接著利用 Sonogashira 耦合，主要以碘化亞銅（CuI）與零價之鈀金屬
錯合物（Pd(PPh3)4）作為催化劑，在三乙基胺之鹼性條件下，將芳香基碘
化物與末端炔基進行耦合反應，可在末端炔基接上不同芳香環取代基 IV-62，得到一系列化合物，如表 4-1。41
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表 4-1：製備末端炔基接上不同芳香環取代基 IV-62
最後參照 Swern Oxidation 反應條件，利用二甲基亞碸（DMSO）作氧 化劑和草醯氯及三乙基胺在低溫下反應，將羥基氧化成醛基，即得合環前 起始物，如表 4-2 所示。63
表 4-2：製備合環前起始物 IV-61
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因此在換溶劑時，直接用較大當量的 NHTf2，在氮氣下迴流，進行合
環測試，先把溶劑換成 1,2-二氯乙烷，發現反應時間縮短至 2-30 分鐘，產 率有 49% （1 當量, entry 9）、58% （2 當量, entry 10）與 25% （3 當量, entry
11）；再來換成 1,2-二溴乙烷，在氮氣下迴流，反應一分鐘即結束，但其圖
譜結果雜亂（entry 12）；最後換成甲苯作為溶劑狀況時，在氮氣下迴流，
可得到 32%產物。由表 4-3 之實驗結果，可發現於 entry 10 有最佳之產率，
故本研究選用 entry 10 為最佳化條件。
表 4-3：四氫-1H- 衍生物 IV-67 環化條件最佳化
用最佳化條件去進行其它取代基之合環反應，如表 4-4 所示。先嘗試 把苯環換成萘環時，發現其產率降至 33%，推測其因萘環基團立體障礙較
大，影響環化反應進行（entry 2）；接著去試較小基團的取代基，如苯環接
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有間位和對位甲基，發現其產率也只有 31%和 43%，其結果都沒有單獨苯 環取代來得佳（entries 3, 4）。
表 4-4：製備四氫-1H- 衍生物 IV-67
而環化產物 IV-67，經過純化後在空氣下靜置，會逐漸地氧化，轉變
成具芳香性的二氫-1H- 衍生物 IV-68，經由核磁共振光譜監測，當全
部轉變成具香性的化合物 IV-68，需要一至二週的時間，再經過管柱色層 分析純化，除去微量雜質，如表 4-5。
表 4-5：製備芳香性二氫-1H- 衍生物 IV-68
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4.3.3 環化產物化學結構鑑定
此章節對於環化產物結構進行深入探討，本研究由起始物 IV-61a 和 產物 IV-67a 的1H NMR 和13C NMR 光譜進行圖譜分析。首先來看到氫 圖比對的部份，如圖 4-2 所示，在產物 IV-67a 的圖譜上，可以明顯的看
出醛基的特徵峰 Ha消失，反而在 6－7 ppm 處多了一雙鍵的氫訊號；另外
原本起始物 IV-61a 的 H-6 上二個氫訊號原本的化學位移相同，在產物的圖 譜上都為單一個氫訊號。
圖 4-2：起始物 IV-61a 和產物 IV-67a 的 1H NMR 圖譜
碳譜的部份，先看到起始物 IV-61a 碳譜，如圖 4-3 所示，醛基特徵峰 位於 202.5 ppm，還有 85.2 ppm 和 84.4 ppm 為炔基之訊號。而產物 IV-67a 的13C NMR 和 DEPT 135 圖譜，如圖 4-4 所示，在化學位移 192.5 ppm 處 有一羰基訊號，於雙鍵區多了二個碳，比對 DEPT 135，其中一個碳為四 級碳，另一個碳為次甲基。
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圖 4-3：起始物 IV-61a 的 13C NMR 圖譜
圖 4-4：產物 IV-67a 的13C NMR 和 DEPT 135 圖譜
由圖譜分析資訊可推測炔基參與反應並生成一雙鍵，根據實驗室文獻，
60,61因此本文推測其經過炔-醛置換反應，而得到產物 IV-67a。
而環化產物 IV-67，經過管柱色層分析純化後靜置在空氣下，會逐漸 地氧化，轉變成具芳香性的化合物 IV-68，經由核磁共振光譜分析，兩者
的圖譜有很大的差異。同樣先由1H NMR 圖譜進行比較，如圖 4-5 所示，
經過氧化後的產物 IV-68 之氫譜，在雙鍵區有二個氫分別為 Hb和 Hc，因
Hb靠近氮，所以化學位移較靠近低場；而於高場區只剩下三個訊號，且各
含有二個氫數。比對碳譜的部份，如圖 4-6 所示，在 101.5 和 121.8 ppm 處多二個雙鍵的碳 C-5 和 C-7b，因 C-5 靠近氮原子，會往低磁場移動；而 在高磁場區的碳都為二級碳。綜合以上資訊，推測其可能因在空氣中氧化，
生成較穩定具芳香性的產物 IV-68。
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圖 4-5：起始物 IV-67a 和產物 IV-68a 的 1H NMR 圖譜
圖 4-6：IV-67a 的13C NMR 和 IV-68a 的13C NMR 和 DEPT 135 圖譜
