenebis[N-(benzofuran-2-yl)methylidene-4-fluoroaniline] (14e)………. 76
5,5'-Methylenebis[N-(benzofuran-2-yl)methylidene-4-chloroaniline] (14f)…….…. 77
5,5'-Methylenebis[N-(benzofuran-2-yl)methylidene-4-bromoaniline] (14g)……… 77
5,5'-Methylenebis[N-(benzofuran-2-yl)methylidene-4-iodoaniline] (14h)………….. 78
5,5'-Methylenebis[N-(benzofuran-2-yl)methylidene-2-fluoroaniline] (14i)……...…. 78
5,5'-Methylenebis[N-(benzofuran-2-yl)methylidene-4-trifuloromethylaniline] (14j). 79
5,5'-Methylenebis[N-(benzofuran-2-yl)(methylidene)pyridin-2-amine] (14k)…….... 79
5,5'-Methylenebis[N-(benzofuran-2-yl)(methylidene)pyrazin-2-amine] (14l)…...…. 80
5,5'-Methylenebis[N-(benzofuran-2-yl)(methylidene)benylamine] (14m)……...…… 80
5,5'-Methylenebis[N-(benzofuran-2-yl)methylidene-4-methylbenylamine] (14n)....... 81
5,5'-Methylenebis[N-(benzofuran-2-yl)methylidene-4-methoxybenzylamine] (14o).. 82
5,5'-Methylenebis[N-(benzofuran-2-yl)(methylidene)ethylamine] (14p)…………..... 82
5,5'-Methylenebis[N-(benzofuran-2-yl)(methylidene)isopropylamine] (14q)……….. 83
5,5'-Methylenebis[N-(benzofuran-2-yl)methylidene-2-hydroxyethylamine] (14r)….. 83
5,5'-Methylenebis[N-(benzofuran-2-yl)methylidene-2-methoxyethylamine] (14s)…. 84
5,5'-Methylenebis[N-(benzofuran-2-yl)(methylidene)cyclopropylamine] (14t)……... 85
5,5'-Methylenebis[N-(benzofuran-2-yl)(methylidene)cycloheptylamine] (14u)….…. 85
Standard Procedure 2 for the Preparation of Bis[(benzofuranyl)thiazolidinones] (2).. 86
(2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5'-Methylenebis[2-(3''-phenyl-4''-oxo- 1'',3''-thiazolidin-2''-yl)benzofuran] (2a)……………………………………...……… 86
(2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5'-Methylenebis(2-[3''-(4-methylphenyl)- 4''-oxo-1'',3''-thiazolidin-2''-yl]benzofuran) (2b)……………………….…………….. 87
(2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5'-Methylenebis(2-[3''-(3,5- dimethylphenyl)-4''-oxo-1'',3''-thiazolidin-2''-yl]benzofuran) (2c)…………….…….. 88
(2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5'-Methylenebis(2-[3''-(4- methoxyphenyl)-4''-oxo-1'',3''-thiazolidin-2''-yl]benzofuran) (2d)………………...… 89
(2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5'-Methylenebis(2-[3''-(4-fluorophenyl)- 4''-oxo-1'',3''-thiazolidin-2''-yl]benzofuran) (2e)…………………………….…….…. 89
(2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5'-Methylenebis(2-[3''-(4- chlorophenyl)-4''-oxo-1'',3''-thiazolidin-2''-yl]benzofuran) (2f)……………………… 90
(2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5'-Methylenebis(2-[3''-(4-bromophenyl)- 4''-oxo-1'',3''-thiazolidin-2''-yl]benzofuran) (2g)……………………………...……… 91
(2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5'-Methylenebis(2-[3''-(4-iodophenyl)- 4''-oxo-1'',3''-thiazolidin-2''-yl]benzofuran) (2h)…………………………………...… 92
(2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5'-Methylenebis(2-[3''-(2-fluorophenyl)- 4''-oxo-1'',3''-thiazolidin-2''-yl]benzofuran) (2i)…………………………………...…. 92
(2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5'-Methylenebis(2-[3''-(4- trifluoromethyl phenyl)-4''-oxo-1'',3''-thiazolidin-2''-yl]benzofuran) (2j)…………… 93
(2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5'-Methylenebis(2-[3''-(pyridin-2- yl)-4''-oxo-1'',3''-thiazolidin-2''-yl]benzofuran) (2k)……………………………….… 94
(2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5'-Methylenebis(2-[3''-(pyrazin-2-yl)-4''- oxo-1'',3''-thiazolidin-2''-yl]benzofuran) (2l)………………………………………... 95
(2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5'-Methylenebis[2-(3''-benzyl-4''- oxo-1'',3''-thiazolidin-2''-yl)benzofuran] (2m)…………………….………………… 95
(2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5'-Methylenebis(2-[3''-(4-methylbenzyl)- 4''-oxo-1'',3''-thiazolidin-2''-yl]benzofuran) (2n)…………………………………….. 96
(2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5'-Methylenebis(2-[3''-(4- methoxybenzyl)-4''-oxo-1'',3''-thiazolidin-2''-yl]benzofuran) (2o)…………………… 97
(2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5'-Methylenebis[2-(3''-ethyl-4''-oxo- 1'',3''-thiazolidin-2''-yl)benzofuran] (2p)…………………………………………...… 98
(2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5'-Methylenebis[2-[3''-isopropyl(-4''- oxo-1'',3''-thiazolidin-2''-yl)benzofuran] (2q)………………………………………… 99
(2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5'-Methylenebis(2-[3''-(2-hydroxyethyl)- 4''-oxo-1'',3''-thiazolidin-2''-yl]benzofuran) (2r)……………...…………………….. 100
(2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5'-Methylenebis(2-[3''-(2-methoxyethyl)- 4''-oxo-1'',3''-thiazolidin-2''-yl]benzofuran) (2s)……………………………...…….. 100
(2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5'-Methylenebis[2-(3''-cyclopropyl-4''- oxo-1'',3''-thiazolidin-2''-yl)benzofuran] (2t)………………..……………………… 101
(2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5'-Methylenebis[2-(3''-cycloheptyl-4''- oxo-1'',3''-thiazolidin-2''-yl)benzofuran] (2u)……………………………………….. 102
Standard Procedure 3 for the Preparation of Bis[(benzofuranyl)thiazinanones] (3)… 103
(2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5'-Methylenebis[2-(3''-phenyl-4''-oxo- 1'',3''-thiazinan-2''-yl)benzofuran] (3a)……………………………………..……….. 103
(2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5'-Methylenebis(2-[3''-(4-methylphenyl)- 4''-oxo-1'',3''-thiazinan-2''-yl]benzofuran) (3b)………………………………...…… 104
(2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5'-Methylenebis(2-[3''-(3,5- dimethylphenyl)-4''-oxo-1'',3''-thiazinan-2''-yl]benzofuran) (3c)…………………… 105
(2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5'-Methylenebis(2-[3''-(4- methoxyphenyl)-4''-oxo-1'',3''- thiazinan-2''-yl]benzofuran) (3d)…………..…….… 106
(2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5'-Methylenebis(2-[3''-(4-fluorophenyl)- 4''-oxo-1'',3''- thiazinan-2''-yl]benzofuran) (3e)……………………………...……… 106
(2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5'-Methylenebis(2-[3''-(4-chlorophenyl)- 4''-oxo-1'',3''- thiazinan-2''-yl]benzofuran) (3f)……………………………………… 107
