22：嘗試金、銀共催化，三氯化鐵輔佐之環化反應

經由起始物製備過程，確認可利用硝酸銀與 N-溴琥珀醯亞胺（ N- bromosuccinimide, NBS）成功將苯乙炔與末端炔化合物經由溴化反應得到溴化物且有高產率；並利用五水合硫酸銅與 1,10-鄰二氮菲催化進行耦合反應，分別成功得到含保護基的炔醯胺（ynamides）化合物且皆有高產率。

嘗試環化反應，利用金、銀共催化系統，加入三氯化鐵輔佐，反應相當複雜，無法得到預期產物，需再嘗試其他條件篩選，如單獨使用過渡金屬、路易士酸、布忍司特酸，或改變起始物保護基，亦可改變為羰基、羥基嘗試環化反應。

第五章實驗部分

5.1 分析儀器及基本實驗操作

1. 核磁共振光譜（Nuclear Magnetic Resonance Spectroscopy），簡稱（NMR）：

係以 Bruker AV III HD-400 NMR（400 MHz）、AV-400 NMR（400 MHz）

和 AV-500 NMR（500 MHz）核磁共振光譜儀測定樣品。樣品以氘化氯 仿（chloroform-d₁，CDCl₃），化學位移（, chemical shift）以 ppm 為單位；¹H NMR 光譜化學位移以四甲基矽烷（tetramethylsilane，簡稱 TMS）

為內標準，定義其化學位移為 0 ppm。分裂形式（splitting pattern）定

2. 紅外線光譜儀（Infrared Spectroscopy，簡稱 IR）：係使用 Perkin Elmer Spectrum 500 和 Perkin Elmer Spectrum RX 型光譜儀作為測定儀器。以 polystyrene 之 1601cm^-1 吸收作為內標準來校正。光譜單位為波數

（cm^-1）。

3. 質譜(Mass Spectrometry，簡稱 MS)：委託中央研究院化學研究所質譜服務中心代測，是使用 Waters Micromass LCT Premier TOF Mass Spec-trometer (LCMS ESI MSD System)測定，低解析質譜僅列出強度大及重要的解離峰現（m/z），其相對基峰(base peak）的百分比強度列在括弧內；高解析度質譜僅列出分子峰。

4. X-光單晶繞射光譜：委託國立台灣師範大學化學系貴重儀器中心郭頂審助教代測，使用 Bruker apex II 作為測定儀器。CCDC number，此編號

經由劍橋晶體數據中心（The Cambridge Crystallographic Data Center, CCDC）免費認證，網址為 www.ccdc.cam.ac.uk/data_request/cif.。於附錄中附上 check cif 的 pdf 檔。

5. 薄層色層分析（Thin Layer Chromatography，簡稱 TLC）：係使用 Merck Silica gel 60 F₂₅₄ 0.2mm 厚度的鋁箔薄片，鋁箔薄片展開後，以紫外燈或顯色液來檢視薄層色層分析片。

6. 管柱色層分析（Column Chromatography）：係使用友和 Silica gel 230–400 mesh ATSM 作為相吸附劑，依 Still 的操作方法並使用加壓快速層析

（flash column chromatography）來分離。⁵⁹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。

7. 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。

8. 所有反應物和溶劑均為試藥級或分析級，若需進一步純化或乾燥，則依

標準處理手續。乙醚（Ether）、甲苯（Toluene）、四氫呋喃（THF）、二

氯甲烷（CH₂Cl₂）、乙腈（Acetonitrile）均經過溶劑純化系統乾燥及純化（Active Alumina column）。三乙基胺（NEt₃）在使用前是以氫化鈣

（CaH₂）乾燥後蒸餾而得。

9. 所有反應均以磁攪拌子在攪拌器上進行，低溫反應是以乾冰加工業級

丙酮或是冰塊加氯化鈉（NaCl）控制冷卻槽的溫度。反應時間的控制則是以薄層色層分析（TLC）來測定。

5.2 Lewis Acid-Promoted Synthesis of Azaspiro[4.5]dec-6-ene 5.2.1 Experimental

Synthesis of 4-Methyl-N-(prop-2-yn-1-yl)benzenesulfon amide (II-43). To a solution of propargyl amine (3.9 mL, 50.0 mmol) and Et₃N (8.3 mL, 60.0 mmol) in dry CH₂Cl₂ (150.0 mL), tosyl chloride (10.486 g, 55.0 mmol) was a dded