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為確切標記碳氫之間化學位移和產物空間結構，本研究進行 2D NMR 實驗，結果如圖 4-7 和圖 4-8 所示。首先於1H－1H COSY NMR 的圖譜（圖 4-7），從圖譜中可得知 H-2 與 H-1 和 H-3 有耦合；H-1 與 H-2 有耦合；H-3
與 H-2 有耦合，因此定出 骨架上不具芳香性的環上之相對氫的位置。
另外，於 NOESY 的圖譜中（圖 4-8）若有耦合訊號，代表在空間中距離 小於 5 Å ，從圖譜上可以看到 H-5 與 H-3 有耦合，而 H-7 與 H-1 有耦合，
所以得知與 H-5 及與 H-7 的絕對位置。
圖 4-7：化合物 IV-68a 的1H－1H COSY NMR 圖譜
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圖 4-8：化合物 IV-68a 的 NOESY 圖譜
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4.3.4 化學反應機制探討
合成 其反應機制推測如流程 4-16 所示，雙三氟甲基磺酸亞胺會先
質子化醛基，接著進行炔-醛置換反應，先行[2 + 2]環化加成，再行反[2 + 2]
開環，即得到四氫-1H- 化合物 IV-67。而化合物 IV-67 在空氣中，易自
行氧化，進而得到二氫-1H-芳香化產物 IV-68。
流程 4-16：合成 衍生物 IV-67 和 IV-68 的反應機構
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4.4 結論
以 2.0 當量 NHTf2輔佐 1-(3-芳香基丙炔基)吡咯啶-2-甲醛化合物，進 行炔-醛置換反應，在高溫，氮氣下，以
1,2-二氯乙烷為溶劑，得到四氫-1H-衍生物。反應時間 1-5 分，產率有 31-58%。四氫-1H- 衍生物於空
氣下，逐漸地氧化形成具芳香性二氫-1H- 衍生物。
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2. 薄層色層分析（Thin Layer Chromatography，簡稱 TLC）：使用 Merck Silica gel 60 F254 0.2 mm 厚度的鋁箔薄片，鋁箔薄片展開後，以紫外燈
4. 管柱色層分析（Column Chromatography）：使用友和 Silica gel 230–400 mesh ATSM 作為相吸附劑，依 Still 的操作方法用加壓快速層析（flash column chromatography）來分離。64沖堤液（eluent）若是兩種溶劑系 統，是以體積比值而配製，記錄方法為兩種溶劑之體積比值。
5. 熔點（melting point，簡稱 mp）:係由 Mel-Temp 熔點測定儀器所測定。
此儀器並未作校正。
6. 核磁共振光譜（Nuclear Magnetic Resonance Spectroscopy，簡稱 NMR）： 本研究以 Bruker AV III HD-400 型、AV-400 型和 AV-500 型三種核磁共 振光譜儀來測定樣品。所使用溶劑為含氘-氯仿（chloroform-d1，CDCl3）， 化學位移（, chemical shift）以 ppm 為單位；1H NMR（400 MHz）光 譜化學位移以四甲基矽烷（tetramethylsilane，簡稱 TMS）為內基準，
定義其化學位移為 0 ppm。分裂形式（splitting pattern）定義如下：s，
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7. 紅外線光譜儀（Infrared Spectroscopy，簡稱 IR）：使用 Perkin Elmer Spectrum 500 和 Perkin Elmer Spectrum RX 型光譜儀作為測定儀器。 www.ccdc.cam.ac.uk/data_request/cif.。於附錄中附上 check cif 的 pdf 檔。
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5.2 Lewis Acid-Promoted Synthesis of Octahydroisoquinolines 5.2.1 Experimental stirred at 29 °C for 4 h. The reaction mixture was extracted with CH2Cl2 (100 mL × 3). The combined extracts were washed with water (300 mL × 3) and brine (300 mL × 3), dried over anhydrous MgSO4 (20 g), and concentrated to give a crude oil. The crude mixture was purified by flash column chromatography (silica gel, ethyl acetate/hexanes = 1/3) to afford 2-(hydroxymethyl)cyclohex-2-enol II-68 (4.33 g, 34.32 mmol, 43% , Rf = 0.15 in ethyl acetate/hexanes = 1/5).