(2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5'-Methylenebis(2-[3''-(4-bromophenyl)- 4''-oxo-1'',3''- thiazinan-2''-yl]benzofuran) (3g)……………………………………... 108
(2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5'-Methylenebis(2-[3''-(4-iodophenyl)- 4''-oxo-1'',3''- thiazinan-2''-yl]benzofuran) (3h)………………………………..…… 109
(2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5'-Methylenebis(2-[3''-benzyl-4''-oxo- 1'',3''-thiazinan-2''-yl]benzofuran) (3m)…………………………………………….. 109
(2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5'-Methylenebis(2-[3''-(4-methylbenzyl)- 4''-oxo-1'',3''-thiazinan-2''-yl]benzofuran) (3n)…………………………………...… 110
(2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5'-Methylenebis(2-[3''-(4- methoxybenzyl)-4''-oxo-1'',3''-thiazinan-2''-yl]benzofuran) (3o)…………………… 111
(2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5'-Methylenebis(2-[3''-ethyl-4''-oxo- 1'',3''-thiazinan-2''-yl]benzofuran) (3p)……...…………………………………...…. 112
(2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5'-Methylenebis(2-[3''-isopropyl-4''-oxo- 1'',3''-thiazinan-2''-yl]benzofuran) (3q)……… ..…………………………………… 113
(2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5'-Methylenebis(2-[3''-(2-hydroxyethyl)- 4''-oxo-1'',3''-thiazinan-2''-yl]benzofuran) (3r)……………………………………… 113
(2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5'-Methylenebis(2-[3''-(2-methoxyethyl)- 4''-oxo-1'',3''-thiazinan-2''-yl]benzofuran) (3s)……………………………………… 114
(2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5'-Methylenebis(2-[3''-cyclopropyl-4''- oxo-1'',3''-thiazinan-2''-yl]benzofuran) (3t)…………………………………………. 115
(2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5'-Methylenebis(2-[3''-cycloheptyl-4''- oxo-1'',3''-thiazinan-2''-yl]benzofuran) (3u)………………………………………… 116
Standard Procedure 4 for the Preparation of N-Me-amides (19)…………….….…… 117
N-Phenyl-2-(methylamino)acetamide (19a)………………………………………… 117
N-(4-Methylphenyl)-2-(methylamino)acetamide (19b)…………………………….. 118
N-(2,3-Dimethylphenyl)-2-(methylamino)acetamide (19c)……………………...… 118
N-(2,5-Dimethylphenyl)-2-(methylamino)acetamide (19d)...…………………….... 119
N-(3,5-Dimethylphenyl)-2-(methylamino)acetamide (19e)………………………… 120
N-(2-Ethylphenyl)-2-(methylamino)acetamide (19f)……………………………...... 120
N-(3-Isopropylphenyl)-2-(methylamino)acetamide (19g)………………………….. 121
N-(4-Methoxyphenyl)-2-(methylamino)acetamide (19h)…………………………... 121
N-(Benzo[d][1,3]dioxol-5-yl)-2-(methylamino)acetamide (19i)………………….... 122
N-(4-Fluorophenyl)-2-(methylamino)acetamide (19j)……………………………… 122
N-(4-Chlorophenyl)-2-(methylamino)acetamide (19k)…………………………….. 123
N-(4-Bromophenyl)-2-(methylamino)acetamide (19l)……………………………… 124
N-(4-Iodophenyl)-2-(methylamino)acetamide (19m)…...…………………………. 124
N-(3-Trifluoromethylphenyl)-2-(methylamino)acetamide (19n)……………...……. 125
Standard Procedure 5 for the Preparation of Bis[(benzofuranyl)imidazolidin-4-ones] 125
(2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5'-Methylenebis[2-(N-methyl-3''-phenyl- 4''-oxo-1'',3''-imidazolidin-2''-yl)benzofuran] (4a)………………………………….. 126
(2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5'-Methylenebis(2-[N-methyl-3''-(4- methylphenyl)-4''-oxo-1'',3''-imidazolidin-2''-yl]benzofuran) (4b)…………………. 127
(2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5'-Methylenebis(2-[N-methyl-3''-(2,3- dimethylphenyl)-4''-oxo-1'',3''-imidazolidin-2''-yl]benzofuran) (4c)…….…………. 128
(2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5'-Methylenebis(2-[N-methyl-3''-(2,5- dimethylphenyl)-4''-oxo-1'',3''-imidazolidin-2''-yl]benzofuran) (4d)………………. 129
(2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5'-Methylenebis[2-(N-methyl-3''-(3,5- dimethylphenyl)-4''-oxo-1'',3''-imidazolidin-2''-yl)benzofuran] (4e)……….………. 130
(2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5'-Methylenebis(2-[N-methyl-3''-(2- ethylphenyl)-4''-oxo-1'',3''-imidazolidin-2''-yl]benzofuran) (4f)……………………. 131
(2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5'-Methylenebis(2-[N-methyl-3''-(3- isopropylphenyl)-4''-oxo-1'',3''-imidazolidin-2''-yl]benzofuran) (4g)……………..... 131
(2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5'-Methylenebis(2-[N-methyl-3''-(4- methoxyphenyl)-4''-oxo-1'',3''-imidazolidin-2''-yl]benzofuran) (4h)……………….. 132
(2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5'-Methylenebis(2-[N-methyl-3''- (benzo[d][1,3]dioxol-5-yl)-4''-oxo-1'',3''-imidazolidin-2''-yl]benzofuran) (4i)……... 133
(2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5'-Methylenebi(2-[N-methyl-3''-(4- fluorophenyl)-4''-oxo-1'',3''-imidazolidin-2''-yl]benzofuran) (4j)……………...…… 134
(2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5'-Methylenebis(2-[N-methyl-3''-(4- chlorophenyl)-4''-oxo-1'',3''-imidazolidin-2''-yl]benzofuran) (4k)…………….……. 135
(2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5'-Methylenebis(2-[N-methyl-3''-(4- bromophenyl)-4''-oxo-1'',3''-imidazolidin-2''-yl]benzofuran) (4l)………………….. 136
(2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5'-Methylenebis(2-[N-methyl-3''-(4- iodophenyl)-4''-oxo-1'',3''-imidazolidin-2''-yl]benzofuran) (4m)…………………… 137
(2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5'-Methylenebis(2-[N-methyl-3''-(3- trifluoromethyl)phenyl-4''-oxo-1'',3''-imidazolidin-2''-yl]benzofuran) (4n)………… 138
Diethyl-5,5'-methylenebis(benzofuran-2-carboxylate) (21)………………………… 139
5,5'-Methylenebis(benzofuran-2-carboxylic acid) (22)……………………………... 139
Standard Procedure 6 for the Preparation of mono-N-alkylate-2-phenyldiamine….. 140
N-Benzylbenzene-1,2-diamine (25a)……………………………………………...... 141
N-(4-Methylbenzyl)benzene-1,2-diamine (25b)……………………………………. 141
N-(3-Methoxybenzyl)benzene-1,2-diamine (25c)…………………………….…….. 142
N-(4-Methoxybenzyl)benzene-1,2-diamine (25d)………………………………….. 143
N-(2-Fluorobenzyl)benzene-1,2-diamine (25e)…………………………………….. 143
N-(4-Fluorobenzyl)benzene-1,2-diamine (25f)……………………………………... 144
N-(2-Chlorobenzyl)benzene-1,2-diamine (25g)…………………………………….. 145
N-(4-Chlorobenzyl)benzene-1,2-diamine (25h)…………………………………….. 145
N-(3-Bromobenzyl)benzene-1,2-diamine (25i)……………………………………... 146