Synthesis of 3-Isobutoxycyclohex-2-en-1-one (II-41). To a solution of 1,3-cyclohexanedione (3.360 g, 30.0 mmol) and isobutanol (10.0 mL, 108.0 mmol) in toluene (20.0 mL) was added p-toluenesulfonic acid (0.260 g, 1.50 mmol). The reaction mixture was heated to reflux with a Dean−Stark apparatus to removed water. After 10 h, the mixture was cooled to room temperature followed by addition of triethylamine (0.20 mL, 3.73 mmol), and the mixture was concentrated under reduced pressure. The crude mixture was purified via flash column chromatography over silica gel (1:2 ethyl acetate/hexanes) to give 3-isobutoxycyclohex-2-en-1-one II-41 (4.450 g, 26.40 mmol, 88%, R_f = 0.25 in 50% ethyl acetate/50% hexanes) as a colorless oil: ¹H NMR (400 MHz, CDCl₃) δ 5.18 (s, 1H), 3.45 (d, J = 5.5 Hz, 2H), 2.27 (t, J = 6.4 Hz, 2H), 2.21 (t, J = 6.4 Hz, 2H), 1.85 (m, 3H), 0.83 (d, J = 6.7 Hz, 6H); ¹³C NMR (100 MHz, CDCl₃) δ 199.2, 177.7, 102.3, 74.2, 36.4, 28.6, 27.3, 20.9, 18.7; MS m/z (%) 169 ([M + H]⁺, 100), 141 (54), 113 (88); calcd. for C₁₀H₁₇O₂ 169.1228, found 169.1221.

Synthesis of 3-((Methylthio)methyl)cyclohex-2-enone (II-40). To a stirred solution of tetramethylethylenediamine (9.1 mL, 60.0 mmol)) at 0 ℃ in THF (30.0 mL) was added n-BuLi (1.6 M, 37.5 mL, 60.0 mmol) dropwise, and the mixture was stirred at 0 ℃ for 0.5 h followed by addition of dimethyl sulfide (4.4 mL, 60.0 mmol). The resulting mixture was stirred at room temperature for 4 h. The mixture was cooled to −78 ℃ , and then 3-isobutoxy- 2-cyclohex-2-en-1-one (5.040 g, 30.0 mmol) in THF (30.0 mL) was added. The reaction mixture was further stirred for 2 h at room temperature followed by addition of 2.5 N HCl_(aq) (40.0 mL) at 0 ℃. The reaction mixture was extracted with ether (30 mL × 4). The combined organic solution was washed with water (200 mL × 3) and brine (200 mL × 3) and dried over anhydrous MgSO₄ (10 g).

The mixture was concentrated under reduced pressure. The crude mixture was purified via flash column chromatography over silica gel (1:10 ethyl acetate/hexanes) to give 3-((methylthio)methyl)cyclohex-2-en-1-one II-40 (3.840 g, 24.60 mmol, 82%, R_f = 0.40 in 50% ethyl acetate/50% hexanes) as a yellow oil: ¹H NMR (400 MHz, CDCl₃) δ 5.90 (s, 1H), 3.20 (s, 2H), 2.46 (t, J = 5.9 Hz, 2H), 2.39 (t, J = 6.6 Hz, 2H), 2.07‒2.01 (m, 2H), 2.00 (s, 3H).

Synthesis of 3-(Iodomethyl)cyclohex-2-enone (II-39). To a stirred solution of 3-((methylthio)methyl)cyclohex-2-en-1-one (3.50 g, 22.40 mmol) in CH₂Cl₂ (25.0 mL) was added methyl iodide (12.710 g, 89.60 mmol) at room temper a-ture. The mixture was heated at 45 ℃ for 3 days in a sealed tube. The reaction mixture was poured into Na₂S₂O_3(aq) (20 mL) and extracted with CH₂Cl₂ (20 mL × 3). The combined organic extracts were dried to give the crude 3-(iodomethyl)cyclohex-2-en-1-one (0.980 g, 4.15 mmol). The crude product II-39 was used for the following step without further purification. ¹H NMR (400 MHz, CDCl₃) δ 6.12 (s, 1H), 4.00 (s, 2H), 2.55 (t, J = 6.6 Hz, 2H), 2.40 (t,

J = 6.7 Hz, 2H), 2.07 (quin, J = 6.4 Hz, 2H).