Synthesis of (6-Oxocyclohex-1-en-1-yl)methyl acetate (II-67).
To the solution of 2-(hydroxymethyl)cyclohex-2-enol II-68 (4.33 g, 34.32 mmol) in CH2Cl2 (171.6 mL) were added triethylamine (4.55 g, 44.61 mmol) and acetic anhydride (4.20 g, 41.18 mmol). The reaction mixture was stirred at 30 °C for 6 h before quenching with 100 mL of saturated ammonium chloride solution. The solution was washed with water (300 mL × 3) and brine (300 mL
× 3), dried over anhydrous MgSO4 (15 g), and concentrated to give a crude oil.
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The crude mixture was purified by flash column chromatography (silica gel, ethyl acetate/hexanes = 1/5) to afford the corresponding acetate II-67 (3.23 g, 19.20 mmol, 56%, Rf = 0.37 in ethyl acetate/hexanes = 1/5).
Synthesis of (6-Hydroxycyclohex-1-en-1-yl)methylacetate (II-66).
To the solution of the above acetate II-67 in 171 mL of CH2Cl2 was added CeCl3·7H2O (7.90 g, 21.12 mmol) followed by addition of NaBH4 (0.73 g, 19.2 mmol) at 0 °C under nitrogen. The reaction was stirred at 0 °C for 30 min before quenching with 100 mL of saturated ammonium chloride solution. The resulting mixture was extracted with CH2Cl2 (200 mL × 3), and the combined extracts were washed with water and brine and dried over MgSO4 (10 g). The filtrate was concentrated in vacuo to give (6-hydroxycyclohex-1-en-1-yl)
methylacetate II-66 (3.23 g, 19.01 mmol, 99%, Rf= 0.125 in ethyl and tert-butyldimethylsilyl chloride (4.30 g, 41.18 mmol). The reaction mixture was heated at reflux for 12 h, after which time the reaction mixture was filtered through a bed of Celite. The resulting solution was concentrated, and the
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residue was separated by flash column chromatography (silica gel, ethyl acetate/hexanes=1/20) to afford (6-tert-butyldimethylsiloxycyclohex-1-en-1-yl) round-bottom flask was added K2CO3 (1.93 g, 13.88 mmol). The reaction was stirred at 30 °C for 1 h followed by quenching with 200 mL of saturated ammonium chloride. The resulting mixture was washed with water (200 mL × 3) and brine (200 mL × 3) and dried over MgSO4 (10 g) to give (3-((tert-butyldimethylsilyl)oxy)cyclohex-1-en-1-yl)methanol II-64 (3.30 g, 13.6 mmol, 98%, Rf = 0.25 in ethyl acetate/hexanes = 1/3 ).