N-(Furan-2-ylmethyl)benzene-1,2-diamine (25j)……………...…………………… 147
N-Isopropylbenzene-1,2-diamine (25k)…………………………………………….. 147
N-Cyclopentylbenzene-1,2-diamine (25l)……………………………………..……. 148
N-Cyclohexylbenzene-1,2-diamine (25m)……..…………………………………… 149
Standard Procedure 7 for the Preparation of bisamide (26a-m)…………………….. 149
5,5'-Methylenebis(N-[2-(benzylamino)phenyl]benzofuran-2-carboxamide) (26a).... 150
5,5'-Methylenebis(N-[2-(p-methylbenzylamino)phenyl]benzofuran-2-carboxamide) (26b)………………………………………………………………………………….151
5,5'-Methylenebis(N-[2-(m-methoxybenzylamino)phenyl]benzofuran-2-carboxamide) (26c)………………………………………………………………………………… 152
5,5'-Methylenebis(N-[2-(p-methoxybenzylamino)phenyl]benzofuran-2-carboxamide) (26d)………………………………………………………………………………… 153
5,5'-Methylenebis(N-[2-(o-fluorobenzylamino)phenyl]benzofuran-2-carboxamide)
(26e)………………………………………………………………………………… 154
5,5'-Methylenebis(N-[2-(p-fluorobenzylamino)phenyl]benzofuran-2-carboxamide) (26f)………………………………………………………………………………… 155
5,5'-Methylenebis(N-[2-(o-chlorobenzylamino)phenyl]benzofuran-2-carboxamide)
(26g)………………………………………………………………………………… 156
5,5'-Methylenebis(N-[2-(p-chlorobenzylamino)phenyl]benzofuran-2-carboxamide)
(26h)………………………………………………………………………………… 157
5,5'-Methylenebis(N-[2-(m-bromobenzylamino)phenyl]benzofuran-2-carboxamide) (26i)…………………………………………………………………………………..158
5,5'-Methylenebis[N-(2-[(furan-2-ylmethyl)amino]phenyl)benzofuran-2-carboxamide] (26j)…………………………………………………………………………………. 159
5,5'-Methylenebis(N-[2-(isopropylamino)phenyl]benzofuran-2-carboxamide) (26k)160
5,5'-Methylenebis(N-[2-(cyclopentylamino)phenyl]benzofuran-2-carboxamide)
(26l)…………………………………………………………………………….…… 161
5,5'-Methylenebis(N-[2-(cyclohexylamino)phenyl]benzofuran-2-carboxamide)
(26m)…………………………………………………………………………………162
Standard Procedure 8 for the Preparation of Bis(benzofuran-benzimidazole)s……. 163
5,5'-Methylenebis[2-(1-benzylbenzimidazol-2-yl)benzofuran] (5a)………..………. 163
5,5'-Methylenebis(2-[1-(p-methylbenzyl)benzimidazol-2-yl]benzofuran) (5b)…….. 164
5,5'-Methylenebis(2-[1-(m-methoxybenzyl)benzimidazol-2-yl]benzofuran) (5c)…... 165
5,5'-Methylenebis(2-[1-(p-methoxybenzyl)benzimidazol-2-yl]benzofuran) (5d)….. 166
5,5'-Methylenebis(2-[1-(o-fluorobenzyl)benzimidazol-2-yl]benzofuran) (5e)……... 166
5,5'-Methylenebis(2-[1-(p-fluorobenzyl)benzimidazol-2-yl]benzofuran) (5f)……... 167
5,5'-Methylenebis(2-[1-(o-chlorobenzyl)benzimidazol-2-yl]benzofuran) (5g)…….. 168
5,5'-Methylenebis(2-[1-(p-chlorobenzyl)benzimidazol-2-yl]benzofuran) (5h)……. 169
5,5'-Methylenebis(2-[1-(m-bromobenzyl)benzimidazol-2-yl]benzofuran) (5i)……. 169
5,5'-Methylenebis(2-[1-(furan-2-ylmethyl)benzimidazol-2-yl]benzofuran) (5j)…… 170
5,5'-Methylenebis(2-[1-isopropylbenzimidazol-2-yl]benzofuran) (5k)……………... 171
5,5'-Methylenebis(2-[1-cyclopentylbenzimidazol-2-yl]benzofuran) (5l)…………… 172
5,5'-Methylenebis(2-[1-cyclohexylbenzimidazol-2-yl]benzofuran) (5m)…………... 172
5,5'-Methylenebis(N-[2-(tert-butylcarbamate)phenyl]benzofuran-2-carboxamide)
(29)………………………………………………………………………………….. 173
5,5'-Methylenebis[2-(benzimidazol-2-yl)benzofuran] (5n)………………………… 174
Standard Procedure 9 for the Preparation of glycoamide (32)………………….…... 174
2-Hydroxy-N-phenylacetamide (32a)………………………………………………. 175
2-Hydroxy-N-(4-methylphenyl)acetamide (32b)…………………………………… 175
2-Hydroxy-N-(4-methoxyphenyl)acetamide (32c)…………………………………. 176
2-Hydroxy-N-(4-fluorophenyl)acetamide (32d)……………………………………. 176
2-Hydroxy-N-(4-bromophenyl)acetamide (32e)…………………………………… 177
Standard Procedure 10 for the Preparation of bis(benzofuran-1,3-oxazolidin-4-one)s. 177
(2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5'-Methylenebis[2-(N-methyl-3''-phenyl- 4''-oxo-1'',3''-oxazolidin-2''-yl)benzofuran] (6a)……………………………………... 178
(2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5'-Methylenebis(2-[N-methyl-3''-(4- methylphenyl)-4''-oxo-1'',3''-oxazolidin-2''-yl]benzofuran) (6b)…………………….. 179
(2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5'-Methylenebis(2-[N-methyl-3''-(4- methoxyphenyl)-4''-oxo-1'',3''-oxazolidin-2''-yl]benzofuran) (6c)…………………… 180
(2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5'-Methylenebis(2-[N-methyl-3''-(4- fluorophenyl)-4''-oxo-1'',3''-oxazolidin-2''-yl]benzofuran) (6d)……………………… 181
(2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5'-Methylenebis(2-[N-methyl-3''-(4- bromophenyl)-4''-oxo-1'',3''-oxazolidin-2''-yl]benzofuran) (6e)……………………... 181
4',4''-Methylenebis[2-(2'-formylphenoxy)acetonitrile] (34)………………………….. 182
5,5'-Methylenebis(benzofuran-2-carbonitrile) (35)…………………………………... 183
5,5'-Methylenebis[2-(4'',5''-dihydo-1H-imidazol-2''-yl)benzofuran] (7)……………... 184
6. References ………………………………………………………………………………….. 184
7. Spectra …………………………………………………………………………………....... 198
1H NMR spectrum of 5,5'-Methylenebis[2-(2'',2''-diethoxy)ethoxy]benzaldehyde (11)…………………………………………………………………………………… 199
13C NMR spectrum of 5,5'-Methylenebis[2-(2'',2''-diethoxy)ethoxy]benzaldehyde (11)………………………………………………………………………………….. 199
1H NMR spectrum of 5,5'-Methylenebis(benzofuran-2-carbaldehyde) (12)……..…. 200
13C NMR spectrum of 5,5'-Methylenebis(benzofuran-2-carbaldehyde) (12)……....... 200
1H NMR spectrum of (2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5'-Methylenebis[2-(3''- phenyl-4''-oxo-1'',3''-thiazolidin-2''-yl)benzofuran] (2a)………………………….… 201
13C NMR spectrum of (2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5'-Methylenebis[2-(3''- phenyl-4''-oxo-1'',3''-thiazolidin-2''-yl)benzofuran] (2a)……………………….…… 201
1H NMR spectrum of (2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5'-Methylenebis(2- [3''-(4-methylphenyl)- 4''-oxo-1'',3''-thiazolidin-2''-yl]benzofuran) (2b)…..………… 202
13C NMR spectrum of (2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5'-Methylenebis(2- [3''-(4-methylphenyl)- 4''-oxo-1'',3''-thiazolidin-2''-yl]benzofuran) (2b)…..………… 202
1H NMR spectrum of (2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5'-Methylenebis(2- [3''-(3,5- dimethylphenyl)-4''-oxo-1'',3''-thiazolidin-2''-yl]benzofuran) (2c)………... 203