Synthesis of 4-Methyl-N-((3-oxocyclohex-1-en-1-yl)methyl)-N-(prop- 2-yn-1-yl)benzenesulfonamide (II-38). To the crude 3-(iodomethyl)-cyclohex- 2-en-1-one (0.980 g, 4.15 mmol) and K₂CO₃ (0.688 g, 4.98 mmol) in acetone (6.0 mL) was added 4-methyl-N-(prop-2-yn-1-yl)benzene sulfonamide (0.910 g, 3.19 mmol) in acetone (6.0 mL) via syringe. The mixture was reacted at room temperature for 10 h. The reaction mixture was concentrated, poured into s atu-rated NH₄Cl_(aq), and extracted with CH₂Cl₂ (10 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 crude mixture was purified via flash column

General Procedure II-1. Arylation of Terminal Alkynes Employing So-nogashira Reaction Conditions: Synthesis of 4-Methyl-N-((3-oxocyclo hex-1-en-1-yl)methyl)-N-(3-phenylprop-2-yn-1-yl)benzenesulfonamide

with water (200 mL × 3) and brine (200 mL × 3) and dried over anhydrous MgSO₄ (10 g). The filtrate was concentrated in vacuo to give a crude oil. The crude mixture was purified by flash column chromatography over silica gel (1:10 ethyl acetate/hexanes) to produce 4-methyl-N-((3-oxocyclohex-1-en- 1-yl)methyl)-N-(3-phenylprop-2-yn-1-yl)benzenesulfonamide II-37a (2.70 g, 5.30 mmol, 48%, R_f = 0.57 in 50% ethyl acetate/50% hexanes) as a white

General Procedure II-2. Reduction of α,β-unsaturated ketone Employing Luche Reaction Conditions: Synthesis of N-((3-Hydroxycyclohex-1-en-1-yl) methyl)-4-methyl-N-(3-phenylprop-2-yn-1-yl)benzenesulfonamide (II-36a).

To the solution of 4-methyl-N-((3-oxocyclohex-1-en-1-yl)methyl)-N-(3-phenyl prop-2-yn-1-yl)benzenesulfonamide II-37a (1.573 g, 4.00 mmol) and CeCl₃·7H₂O (1.639 g, 4.40 mmol) in MeOH (20.0 mL) at 0 ℃ was added NaBH₄ (0.303 g, 8.00 mmol), and the mixture was stirred for 1 h. The mixture was concentrated under reduced pressure, poured into 100.0 mL of saturated ammonium chloride solution. The resulting mixture was extracted with CH₂Cl₂ (10 mL × 3) and the combined extracts were washed with water and brine and

dried over anhydrous MgSO₄ (10 g). The filtrate was concentrated in vacuo to give a crude oil. The crude mixture was purified by flash column chromato g-raphy over silica gel (1:3 ethyl acetate/hexanes) to produce N-((3-hydroxycyclohex-1-en-1-yl)methyl)-4-methyl-N-(3-phenylprop-2-yn-1-y l)benzenesulfonamide II-36a (1.035 g, 2.62 mmol, 65%, R_f = 0.20 in 50%

ethyl acetate/50% hexanes) as a white powder: mp 103–104 ℃; ¹H NMR (400 MHz, CDCl₃) δ 7.76 (d, J = 8.0 Hz, 2 H), 7.28–7.21 (m, 5 H), 7.05–7.03 (m, 2

General Procedure II-3 for the Synthesis of TBS-Protected Nitrogen Con-taining Cyclic Enynols (II-35a)

To a stirred solution of II-36a (1.106 g, 2.78 mmol) in CH₂Cl₂ (5.0 mL) were added triethylamine (0.566 g, 5.60 mmol), 4-dimethyl aminopyridine (DMAP, 0.035 g, 0.28 mmol), and tert-butyldimethylsilyl chloride (0.632 g, 4.20 mmol).

The reaction mixture was heated at reflux for 12 h, after which time the reac-tion mixture was added to 10 mL of water and extracted with CH₂Cl₂(100 mL

× 3). The combined organic layer was washed with brine and dried over anhy-drous MgSO₄ (10 g), filtered through a bed of Celite, and concentrated to give the crude mixture II-35a.

General Procedure II-4 Boron Trifluoride Diethyl Etherate-Mediated Carbofluorination of TBS-Protected 3-Phenylpropargyltosylamine-Tether- ed 3-Methylcyclohex-2-en-1-ol (II-35a)

To a solution of II-35a (0.129 g, 0.25 mmol) in CH₂Cl₂ (101.1 mL) at room temperature under an atmosphere of nitrogen was added BF₃·OEt₂ (0.062 mL, 0.51 mmol). The reaction mixture was stirred at room temperature for 1 min, after which time no substrate II-35a was detected, as monitored by TLC. The reaction mixture was quenched with saturated aqueous sodium bicarbonate.

The organic phase was separated, and the aqueous phase was extracted with CH₂Cl₂ (2 × 20 mL). The combined organic layers were washed with brine (100 mL × 3), dried over anhydrous MgSO₄ (10 g), and concentrated to give the crude mixture II-69a.