Synthesis of
N-((6-((tert-Butyldimethylsilyl)oxy)cyclohex-1-en-1-yl)methyl)-4-methyl-N-(prop-2-yn-1-yl)benzenesulfonamide (II-62).
To the above crude product II-64 in 68 mL of THF at 0 °C under nitrogen were added diisopropyl azodicarboxylate (DIAD, 3.30 g, 16.3 mmol), triphenylphosphine (4.28 g, 16.3 mmol), and N-tosylprop-2-yn-1-amine II-63 (2.85 g, 13.6 mmol). The reaction was stirred at 0 °C for 2 h before quenching with 100 mL of water. The resulting mixture was extracted with CH2Cl2 (200
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mL × 3), and the combined extracts were washed with water (200 mL × 3) and brine (200 mL × 3) and dried over MgSO4 (10 g). The filtrate was concentrated in vacuo to give a crude oil. The crude mixture was purified by flash column chromatography (silica gel, ethyl acetate/hexanes = 1/20) to give N-((6-((tert-butyldimethylsilyl)oxy)cyclohex-1-en-1-yl)methyl)-4-methyl-N-(pr op-2-yn-1-yl)-p-toluenesulfonamide II-62 (4.77 g, 11.0 mmol, 78%, Rf = 0.45 in ethyl acetate/hexanes = 1/5). (25.40 mg, 0.022 mmol), CuI (0.084 g, 0.44 mmol), and iodobenzene (2.69 g, 13.2 mmol). The reaction mixture was stirred at 40 °C for 12 h before quenching with 100 mL of saturated aqueous ammonium chloride. The resulting solution was extracted with CH2Cl2 (100 mL × 3). The combined organic solution was washed with water (200 mL × 3) and brine (200 mL × 3) and dried over MgSO4 (10 g). The filtrate was concentrated in vacuo to give a crude oil. The crude mixture was purified by flash column chromatography (silica gel, ethyl acetate/hexanes = 1/20) to produce N-((6-((tert-butyldimethylsilyl)oxy)cyclohex-1-en-1-yl)methyl)-4-methyl-N-(3-phenylprop-2-yn-1-yl)benzenesulfonamide(4.77 g, 11.0 mmol, 78%, Rf = 0.13 in ethyl acetate/hexanes = 1/5 ).
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Synthesis of
4-Methyl-N-(prop-2-yn-1-yl)benzenesulfonamide (II-63).
Tosyl chloride (7.63 g, 40 mmol, 1.0 equiv.) was dissolved in CH2Cl2 (220 mL), afterward propargyl amine (3.1 mL, 44 mmol, 1.1 equiv) and Et3N (6.7 mL, 48 mmol, 1.2 equiv.) was added dropwise at 0 °C under air. The reaction was stirred at room temperature for 2 h before quenching with 150 mL of saturated ammonium chloride solution. The resulting mixture was extracted with CH2Cl2 (200 mL × 3), and the combined extracts were washed with water and brine and dried over MgSO4 (10 g). The filtrate was concentrated in vacuo to give 4-methyl-N-(prop-2-yn-1-yl) benzenesulfonamide II-63 as a pale yellow solid.
Synthesis of But-2-yn-1-yl-4-methylbenzenesulfonate (II-72).
To a solution of 2-butyn-1-ol (1.0 g, 14.3 mmol) in Et2O (14.3 mL) was added tosyl chloride (2.99 g, 15.7 mmol). The reaction was cooled to –15 °C, followed by slow addition of KOH (4 g, 71.3 mmol). The reaction was stirred at –15 °C for 1 h. After that, it was allowed to stir at room temperature for 2 h.