13C NMR spectrum of (2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5'-Methylenebis(2- [3''-(3,5- dimethylphenyl)-4''-oxo-1'',3''-thiazolidin-2''-yl]benzofuran) (2c)………... 203
1H NMR spectrum of (2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5'-Methylenebis(2- [3''-(4-methoxyphenyl)- 4''-oxo-1'',3''-thiazolidin-2''-yl]benzofuran) (2d)………...…. 204
13C NMR spectrum of (2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5'-Methylenebis(2- [3''-(4-methoxyphenyl)- 4''-oxo-1'',3''-thiazolidin-2''-yl]benzofuran) (2d)……..……. 204
1H NMR spectrum of (2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5'-Methylenebis(2- [3''-(4-fluorophenyl)- 4''-oxo-1'',3''-thiazolidin-2''-yl]benzofuran) (2e)……………… 205
13C NMR spectrum of (2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5'-Methylenebis(2- [3''-(4-fluorophenyl)- 4''-oxo-1'',3''-thiazolidin-2''-yl]benzofuran) (2e)……………… 205
1H NMR spectrum of (2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5'-Methylenebis(2- [3''-(4-chlorophenyl)- 4''-oxo-1'',3''-thiazolidin-2''-yl]benzofuran) (2f)……………… 206
13C NMR spectrum of (2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5'-Methylenebis(2- [3''-(4-chlorophenyl)- 4''-oxo-1'',3''-thiazolidin-2''-yl]benzofuran) (2f)……………… 206
1H NMR spectrum of (2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5'-Methylenebis(2- [3''-(4-bromophenyl)- 4''-oxo-1'',3''-thiazolidin-2''-yl]benzofuran) (2g)……………… 207
13C NMR spectrum of (2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5'-Methylenebis(2- [3''-(4-bromophenyl)- 4''-oxo-1'',3''-thiazolidin-2''-yl]benzofuran) (2g)……………… 207
1H NMR spectrum of (2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5'-Methylenebis(2- [3''-(4-iodophenyl)- 4''-oxo-1'',3''-thiazolidin-2''-yl]benzofuran) (2h)...……………… 208
13C NMR spectrum of (2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5'-Methylenebis(2- [3''-(4-iodophenyl)- 4''-oxo-1'',3''-thiazolidin-2''-yl]benzofuran) (2h)...……………… 208
1H NMR spectrum of (2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5'-Methylenebis(2- [3''-(2-fluorophenyl)- 4''-oxo-1'',3''-thiazolidin-2''-yl]benzofuran) (2i).....…………… 209
13C NMR spectrum of (2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5'-Methylenebis(2- [3''-(2-fluorophenyl)- 4''-oxo-1'',3''-thiazolidin-2''-yl]benzofuran) (2i).....…...……… 209
1H NMR spectrum of (2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5'-Methylenebis(2- [3''-(4-trifluoromethyl phenyl)-4''-oxo-1'',3''-thiazolidin-2''-yl]benzofuran) (2j)….… 210
13C NMR spectrum of (2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5'-Methylenebis(2- [3''-(4-trifluoromethyl phenyl)-4''-oxo-1'',3''-thiazolidin-2''-yl]benzofuran) (2j)….… 210
1H NMR spectrum of (2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5'-Methylenebis(2- [3''-(pyridin-2-yl)-4''-oxo-1'',3''-thiazolidin-2''-yl]benzofuran) (2k)……………….… 211
13C NMR spectrum of (2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5'-Methylenebis(2- [3''-(pyridin-2-yl)-4''-oxo-1'',3''-thiazolidin-2''-yl]benzofuran) (2k)……………….… 211
1H NMR spectrum of (2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5'-Methylenebis(2- [3''-(pyrazin-2-yl)-4''-oxo-1'',3''-thiazolidin-2''-yl]benzofuran) (2l)………….…….… 212
13C NMR spectrum of (2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5'-Methylenebis(2- [3''-(pyrazin-2-yl)-4''-oxo-1'',3''-thiazolidin-2''-yl]benzofuran) (2l)………….…….… 212
1H NMR spectrum of (2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5-Methylenebis[2- (3''-benzyl-4''-oxo- 1'',3''-thiazolidin-2''-yl)benzofuran] (2m)…..…………...…….… 213
13C NMR spectrum of (2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5-Methylenebis[2- (3''-benzyl-4''-oxo- 1'',3''-thiazolidin-2''-yl)benzofuran] (2m)……………...……...… 213
1H NMR spectrum of (2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5-Methylenebis(2- [3''-(4-methylbenzyl)- 4''-oxo-1'',3''-thiazolidin-2''-yl]benzofuran) (2n)…...…..….… 214
13C NMR spectrum of (2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5-Methylenebis(2- [3''-(4-methylbenzyl)- 4''-oxo-1'',3''-thiazolidin-2''-yl]benzofuran) (2n)…...…..….… 214
xxiii
1H NMR spectrum of (2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5-Methylenebis(2- [3''-(4-methoxybenzyl)- 4''-oxo-1'',3''-thiazolidin-2''-yl]benzofuran) (2o).…..…....… 215
13C NMR spectrum of (2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5-Methylenebis(2- [3''-(4-methoxybenzyl)- 4''-oxo-1'',3''-thiazolidin-2''-yl]benzofuran) (2o).…..…....… 215
1H NMR spectrum of (2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5-Methylenebis[2- (3''-ethyl-4''-oxo-1'',3''- thiazolidin-2''-yl)benzofuran] (2p).……….………...…...… 216
13C NMR spectrum of (2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5-Methylenebis[2- (3''-ethyl-4''-oxo-1'',3''- thiazolidin-2''-yl)benzofuran] (2p).……….………...…...… 216
1H NMR spectrum of (2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5-Methylenebis[2- [3''-isopropyl(-4''-oxo- 1'',3''-thiazolidin-2''-yl)benzofuran] (2q).……….…...…...… 217
13C NMR spectrum of (2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5-Methylenebis[2- [3''-isopropyl(-4''-oxo- 1'',3''-thiazolidin-2''-yl)benzofuran] (2q).……….…...…...… 217
1H NMR spectrum of (2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5-Methylenebis(2- [3''-(2-hydroxyethyl)- 4''-oxo-1'',3''-thiazolidin-2''-yl]benzofuran) (2r).….....….....… 218
13C NMR spectrum of (2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5-Methylenebis(2- [3''-(2-hydroxyethyl)- 4''-oxo-1'',3''-thiazolidin-2''-yl]benzofuran) (2r).….....….....… 218
1H NMR spectrum of (2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5-Methylenebis(2- [3''-(2-methoxyethyl)- 4''-oxo-1'',3''-thiazolidin-2''-yl]benzofuran) (2s).….....….....… 219
13C NMR spectrum of (2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5-Methylenebis(2- [3''-(2-methoxyethyl)- 4''-oxo-1'',3''-thiazolidin-2''-yl]benzofuran) (2s).….....….....… 219