5.2.2 Synthesis of O-Silyl-Protected 3-(3-Arylpropargyltosylamino)me- thyl-cyclohex-2-en-1-ols (II-35)

N-((3-((tert-Butyldimethylsilyl)oxy)cyclohex-1-en-1-yl)methyl)-4-methyl-N-(3-phenylprop-2-yn-1-yl)benzenesulfonamide (II-35a)

In General Procedure II-3, to a stirred solution of II-36a (1.106 g, 2.78 mmol) in CH₂Cl₂ (5.0 mL) were added triethylamine (0.566 g, 5.60 mmol), 4-dimethyl aminopyridine (DMAP, 0.035 g, 0.28 mmol), and tert-butyldimethylsilyl chlo-ride (0.632 g, 4.20 mmol). The crude mixture was purified by flash column

N-(3-(4-Bromophenyl)prop-2-yn-1-yl)-N-((3-((tert-butyldimethylsilyl)oxy)c yclohex-1-en-1-yl)methyl)-4-methylbenzenesulfonami de (II-35b)

In General Procedure II-3, to a stirred solution of II-36b (1.106 g, 2.78 mmol) in CH₂Cl₂ (5.0 mL) were added triethylamine (0.566 g, 5.60 mmol), 4-dimethyl aminopyridine (DMAP, 0.035 g, 0.28 mmol), and tert-butyldimethylsilyl chlo-ride (0.632 g, 4.20 mmol). The crude mixture was purified by flash column chromatography over silica gel (10% ethyl acetate/hexanes) to give II-35b (0.308 g, 0.52 mmol, 35%, R_f = 0.60 in 17% ethyl acetate/83% hexanes) as a yellow oil: ¹H NMR (400 MHz, CDCl₃) δ 7.74 (d, J = 8.2 Hz, 2H), 7.35 (d, J = 8.4 Hz, 2H), 7.24 (d, J = 8.1 Hz, 2H), 6.89 (d, J = 8.4 Hz, 2H), 5.63 (s, 1H), 4.26 (d, J = 18.5 Hz, 1H), 4.22 (br s, 1H), 4.14 (d, J = 18.5 Hz, 1H), 3.79 (d, J

= 13.4 Hz, 1H), 3.68 (d, J = 13.4 Hz, 1H), 2.33 (s, 3H), 2.08‒1.96 (m, 2H), 1.88‒1.74 (m, 2H), 1.60‒1.45 (m, 2H), 0.86 (s, 9H), 0.04 (d, J = 2.7 Hz, 6H);

13C NMR (100 MHz, CDCl₃) δ 143.3, 136.0, 134.0, 132.8 (2C), 131.3 (3C), 129.4 (2C), 127.7 (2C), 122.5, 121.1, 84.5, 83.0, 66.7, 52.5, 36.3, 32.2, 25.9, 25.8 (3C), 21.3, 19.5, 18.1, -4.6, -4.7 ; IR (CH₂Cl₂) 3442, 2930, 2857, 1634, 1486, 1351, 1255, 1164, 1072, 835, 662 cm^-1; MS (ESI) m/e (%) 610.1 ([M + Na]⁺, 100), 612.1 ([M + 2 + Na]⁺, 90), 199.0 (20), 190.0 (50); HRMS (ESI) calc. for C₂₉H₃₈NO₃SSiNa⁷⁹Br [M + Na]⁺ 610.1423; found 610.1430.

N-((3-((tert-Butyldimethylsilyl)oxy)cyclohex-1-en-1-yl)methyl)-4-methyl-N-(3-(p-tolyl)prop-2-yn-1-yl)benzenesulfonamide (II-35c)

In General Procedure II-3, to a stirred solution of II-36c (1.106 g, 2.78 mmol) in CH₂Cl₂ (5.0 mL) were added triethylamine (0.566 g, 5.60 mmol), 4-dimethyl aminopyridine (DMAP, 0.035 g, 0.28 mmol), and tert-butyldimethylsilyl chlo-ride (0.632 g, 4.20 mmol). The crude mixture was purified by flash column chromatography (silica gel, 10% ethyl acetate/hexanes) to give II-35c (0.988 g, 1.89 mmol, 94%, R_f = 0.35 in 17% ethyl acetate/83% hexanes) as a yellow oil:

1H NMR (400 MHz, CDCl₃) δ 7.76 (d, J = 8.3 Hz, 2H), 7.24 (d, J = 8.1 Hz, 2H), 7.03 (d, J = 7.9 Hz, 2H), 6.93 (d, J = 8.1 Hz, 2H), 5.66 (s, 1H), 4.29 (d, J

= 18.4 Hz, 1H), 4.24 (br s, 1H), 4.15 (d, J = 18.4 Hz, 1H), 3.81 (d, J = 13.4 Hz, 1H), 3.69 (d, J = 13.4 Hz, 1H), 2.34 (s, 3H), 2.31 (s, 3H), 2.11‒1.96 (m, 2H), 1.88‒1.75 (m, 2H), 1.62‒1.46 (m, 2H), 0.87 (s, 9H), 0.05 (d, J = 0.7 Hz, 6H);