The mixture was quenched with crushed ice. The aqueous layer was extracted with Et2O, the combined organic layers were washed with brine, and dried over MgSO4. The filtrate was concentrated in vacuo to give but-2-yn-1-yl- 4-methylbenzenesulfonate II-72 (3.2 g, 14.1 mmol, 99%) as a white solid.
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Synthesis of But-2-yn-1-aminium chloride (II-73).
To a solution of but-2-yn-1-yl-4-methylbenzenesulfonate II-72 (3.2g, 14.3 mmol) in 13.9 mL of CHCl3 was added hexamethylenetetramine (2.20 g, 15.7 mmol). The reaction was stirred at room temperature for 6 h. The mixture was concentrated in vacuo. The residue were added with 14.3 mL EtOH and conc.
HCl (12 M, 5 mL) and the resulging solution was heated at 60 °C for 3 h. After cooling, the reaction mixture was concentrated in vacuo to give but-2-yn-1-aminium chloride II-73 (1.4 g, 13.3 mmol, 93%) as a white solid.
Synthesis of N-(But-2-yn-1-yl)-4-methylbenzenesulfonamide (II-74).
To a solution of but-2-yn-1-aminium chloride II-73 (1.51 g, 14.3 mmol) in 70 mL of CH2Cl2 were added dropwise Et3N (6.0 mL, 42.8 mmol) and tosyl chloride (3.26 g, 17.1 mmol) at 0 °C under air. The reaction was stirred at room temperature for 6 h before quenching with 150 mL of saturated ammonium chloride solution. The resulting mixture was extracted with CH2Cl2 (200 mL × 3), and the combined extracts were washed with water, brine, and dried over MgSO4 (10 g). The filtrate was concentrated in vacuo to give a crude oil. The crude mixture was purified by flash column chromatography (silica gel, ethyl acetate/hexanes = 1/4) to give N-(but-2-yn-1-yl)-4-methylbenzenesulfonamide II-74 (2.11 g, 9.42 mmol, 66%) as a white solid.
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Synthesis of 5,5-Dimethyl-cyclohex-2-enol (II-78).
To a solution of 5,5-dimethyl-1,3-cyclohexanedione (10.0 g, 71.3 mmo.) in MeOH (142 mL) was added I2 (0.54 g, 2.14 mmol). The reaction mixture was stirred at room temperature for 10 min before quenching with 100 mL of saturated sodium thiosulfate solution. The resulting mixture was extracted with CH2Cl2 (100 mL × 3), the combined extracts were washed with water, brine, and dried over MgSO4 (10 g). The filtrate was concentrated in vacuo to give 3-methoxy-5,5-dimethylcyclohex-2-enone. Lithium aluminum hydride (1.54 g, 40.5 mmol) was diluted with dry Et2O ( 22 mL) at 0 °C under nitrogen. To the solution above, solution of 3-Methoxy-5,5-dimethylcyclohex-2-enone in 10 mL Et2O was added dropwise via a syringe. The reaction was stirred at 0 °C for 3 h before quenching with sulfuric acid solution. The resulting mixture was extracted with Et2O (200 mL × 3). The combined extracts were washed with water, brine, and dried over MgSO4 (10 g). The filtrate was concentrated in vacuo to give a crude oil. Flash column chromatography of the crude oil (silica gel, ethyl acetate/hexanes = 1/3) gave 5,5-dimethyl-cyclohex-2-enol (3.17 g, 25.6 mmol, 78%) as a yellow oil.
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General Procedure II:
FeCl3-Promoted Cyclization to Synthesis of Octahydroisoquinolines(II-80).
To a solution of II-61 (0.10 g, 0.2 mmol) in 2.0 mL of CH2Cl2 at room temperature under air was added FeCl3 (38 mg, 0.24 mmol). The reaction mixture was stirred for 1 min until no II-61 was detected by TLC. The reaction mixture was quenched with water (20 mL). The organic phase was separated.