1H NMR spectrum of (2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5-Methylenebis[2- (3''-cyclopropyl-4''-oxo- 1'',3''-thiazolidin-2''-yl)benzofuran] (2t)……………….…... 220
13C NMR spectrum of (2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5-Methylenebis[2- (3''-cyclopropyl-4''-oxo- 1'',3''-thiazolidin-2''-yl)benzofuran] (2t)……………….…... 220
1H NMR spectrum of (2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5-Methylenebis[2- (3''-cycloheptyl-4''-oxo- 1'',3''-thiazolidin-2''-yl)benzofuran] (2u)…………………... 221
13C NMR spectrum of (2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5-Methylenebis[2- (3''-cycloheptyl-4''-oxo- 1'',3''-thiazolidin-2''-yl)benzofuran] (2u)…………………... 221
1H NMR spectrum of (2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5-Methylenebis[2- (3''-phenyl-4''-oxo-1'',3''-thiazinan-2''-yl)benzofuran] (3a)…………………………... 222
13C NMR spectrum of (2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5-Methylenebis[2- (3''-phenyl-4''-oxo-1'',3''-thiazinan-2''-yl)benzofuran] (3a)…………………………... 222
1H NMR spectrum of (2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5-Methylenebis(2- [3''-(4-methylphenyl)-4''-oxo-1'',3''-thiazinan-2''-yl]benzofuran) (3b)……………..... 223
13C NMR spectrum of (2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5-Methylenebis(2- [3''-(4-methylphenyl)-4''-oxo-1'',3''-thiazinan-2''-yl]benzofuran) (3b)……………..... 223
1H NMR spectrum of (2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5-Methylenebis(2- [3''-(3,5-dimethylphenyl)-4''-oxo-1'',3''-thiazinan-2''-yl]benzofuran) (3c)…….…....... 224
13C NMR spectrum of (2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5-Methylenebis(2- [3''-(3,5-dimethylphenyl)-4''-oxo-1'',3''-thiazinan-2''-yl]benzofuran) (3c)………........ 224
1H NMR spectrum of (2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5-Methylenebis(2- [3''-(4-methoxyphenyl)-4''-oxo-1'',3''-thiazinan-2''-yl]benzofuran) (3d)……….......... 225
13C NMR spectrum of (2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5-Methylenebis(2- [3''-(4-methoxyphenyl)-4''-oxo-1'',3''-thiazinan-2''-yl]benzofuran) (3d)…….…......... 225
1H NMR spectrum of (2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5-Methylenebis(2- [3''-(4-fluorophenyl)-4''-oxo-1'',3''-thiazinan-2''-yl]benzofuran) (3e)………..…......... 226
13C NMR spectrum of (2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5-Methylenebis(2- [3''-(4-fluorophenyl)-4''-oxo-1'',3''-thiazinan-2''-yl]benzofuran) (3e)………..…......... 226
1H NMR spectrum of (2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5-Methylenebis(2- [3''-(4-chlorophenyl)-4''-oxo-1'',3''-thiazinan-2''-yl]benzofuran) (3f)………..…......... 227
13C NMR spectrum of (2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5-Methylenebis(2- [3''-(4-chlorophenyl)-4''-oxo-1'',3''-thiazinan-2''-yl]benzofuran) (3f)………..…......... 227
1H NMR spectrum of (2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5-Methylenebis(2- [3''-(4-bromophenyl)-4''-oxo-1'',3''-thiazinan-2''-yl]benzofuran) (3g)………….......... 228
13C NMR spectrum of (2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5-Methylenebis(2- [3''-(4-bromophenyl)-4''-oxo-1'',3''-thiazinan-2''-yl]benzofuran) (3g)………….......... 228
1H NMR spectrum of (2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5-Methylenebis(2- [3''-(4-iodophenyl)-4''-oxo-1'',3''-thiazinan-2''-yl]benzofuran) (3h)…………............. 229
13C NMR spectrum of (2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5-Methylenebis(2- [3''-(4-iodophenyl)-4''-oxo-1'',3''-thiazinan-2''-yl]benzofuran) (3h)…………............. 229
1H NMR spectrum of (2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5-Methylenebis(2- [3''-benzyl-4''-oxo-1'',3''-thiazinan-2''-yl]benzofuran) (3m)……………….…............. 230
13C NMR spectrum of (2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5-Methylenebis(2- [3''-benzyl-4''-oxo-1'',3''-thiazinan-2''-yl]benzofuran) (3m)………………….............. 230
1H NMR spectrum of (2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5-Methylenebis(2- [3''-(4-methylbenzyl)-4''-oxo-1'',3''-thiazinan-2''-yl]benzofuran) (3n)……….............. 231
13C NMR spectrum of (2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5-Methylenebis(2- [3''-(4-methylbenzyl)-4''-oxo-1'',3''-thiazinan-2''-yl]benzofuran) (3n)……….............. 231
1H NMR spectrum of (2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5-Methylenebis(2- [3''-(4-methoxybenzyl)-4''-oxo-1'',3''-thiazinan-2''-yl]benzofuran) (3o)………........... 232
13C NMR spectrum of (2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5-Methylenebis(2- [3''-(4-methoxybenzyl)-4''-oxo-1'',3''-thiazinan-2''-yl]benzofuran) (3o)………........... 232
1H NMR spectrum of (2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5-Methylenebis(2- [3''-ethyl-4''-oxo-1'',3''-thiazinan-2''-yl]benzofuran) (3p)………………..……........... 233
13C NMR spectrum of (2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5-Methylenebis(2- [3''-ethyl-4''-oxo-1'',3''-thiazinan-2''-yl]benzofuran) (3p)………………..……........... 233
1H NMR spectrum of (2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5-Methylenebis(2- [3''-isopropyl-4''-oxo-1'',3''-thiazinan-2''-yl]benzofuran) (3q)…………...……........... 234
13C NMR spectrum of (2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5-Methylenebis(2- [3''-isopropyl-4''-oxo-1'',3''-thiazinan-2''-yl]benzofuran) (3q)…………...……........... 234
1H NMR spectrum of (2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5-Methylenebis(2- [3''-(2-hydroxyethyl)-4''-oxo-1'',3''-thiazinan-2''-yl]benzofuran) (3r)….......…........... 235
13C NMR spectrum of (2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5-Methylenebis(2- [3''-(2-hydroxyethyl)-4''-oxo-1'',3''-thiazinan-2''-yl]benzofuran) (3r)….......…........... 235
1H NMR spectrum of (2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5-Methylenebis(2- [3''-(2-methoxyethyl)-4''-oxo-1'',3''-thiazinan-2''-yl]benzofuran) (3s)….......…........... 236