13C NMR (100 MHz, CDCl₃) δ 143.2, 138.4, 136.0, 134.1, 131.3 (2C), 131.1, 129.4 (2C), 128.7 (2C), 127.7 (2C), 119.1, 85.8, 80.9, 66.7, 52.4, 36.4, 32.3, 25.8 (3C), 21.3, 19.5, 18.1, -4.6, -4.7; IR (CH₂Cl₂) 3442, 2929, 2857, 1662, 1349, 1163, 1092, 816, 672 cm^-1; MS (ESI) m/e (%) 546.2 ([M + Na]⁺, 10), 448.1 (15), 433.2 (25), 432.2 (100), 430.1 (50); HRMS (ESI) calc. for C₃₀H₄₁NO₃SSiNa [M + Na]⁺ 546.2474; found 546.2477.

N-((3-((tert-Butyldimethylsilyl)oxy)cyclohex-1-en-1-yl)methyl)-4-methyl-N-(3-(m-tolyl)prop-2-yn-1-yl)benzenesulfonamide (II-35d)

In General Procedure II-3, to a stirred solution of II-36d (1.106 g, 2.78 mmol) in CH₂Cl₂ (5.0 mL) were added triethylamine (0.566 g, 5.60 mmol), 4-dimethyl aminopyridine (DMAP, 0.035 g, 0.28 mmol), and tert-butyldimethylsilyl chlo-ride (0.632 g, 4.20 mmol). The crude mixture was purified by flash column chromatography (silica gel, 10% ethyl acetate/hexanes) to give II-35d (0.634 g, 1.21 mmol, 90%, R_f = 0.38 in 17% ethyl acetate/83% hexanes) as a pale yellow (2C), 129.1, 128.5, 127.9, 127.7 (2C), 122.0, 85.8, 81.1, 66.7, 52.3, 36.3, 32.2, 25.8 (4C), 21.3, 21.0, 19.4, 18.1, -4.7 (2C); IR (CH₂Cl₂) 3448, 2936, 2860, 2363, 2228, 1670, 1601, 1436, 1349, 1256, 1163, 1093, 911, 785, 745, 662, 547 cm^-1; MS (ESI) m/e (%) 546.2 ([M + Na]⁺, 10), 460.2 (10), 434.2 (25), 432.2 (100), 430.1 (30); HRMS (ESI) calc. for C₃₀H₄₁NO₃SSiNa [M + Na]⁺ 546.2474;

found 546.2473.

N-((3-((tert-Butyldimethylsilyl)oxy)cyclohex-1-en-1-yl)methyl)-4-methyl-N-(3-(naphthalen-1-yl)prop-2-yn-1-yl)benzenesulfonamide (II-35e)

In General Procedure II-3, to a stirred solution of II-36e (1.106 g, 2.78 mmol) in CH₂Cl₂ (5.0 mL) were added triethylamine (0.566 g, 5.60 mmol), 4-dimethyl aminopyridine (DMAP, 0.035 g, 0.28 mmol), and tert-butyldimethylsilyl chlo-ride (0.632 g, 4.20 mmol). The crude mixture was purified by flash column

N-(3-([1,1'-Biphenyl]-4-yl)prop-2-yn-1-yl)-N-((3-((tert-butyldimethylsilyl)o xy)cyclohex-1-en-1-yl)methyl)-4-methylbenzenesulfonamide (II-35f)

In General Procedure II-3, to a stirred solution of II-36f (1.106 g, 2.78 mmol) in CH₂Cl₂ (5.0 mL) were added triethylamine (0.566 g, 5.60 mmol), 4-dimethyl aminopyridine (DMAP, 0.035 g, 0.28 mmol), and tert-butyldimethylsilyl chlo-ride (0.632 g, 4.20 mmol). The crude mixture was purified by flash column

N-((3-((tert-Butyldimethylsilyl)oxy)cyclohex-1-en-1-yl)methyl)-N-(3-(4-met hoxyphenyl)prop-2-yn-1-yl)-4-methylbenzenesulfonamide (II-35g)

In General Procedure II-3, to a stirred solution of II-36g (1.106 g, 2.78 mmol) in CH₂Cl₂ (5.0 mL) were added triethylamine (0.566 g, 5.60 mmol), 4-dimethyl aminopyridine (DMAP, 0.035 g, 0.28 mmol), and tert-butyldimethylsilyl chlo-ride (0.632 g, 4.20 mmol). The crude mixture was purified by flash column chromatography over silica gel (10% ethyl acetate/hexanes) to give II-35g (0.547 g, 1.01 mmol, 91%, R_f = 0.28 in 17% ethyl acetate/83% hexanes) as a yellow oil: ¹H NMR (400 MHz, CDCl₃) δ 7.85 (d, J = 8.2 Hz, 2H), 7.34 (d, J = 8.1 Hz, 2H), 7.08 (d, J = 8.8 Hz, 2H), 6.84 (d, J = 8.8 Hz, 2H), 5.76 (s, 1H), 4.38 (d, J = 18.4 Hz, 1H), 4.33 (br s, 1H), 4.24 (d, J = 18.4 Hz, 1H), 3.90 (d, J