The aqueous phase was extracted with ethyl ether (20 mL × 3). The combined organic layers were washed with brine (50 mL × 3), dried over anhydrous MgSO4 (5 g), and concentrated to give the crude mixture.
General Procedure III:
BF3-Promoted Cyclization to Synthesis of Octahydroisoquinolines (II-81).
To a solution of II-61 (0.10 g, 0.2 mmol) in 2.0 mL of CH3CN at room temperature under air was added via syringe a solution of BF3˙OEt2 (0.024 mL, 0.2 mmol). The reaction mixture was stirred for 1 min until no II-61 was detected by TLC. The reaction mixture was quenched with saturated aqueous NaHCO3 (20 mL). The organic phase was separated. The aqueous phase was extracted with CH2Cl2 (20 mL × 3). The combined organic layers were washed with brine (50 mL × 3), dried over anhydrous MgSO4 (5 g), and concentrated to give the crude mixture.
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111
N-((6-(tert-Butyldimethylsilyloxy)cyclohex-1-enyl)methyl)-4-methyl-N-(3-(
4-nitrophenyl)prop-2-ynyl)benzenesulfonamide (II-61b).
In General Procedure I, to a solution of II-62 (0.800 g, 1.84 mmol) in Et3N (1.84 mL) were added Pd(PPh3)4 (5 mg, 0.004 mmol), CuI (14 mg, 0.074 mmol), and aryl iodide (0.551 g, 2. 21 mmol). The reaction mixture was stirred at 40 °C for 8 h, and the crude mixture was purified by flash column
112
N-((6-(tert-Butyldimethylsilyloxy)cyclohex-1-enyl)methyl)-4-methyl-N-(3-(
3-nitrophenyl)prop-2-ynyl)benzenesulfonamide (II-61c).
In General Procedure I, to a solution of II-62 (0.500 g, 1.15 mmol) in Et3N (1.15 mL) were added Pd(PPh3)4 (3 mg, 0.002 mmol), CuI (9 mg, 0.046 mmol), and aryl iodide (0.344 g, 1. 38 mmol). The reaction mixture was stirred at 40 °C for 8 h, and the crude mixture was purified by flash column
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N-((6-(tert-Butyldimethylsilyloxy)cyclohex-1-enyl)methyl)-4-methyl-N-(3-(
2-nitrophenyl)prop-2-ynyl)benzenesulfonamide (II-61d).
In General Procedure I, to a solution of II-62 (0.500 g, 1.15 mmol) in Et3N (1.15 mL) were added Pd(PPh3)4 (3 mg, 0.002 mmol), CuI (9 mg, 0.046 mmol), and aryl iodide (0.344 g, 1. 38 mmol). The reaction mixture was stirred at 40 °C for 8 h, and the crude mixture was purified by flash column 130.2, 129.2 (2C), 128.7, 128.0 (2C), 124.5, 117.8, 90.5, 81.0, 65.0, 50.0, 36.8, 32.3, 26.0 (3C), 25.4, 21.3, 18.1, 17.3, −4.4, −4.6; IR (CH2Cl2) 2930, 2857, 1716, 1607, 1530, 1348 cm−1; MS (ESI) m/e (%) 577.7 ([M + Na]+, 100);
HRMS (ESI) calcd for C29H38N2O5NaSSi [M + Na]+ 577.2168, found 577.2159.
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Ethyl 4-(3-(N-((6-(tert-butyldimethylsilyloxy)cyclohex-1-enyl)methyl)-4- methylphenylsulfonamido)prop-1-ynyl)benzoate (II-61e).
In General Procedure I, to a solution of II-62 (0.600 g, 1.38 mmol) in Et3N (1.38 mL) were added Pd(PPh3)4 (3 mg, 0.003 mmol), CuI (11 mg, 0.055 mmol), and aryl iodide (0.458 g, 1. 66 mmol). The reaction mixture was stirred at 40 °C for 8 h, and the crude mixture was purified by flash column