13C NMR spectrum of (2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5-Methylenebis(2- [3''-(2-methoxyethyl)-4''-oxo-1'',3''-thiazinan-2''-yl]benzofuran) (3s)….......…........... 236
1H NMR spectrum of (2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5-Methylenebis(2- [3''-cyclopropyl-4''-oxo-1'',3''-thiazinan-2''-yl]benzofuran) (3t)….......….................... 237
13C NMR spectrum of (2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5-Methylenebis(2- [3''-cyclopropyl-4''-oxo-1'',3''-thiazinan-2''-yl]benzofuran) (3t)….......…................... 237
1H NMR spectrum of (2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5-Methylenebis(2- [3''-cycloheptyl-4''-oxo-1'',3''-thiazinan-2''-yl]benzofuran) (3u)….......….................... 238
13C NMR spectrum of (2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5-Methylenebis(2- [3''-cycloheptyl-4''-oxo-1'',3''-thiazinan-2''-yl]benzofuran) (3u)….......….................... 238
1H NMR spectrum of (2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5-Methylenebis[2- (N-methyl-3''-phenyl-4''-oxo-1'',3''-imidazolidin-2''-yl)benzofuran] (4a)…................ 239
13C NMR spectrum of (2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5-Methylenebis[2- (N-methyl-3''-phenyl-4''-oxo-1'',3''-imidazolidin-2''-yl)benzofuran] (4a)…................ 239
1H NMR spectrum of (2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5-Methylenebis(2- [N-methyl-3''-(4-methylphenyl)-4''-oxo-1'',3''-imidazolidin-2''-yl]benzofuran) (4b)... 240
13C NMR spectrum of (2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5-Methylenebis(2- [N-methyl-3''-(4-methylphenyl)-4''-oxo-1'',3''-imidazolidin-2''-yl]benzofuran) (4b)... 240
1H NMR spectrum of (2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5-Methylenebis(2- [N-methyl-3''-(2,3-dimethylphenyl)-4''-oxo-1'',3''-imidazolidin-2''-yl]benzofuran)
(4c)…………………………..……………………………………………………….. 241
13C NMR spectrum of (2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5-Methylenebis(2- [N-methyl-3''-(2,3-dimethylphenyl)-4''-oxo-1'',3''-imidazolidin-2''-yl]benzofuran)
(4c)…………………………..……………………………………………………….. 241
1H NMR spectrum of (2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5-Methylenebis(2- [N-methyl-3''-(2,5-dimethylphenyl)-4''-oxo-1'',3''-imidazolidin-2''-yl]benzofuran)
(4d)…………………………..……………………………………………………….. 242
13C NMR spectrum of (2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5-Methylenebis(2- [N-methyl-3''-(2,5-dimethylphenyl)-4''-oxo-1'',3''-imidazolidin-2''-yl]benzofuran)
(4d)…………………………..……………………………………………………….. 242
1H NMR spectrum of (2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5-Methylenebis(2- [N-methyl-3''-(3,5-dimethylphenyl)-4''-oxo-1'',3''-imidazolidin-2''-yl]benzofuran)
(4e)…………………………..……………………………………………………….. 243
13C NMR spectrum of (2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5-Methylenebis(2- [N-methyl-3''-(3,5-dimethylphenyl)-4''-oxo-1'',3''-imidazolidin-2''-yl]benzofuran)
(4e)…………………………..……………………………………………………….. 243
1H NMR spectrum of (2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5-Methylenebis(2- [N-methyl-3''-(2-ethylphenyl)-4''-oxo-1'',3''-imidazolidin-2''-yl]benzofuran) (4f)…... 244
13C NMR spectrum of (2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5-Methylenebis(2- [N-methyl-3''-(2-ethylphenyl)-4''-oxo-1'',3''-imidazolidin-2''-yl]benzofuran) (4f)…... 244
1H NMR spectrum of (2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5-Methylenebis(2- [N-methyl-3''-(3-isopropylphenyl)-4''-oxo-1'',3''-imidazolidin-2''-yl]benzofuran)(4g) 245
13C NMR spectrum of (2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5-Methylenebis(2- [N-methyl-3''-(3-isopropylphenyl)-4''-oxo-1'',3''-imidazolidin-2''-yl]benzofuran)(4g) 245
1H NMR spectrum of (2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5-Methylenebis(2- [N-methyl-3''-(4-methoxyphenyl)-4''-oxo-1'',3''-imidazolidin-2''-yl]benzofuran) (4h).246
13C NMR spectrum of (2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5-Methylenebis(2- [N-methyl-3''-(4-methoxyphenyl)-4''-oxo-1'',3''-imidazolidin-2''-yl]benzofuran) (4h).246
1H NMR spectrum of (2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5-Methylenebis(2- [N-methyl-3''-(benzo[d][1,3]dioxol-5-yl)-4''-oxo-1'',3''-imidazolidin-2''-yl]benzofuran) (4i)……………………………………..……………………………….……………...247
13C NMR spectrum of (2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5-Methylenebis(2- [N-methyl-3''-(benzo[d][1,3]dioxol-5-yl)-4''-oxo-1'',3''-imidazolidin-2''-yl]benzofuran) (4i)……………………………………..…………………………….………………...247
1H NMR spectrum of (2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5-Methylenebis(2- [N-methyl-3''-(4-fluorophenyl)-4''-oxo-1'',3''-imidazolidin-2''-yl]benzofuran) (4j)…..248
13C NMR spectrum of (2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5-Methylenebis(2- [N-methyl-3''-(4-fluorophenyl)-4''-oxo-1'',3''-imidazolidin-2''-yl]benzofuran) (4j)…..248
1H NMR spectrum of (2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5-Methylenebis(2- [N-methyl-3''-(4-chlorophenyl)-4''-oxo-1'',3''-imidazolidin-2''-yl]benzofuran) (4k)….249
13C NMR spectrum of (2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5-Methylenebis(2- [N-methyl-3''-(4-chlorophenyl)-4''-oxo-1'',3''-imidazolidin-2''-yl]benzofuran) (4k)….249
1H NMR spectrum of (2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5-Methylenebis(2- [N-methyl-3''-(4-bromophenyl)-4''-oxo-1'',3''-imidazolidin-2''-yl]benzofuran) (4l)…..250
13C NMR spectrum of (2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5-Methylenebis(2- [N-methyl-3''-(4-bromophenyl)-4''-oxo-1'',3''-imidazolidin-2''-yl]benzofuran) (4l)…..250
1H NMR spectrum of (2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5-Methylenebis(2- [N-methyl-3''-(4-iodophenyl)-4''-oxo-1'',3''-imidazolidin-2''-yl]benzofuran) (4m)…...251
13C NMR spectrum of (2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5-Methylenebis(2- [N-methyl-3''-(4-iodophenyl)-4''-oxo-1'',3''-imidazolidin-2''-yl]benzofuran) (4m)…...251