= 13.8 Hz, 1H), 3.87 (s, 3H), 3.78 (d, J = 13.4 Hz, 1H), 2.43 (s, 3H), 2.19‒2.07 (m, 2H), 1.95‒1.85 (m, 2H), 1.70‒1.58 (m, 2H), 0.97 (s, 9H), 0.15 (s, 6H); ¹³C NMR (100 MHz, CDCl₃) δ 159.5, 143.2, 136.0, 134.1, 132.8 (2C), 131.0, 129.3 (2C), 127.7 (2C), 114.3, 113.6 (2C), 85.5, 80.1, 66.7, 55.2, 52.3, 36.4, 32.2, 25.8 (4C), 21.3, 19.5, 18.1, -4.6, -4.7; IR (CH₂Cl₂) 3462, 2931, 2858, 1607, 1510, 1350, 1250, 1163, 1076, 833, 775, 671, 545 cm^-1; MS (ESI) m/e (%) 562.2 ([M + Na]⁺, 100), 557.3 (30), 449.2 (20), 448.2 (95), 446.1 (10);

HRMS (ESI) calc. for C₃₀H₄₁NO₄SSiNa [M + Na]⁺ 562.2423; found 562.2425.

N-((3-((tert-Butyldimethylsilyl)oxy)cyclohex-1-en-1-yl)methyl)-N-(3-(3-met hoxyphenyl)prop-2-yn-1-yl)-4-methylbenzenesulfonamide (II-35h)

In General Procedure II-3, to a stirred solution of II-36h (1.106 g, 2.78 mmol) in CH₂Cl₂ (5.0 mL) were added triethylamine (0.566 g, 5.60 mmol), 4-dimethyl aminopyridine (DMAP, 0.035 g, 0.28 mmol), and tert-butyldimethylsilyl chlo-ride (0.632 g, 4.20 mmol). The crude mixture was purified by flash column 143.3, 135.9, 133.9, 131.1, 129.3 (2C), 129.0, 127.6 (2C), 123.8, 123.1, 116.8, 114.1, 85.5, 81.3, 66.6, 55.0, 52.3, 36.2, 32.2, 25.8, 25.7 (3C), 21.2, 19.4, 18.0, -4.7, -4.8; IR (CH₂Cl₂) 3462, 2936, 2859, 2232, 1667, 1599, 1584, 1464, 1430, 1349, 1290, 1164, 1093, 836, 776, 661, 545 cm^-1; MS (ESI) m/e (%) 562.2 ([M + Na]⁺, 100), 557.3 (20), 449.2 (15), 448.2 (60), 443.2 (10); HRMS (ESI) calc.

for C₃₀H₄₁NO₄SSiNa [M + Na]⁺ 562.2423; found 562.2417.

N-((3-((tert-Butyldimethylsilyl)oxy)cyclohex-1-en-1-yl)methyl)-4-methyl-N-(3-(4-nitrophenyl)prop-2-yn-1-yl)benzenesulfonamide (II-35i)

In General Procedure II-3, to a stirred solution of II-36i (1.106 g, 2.78 mmol) in CH₂Cl₂ (5.0 mL) were added triethylamine (0.566 g, 5.60 mmol), 4-dimethyl aminopyridine (DMAP, 0.035 g, 0.28 mmol), and tert-butyldimethylsilyl chlo-ride (0.632 g, 4.20 mmol). The crude mixture was purified by flash column chromatography over silica gel (10% ethyl acetate/hexanes) to give II-35i (0.424 g, 0.77 mmol, 78%, R_f = 0.25 in 17% ethyl acetate/83% hexanes) as a yellow powder: mp 104‒105 ℃; ¹H NMR (400 MHz, CDCl₃) δ 8.11 (d, J = 8.8 Hz, 2H), 7.76 (d, J = 8.2 Hz, 2H), 7.27 (d, J = 8.0 Hz, 2H), 7.19 (d, J = 8.8 Hz, 2H), 5.64 (s, 1H), 4.32 (d, J = 18.6 Hz, 1H), 4.22 (br s, 1H), 4.21 (d, J = 18.6 Hz, 1H), 3.80 (d, J = 13.4 Hz, 1H), 3.72 (d, J = 13.4 Hz, 1H), 2.35 (s, 3H), 2.09‒1.96 (m, 2H), 1.88‒1.74 (m, 2H), 1.61‒1.46 (m, 2H), 0.86 (s, 9H), 0.04 (d, J = 4.1 Hz, 6H); ¹³C NMR (100 MHz, CDCl₃) δ 147.1, 143.5, 136.0, 133.9, 132.1 (2C), 131.5, 129.5 (2C), 129.0, 127.8 (2C), 123.3 (2C), 87.5, 8 3.7, 66.7, 52.7, 36.3, 32.2, 25.9, 25.8 (3C), 21.4, 19.4, 18.1, -4.6, -4.7 ; IR (CH₂Cl₂) 3413, 2932, 2856, 1596, 1520, 1340, 1163, 1075, 854, 662 cm^-1; MS (ESI) m/e (%) 577.2 ([M + Na]⁺, 100); HRMS (ESI) calc. for C₂₉H₃₈N₂O₅SSiNa [M + Na]⁺ 577.2168; found 577.2169.