1H NMR spectrum of (2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5-Methylenebis(2- [N-methyl-3''-(3-trifluoromethyl)phenyl-4''-oxo-1'',3''-imidazolidin-2''-yl]benzofuran) (4n)………………………………………………………………………………….... 252
13C NMR spectrum of (2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5-Methylenebis(2- [N-methyl-3''-(3-trifluoromethyl)phenyl-4''-oxo-1'',3''-imidazolidin-2''-yl]benzofuran) (4n)………………………………………………………………………………….... 252
1H NMR spectrum of Diethyl-5,5'-methylenebis(benzofuran-2-carboxylate) (21)….. 253
13C NMR spectrum of Diethyl-5,5'-methylenebis(benzofuran-2-carboxylate) (21)…. 253
1H NMR spectrum of 5,5'-Methylenebis(benzofuran-2-carboxylic acid) (22)……..... 254
13C NMR spectrum of 5,5'-Methylenebis(benzofuran-2-carboxylic acid) (22)…….... 254
1H NMR spectrum of 5,5'-Methylenebis[2-(1-benzylbenzimidazol-2-yl)benzofuran] (5a)………………………………………………………………………………….... 255
13C NMR spectrum of 5,5'-Methylenebis[2-(1-benzylbenzimidazol-2-yl)benzofuran]
(5a)………………………………………………………………………………….... 255
1H NMR spectrum of 5,5'-Methylenebis(2-[1-(p-methylbenzyl)benzimidazol-2-yl] benzofuran) (5b)…...……………………………………………………………….... 256
13C NMR spectrum of 5,5'-Methylenebis(2-[1-(p-methylbenzyl)benzimidazol-2-yl] benzofuran) (5b)…………...……………………………………………………….... 256
1H NMR spectrum of 5,5'-Methylenebis(2-[1-(m-methoxybenzyl)benzimidazol-2-yl] benzofuran) (5c)…………………………………………………………………….... 257
13C NMR spectrum of 5,5'-Methylenebis(2-[1-(m-methoxybenzyl)benzimidazol-2-yl] benzofuran) (5c)…………………………………………………………………….... 257
1H NMR spectrum of 5,5'-Methylenebis(2-[1-(p-methoxybenzyl)benzimidazol-2-yl] benzofuran) (5d)………………………………………………………...………….... 258
13C NMR spectrum of 5,5'-Methylenebis(2-[1-(p-methoxybenzyl)benzimidazol-2-yl] benzofuran) (5d)………………………………………………………...………….... 258
1H NMR spectrum of 5,5'-Methylenebis(2-[1-(o-fluorobenzyl)benzimidazol-2-yl] benzofuran) (5e)………………………………………………………...…………..... 259
13C NMR spectrum of 5,5'-Methylenebis(2-[1-(o-fluorobenzyl)benzimidazol-2-yl] benzofuran) (5e)………………………………………………………...…………..... 259
1H NMR spectrum of 5,5'-Methylenebis(2-[1-(p-fluorobenzyl)benzimidazol-2-yl] benzofuran) (5f)………………………………………………………...…………..... 260
13C NMR spectrum of 5,5'-Methylenebis(2-[1-(p-fluorobenzyl)benzimidazol-2-yl] benzofuran) (5f)………………………………………………………...…………..... 260
1H NMR spectrum of 5,5'-Methylenebis(2-[1-(o-chlorobenzyl)benzimidazol-2-yl] benzofuran) (5g)………………………………………………………...…………..... 261
13C NMR spectrum of 5,5'-Methylenebis(2-[1-(o-chlorobenzyl)benzimidazol-2-yl] benzofuran) (5g)………………………………………………………...…………..... 261
1H NMR spectrum of 5,5'-Methylenebis(2-[1-(p-chlorobenzyl)benzimidazol-2-yl] benzofuran) (5h)……………………...………………………………...…………..... 262
13C NMR spectrum of 5,5'-Methylenebis(2-[1-(p-chlorobenzyl)benzimidazol-2-yl] benzofuran) (5h)……………………...………………………………...…………..... 262
1H NMR spectrum of 5,5'-Methylenebis(2-[1-(m-bromobenzyl)benzimidazol-2-yl] benzofuran) (5i)………………….…...………………………………...…………..... 263
13C NMR spectrum of 5,5'-Methylenebis(2-[1-(m-bromobenzyl)benzimidazol-2-yl] benzofuran) (5i)………………….…...………………………………...…………..... 263
1H NMR spectrum of 5,5'-Methylenebis(2-[1-(furan-2-ylmethyl)benzimidazol-2-yl] benzofuran) (5j)………………….…...………………………………...…………..... 264
13C NMR spectrum of 5,5'-Methylenebis(2-[1-(furan-2-ylmethyl)benzimidazol-2-yl] benzofuran) (5j)………………….…...………………………………...…………..... 264
1H NMR spectrum of 5,5'-Methylenebis(2-[1-isopropylbenzimidazol-2-yl] benzofuran) (5k)………………...……...…………………………...…………......... 265
13C NMR spectrum of 5,5'-Methylenebis(2-[1-isopropylbenzimidazol-2-yl] benzofuran) (5k)………………...……...…………………………...……….…........ 265
1H NMR spectrum of 5,5'-Methylenebis(2-[1-cyclopentylbenzimidazol-2-yl]
benzofuran) (5l)……..……...……...…………………………….......…………........ 266
13C NMR spectrum of 5,5'-Methylenebis(2-[1-cyclopentylbenzimidazol-2-yl]
benzofuran) (5l)……..……...……...…………………………….......…………........ 266
1H NMR spectrum of 5,5'-Methylenebis(2-[1-cycloheptylbenzimidazol-2-yl]
benzofuran) (5m)……..….....……...…………………………….......…………........ 267
13C NMR spectrum of 5,5'-Methylenebis(2-[1-cycloheptylbenzimidazol-2-yl]
benzofuran) (5m)……..….....……...…………………………….......…………......... 267
1H NMR spectrum of 5,5'-Methylenebis[2-(benzimidazol-2-yl)benzofuran] (5n)…... 268
HRMS spectrum of 5,5'-Methylenebis[2-(benzimidazol-2-yl)benzofuran] (5n)……. 268
1H NMR spectrum of (2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5-Methylenebis[2- (N-methyl-3''-phenyl-4''-oxo-1'',3''-oxazolidin-2''-yl)benzofuran] (6a)…………..….. 269
13C NMR spectrum of (2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5-Methylenebis[2- (N-methyl-3''-phenyl-4''-oxo-1'',3''-oxazolidin-2''-yl)benzofuran] (6a)…………..….. 269
1H NMR spectrum of (2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5-Methylenebis(2- [N-methyl-3''-(4-methylphenyl)-4''-oxo-1'',3''-oxazolidin-2''-yl]benzofuran) (6b)….. 270
13C NMR spectrum of (2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5-Methylenebis(2- [N-methyl-3''-(4-methylphenyl)-4''-oxo-1'',3''-oxazolidin-2''-yl]benzofuran) (6b)….. 270
1H NMR spectrum of (2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5-Methylenebis(2- [N-methyl-3''-(4-methoxyphenyl)-4''-oxo-1'',3''-oxazolidin-2''-yl]benzofuran) (6c).... 271
13C NMR spectrum of (2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5-Methylenebis(2- [N-methyl-3''-(4-methoxyphenyl)-4''-oxo-1'',3''-oxazolidin-2''-yl]benzofuran) (6c).... 271
1H NMR spectrum of (2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5-Methylenebis(2- [N-methyl-3''-(4-fluorophenyl)-4''-oxo-1'',3''-oxazolidin-2''-yl]benzofuran) (6d)….... 272
13C NMR spectrum of (2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5-Methylenebis(2- [N-methyl-3''-(4-fluorophenyl)-4''-oxo-1'',3''-oxazolidin-2''-yl]benzofuran) (6d)….... 272
1H NMR spectrum of (2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5-Methylenebis(2- [N-methyl-3''-(4-bromophenyl)-4''-oxo-1'',3''-oxazolidin-2''-yl]benzofuran) (6e)…... 273
13C NMR spectrum of (2''R,2'''R)-, (2''S,2'''S)-, and meso-(2''R,2'''S)-5,5-Methylenebis(2- [N-methyl-3''-(4-bromophenyl)-4''-oxo-1'',3''-oxazolidin-2''-yl]benzofuran) (6e)…... 273
1H NMR spectrum of 4',4''-Methylenebis[2-(2'-formylphenoxy)acetonitrile] (34)..... 274
13C NMR spectrum of 4',4''-Methylenebis[2-(2'-formylphenoxy)acetonitrile] (34).... 274
1H NMR spectrum of 5,5'-Methylenebis(benzofuran-2-carbonitrile) (35)………...... 275
13C NMR spectrum of 5,5'-Methylenebis(benzofuran-2-carbonitrile) (35)………..... 275
1H NMR spectrum of 5,5'-Methylenebis[2-(4'',5''-dihydo-1H-imidazol-2''-yl)benzofuran] (7)………..………………………………………………..……….………………..... 276
13C NMR spectrum of 5,5'-Methylenebis[2-(4'',5''-dihydo-1H-imidazol-2''-yl) benzofuran] (7)……………………………………………..……………………...……………..... 276
8. Crystallographic Data ……………………………………………………………………. 277
List of Figures
Figure 1. Classification of alphavirus drawn by Nitesh………….……….……………………... 2
Figure 2. Chemical structures of selected inhibitors of CHIKV replication…………………….. 8
Figure 3. Purines/pyrimidine types of CHIKV inhibitors.………………………………………. 9
Figure 4. Nucleoside types of CHIKV inhibitors.……………………………………………..... 9
Figure 5. Alkaloids types of CHIKV inhibitors.………………….…………………………..... 10
Figure 6. Terpenoids types of CHIKV inhibitors……………………………………..……….. 11
Figure 7. Structure of Suramin and and analysis of its components…………………………… 12
Figure 8. Description of Yellow fever virus (YFV) drawn by Nitesh.………………………… 14
Figure 9. Lead compounds for anti-YFV…………………….………………………………… 17
Figure 10. Inhibitors for yellow fever virus……………………………………………….…… 18
Figure 11. Biologically active Dimeric compounds…...……………………………….……… 19
Figure 12. Comparison of structure of Suramin and Bisbenzofuran conjugates...….…….…… 20
Figure 13. Design of other bisbenzofuran conjugates by Nitesh and Hwu…………....…….…. 21
Figure 14. Benzofuran derivatives as antiviral agents and inhibitors of A fibril.……….……. 22
Figure 15. Thiazolidin-4-ones derivatives as antiviral agents…………………………...….…. 22 Figure 16. Thiazinan-4-ones derivatives as biological active molecules.………………..….… 23
Figure 17. Imidazolidinones as a part of reported drug molecules.………………………...….. 24
Figure 18. Benzimidazole derivatives as a HCV inhibitors.………………………………….... 24
Figure 19. Natural products containing oxazolidinones as core unit..…………………………. 25
Figure 20. Imidazoline ring containing potent natural product.…………………..…………… 25
Figure 21. Molecular frameworks: ORTEP diagram of 35 obtained by X-ray diffraction analysis……………………………………………………………………………………….…. 40
Figure 22. HPLC graph for racemic and isomers of bis-conjugate 2o………………..…….…. 57
Figure 23. Data for bis-conjugated compounds 2p, 2q, 2t, 3p, 3q, and 3s.…………………… 60
Figure 24. Data are represented in tabular form for bisconjugated compounds 2e, 6d, and 4j.. 61
Figure 25. Data are represented as bar for bis-conjugated compounds 2o and its isomers….… 62
Figure 26. Data are represented as bar for bis-conjugated compounds 4c, 4e, 4n, and 5k……. 63
Figure 27. Data are represented for bis-conjugated compounds 2r, 3a, 3n, and 3u………..….. 65
Figure 28. Data are represented in tabular form for bis-conjugated compounds 4b, 4c, 4d, and
xxxviii
4e………………………………………………………………………………………………... 66
Figure 29. Data are represented in tabular form for comparison of compounds 4e, 2c, and 3c.. 67
Figure 30. Data are represented in tabular form for bis-conjugated compounds 5k, 5n, and 7… 67
List of Tables
Table 1. Inhibition of CHIKV by bis-benzofuran conjugates 2 and 3. EC50 values were determin-ed by CPE reduction assays on Vero E6 cells infected with CHIKV LS3…………………...… 45
Table 2. Inhibitory effects of conjugated compounds on CHIKV (899 strain) in Vero cells subtype A and their lipophilicity……………………………………………………………………..….. 47
Table 3. Inhibitory effects of conjugated compounds on YFV-17D (Stamaril) in Huh-7 cells and their lipophilicity………………………………………………………………………………... 51
Table 4. Inhibition of SINV by bis-benzofuran conjugates 2 and 3. EC50 values were determined
by CPE reduction assays on Vero E6 cells infected with BLS2……………………………….. 56
Table 5. Inhibitory effects of 2o and its isomers on CHIKV (899 strain) in Vero cells subtype A
and on YFV-17D (Stamaril) in Huh-7 cells. Specific rotation were determined in parallel and the
[]D29 value for each isomer is shown below………………………………………………..…. 58
Table 6. Crystal data and structure refinement for 35………………………………………… 278
Table 7. Atomic coordinates ( x 104) and equivalent isotropic displacement parameters (Å2x103) for 35. U(eq) is defined as one third of the trace of the orthogonalized Uij tensor…………… 279
Table 8. Bond lengths [Å] and angles [°] for 35…………………………………………….... 280
Table 9. Anisotropic displacement parameters (Å2x 103) for 35. The anisotropic displacement factor exponent takes the form: -22[ h2 a*2U11 + ... + 2 h k a* b* U12 ]……………….…. 282
Table 10. Hydrogen coordinates ( x 104) and isotropic displacement parameters (Å2x 103) for 35………………………………………………………………………………………………. 283
List of Schemes
Scheme 1. Synthesis of benzofuran-2-al dimer and bis(benzofuran–imine)s intermediate…..... 27
Scheme 2. Synthetic strategy for synthesis of bis(benzofuran–1,3-thiazolidin-4-one)s
conjugates………………………………………………………………………………………. 28
Scheme 3. Synthesis of bis(benzofuran–1,3-thiazinan-4-one)s derivative…………………….. 29
Scheme 4. Synthesis of 2-(N-methylamino-N-phenyl)acetamide fragments………………….. 30
Scheme 5. Synthesis of benofuran(imidazolidin-4-one)s dimeric conjugates…………………. 31
Scheme 6. Synthesis of bisbenofuran ester and bisbenzofuraic acid intermediate…………..… 32
Scheme 7. Synthesis of mono-alkylated diamine and benzofuramide dimer………………….. 33
Scheme 8. Synthesis of bis(benzofuran-benzimidazole)s derivatives…………………………. 35
Scheme 9. Synthesis of (benzofuran-benzimidazole) dimeric conjugate……………………… 36
Scheme 10. Synthesis of bis(benzofuran–1,3-thiazinan-4-one)s derivative…………………… 38
Scheme 11. Synthesis of bis(benzofuran–imidazoline) conjugate……………………………... 39
Scheme 12. Viable cells convert MTS to Formazan…………………………………………… 42

                                

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