N-((3-((tert-Butyldimethylsilyl)oxy)cyclohex-1-en-1-yl)methyl)-4-methyl-N-(3-(3-nitrophenyl)prop-2-yn-1-yl)benzenesulfonamide (II-35j)

In General Procedure II-3, to a stirred solution of II-36j (1.106 g, 2.78 mmol) in CH₂Cl₂ (5.0 mL) were added triethylamine (0.566 g, 5.60 mmol), 4-dimethyl aminopyridine (DMAP, 0.035 g, 0.28 mmol), and tert-butyldimethylsilyl chlo-ride (0.632 g, 4.20 mmol). The crude mixture was purified by flash column

Ethyl

4-(3-(N-((3-((tert-butyldimethylsilyl)oxy)cyclohex-1-en-1-yl)methyl)-4-meth ylphenylsulfonamido)prop-1-yn-1-yl)benzoate (II-35k)

In General Procedure II-3, to a stirred solution of II-36k (1.106 g, 2.78 mmol) in CH₂Cl₂ (5.0 mL) were added triethylamine (0.566 g, 5.60 mmol), 4-dimethyl aminopyridine (DMAP, 0.035 g, 0.28 mmol), and tert-butyldimethylsilyl chlo-ride (0.632 g, 4.20 mmol). The crude mixture was purified by flash column

100

Ethyl

3-(3-(N-((3-((tert-butyldimethylsilyl)oxy)cyclohex-1-en-1-yl)methyl)-4-meth ylphenylsulfonamido)prop-1-yn-1-yl)benzoate (II-35l)

In General Procedure II-3, to a stirred solution of II-36l (1.106 g, 2.78 mmol) in CH₂Cl₂ (5.0 mL) were added triethylamine (0.566 g, 5.60 mmol), 4-dimethyl aminopyridine (DMAP, 0.035 g, 0.28 mmol), and tert-butyldimethylsilyl chlo-ride (0.632 g, 4.20 mmol). The crude mixture was purified by flash column

101 brine (200 mL × 3) and dried over anhydrous MgSO₄ (10 g). The crude mixture was purified via flash column chromatography over silica gel (1:3 ethyl ac e-tate/hexanes) to give N-(but-2-yn-1-yl)-4-methyl-N-((3-oxocyclohex- 1-en-1-yl)methyl)benzenesulfonamide (1.010 g, 3.05 mmol, 73%, R_f = 0.57 in 50% ethyl acetate/50% hexanes) as a pale yellow powder. After reduction General Procedure II-2 and protection General Procedure II-3, the crude mixture was purified by flash column chromatography over silica gel (10%

ethyl acetate/hexanes) to give II-52 (0.298 g, 0.67 mmol, 86%, R_f = 0.38 in 17% ethyl acetate/83% hexanes) as a colorless oil: ¹H NMR (400 MHz, CDCl₃) δ 7.73 (d, J = 8.3 Hz, 2H), 7.29 (d, J = 8.1 Hz, 2H), 5.60 (s, 1H), 4.22 (br s,

102

1252, 1161, 1094, 912, 837, 746, 660, 546 cm^-1; MS (ESI) m/e (%) 470.2 ([M + Na]⁺, 35), 435.3 (30), 433.2 (100), 356.1 (60), 354.1 (65), 316.1 (80); HRMS (ESI) calc. for C₂₄H₃₇NO₃SSiNa [M + Na]⁺ 470.2161; found 470.2170.

103

N-((3-((tert-Butyldimethylsilyl)oxy)cyclohex-1-en-1-yl)methyl)-4-methyl-N-(prop-2-yn-1-yl)benzenesulfonamide (II-48)

To the solution of 3-((methylthio)methyl)cyclohex-2-enone II-40 (2.10 g, 5.34 mmol) and CeCl₃·7H₂O (1.990 g, 5.34 mmol) in MeOH (25.0 mL) at 0 ℃ was added NaBH₄ (0.240 g, 6.41 mmol), and the mixture was stirred for 1 h.

The mixture was concentrated under reduced pressure, poured into 100 mL of saturated ammonium chloride solution. The resulting mixture was extracted with CH₂Cl₂ (10 mL × 3) and the combined extracts were washed with water and brine and dried over anhydrous MgSO₄ (10 g). The filtrate was concen-trated in vacuo to give a crude oil. The crude mixture was purified by flash column chromatography over silica gel (1:3 ethyl acetate/hexanes) to produce 3-((methylthio)methyl)cyclohex-2-enol (2.70 g, 5.30 mmol, 48%, R_f = 0.20 in 50% ethyl acetate/50% hexanes). To a stirred solution of 3-((methylthio)methyl) cyclohex-2-enol (2.70 g, 5.30 mmol) in CH₂Cl₂ (5.0 mL) were added triethyl-amine (3.880 g, 38.0 mmol), 4-dimethylaminopyridine (DMAP, 0.230 g, 1.90 mmol), 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

104 added 4-methyl-N-(prop-2-yn-1-yl)benzene sulfonamide (2.355 g, 11.25 mmol) in acetone (12.0 mL) via syringe. The mixture was reacted at room temperature for 10 h. The reaction mixture was concentrated, poured into saturated op-2-yn-1-yl)benzenesulfonamide II-48 (1.01 g, 2.57 mmol, 81%, R_f = 0.57 in 50% ethyl acetate/50% hexanes) as a pale yellow oil: ¹H NMR (400 MHz,

105

(CH₂Cl₂) 3476, 3278, 2937, 2860. 2119, 1599, 1435, 1351, 1253, 1163, 1078, 901, 837, 776, 663, 546 cm^-1; MS (ESI) m/e (%) 456.2 ([M + Na]⁺, 100), 451.2 (20); HRMS (ESI) calc. for C₂₃H₃₅NO₃SSiNa [M + Na]⁺ 456.2005; found 456.2000.

106

N-((3-((tert-Butyldimethylsilyl)oxy)-5,5-dimethylcyclohex-1-en-1-yl)methyl )-4-methyl-N-(3-phenylprop-2-yn-1-yl)benzenesulfonamide (II-60a)

The N-((5,5-dimethyl-3-oxocyclohex-1-en-1-yl)methyl)-4-methyl-N-(prop-2- yn-1-yl)benzenesulfonamide II-57 was synthesized using similar procedures as those of page 97‒99. The N-((5,5-dimethyl-3-oxocyclohex-1-en-1-yl)- me-thyl)-4-methyl-N-(prop-2-yn-1-yl)benzenesulfonamide (4.938 g, 14.29 mmol) underwent General Procedure II-1 followed by General Procedure II-2 fol-lowed by General Procedure II-3 to give a crude mixture. The crude mixture was purified by flash column chromatography over silica gel (10% ethyl ac

107

N-((3-((tert-Butyldimethylsilyl)oxy)-5,5-dimethylcyclohex-1-en-1-yl)methyl )-N-(3-(4-methoxyphenyl)prop-2-yn-1-yl)-4-methylbenzenesulfonamide (II-60b)

108

N-((3-((tert-Butyldimethylsilyl)oxy)-5,5-dimethylcyclohex-1-en-1-yl)methyl )-4-methyl-N-(3-(p-tolyl)prop-2-yn-1-yl)benzenesulfonamide (II-60c)

109

N-((3-((tert-Butyldimethylsilyl)oxy)-5,5-dimethylcyclohex-1-en-1-yl)methyl )-4-methyl-N-(3-(m-tolyl)prop-2-yn-1-yl)benzenesulfonamide (II-60d)

110

N-((3-((tert-Butyldimethylsilyl)oxy)-2-methylcyclohex-1-en-1-yl)methyl)-4-methyl-N-(3-phenylprop-2-yn-1-yl)benzenesulfonamide (II-68)

The 4-methyl-N-((2-methyl-3-oxocyclohex-1-en-1-yl)methyl)-N-(prop-2-yn- 1-yl)benzenesulfonamide II-65 was synthesized using similar procedures as those of page 97‒99. The 4-methyl-N-((2-methyl-3-oxocyclohex-1-en-1-yl)- methyl)-N-(prop-2-yn-1-yl)benzenesulfonamide (4.938 g, 14.29 mmol) under-went General Procedure II-1 followed by General Procedure II-2 followed by General Procedure II-3 to give a crude mixture. The crude mixture was 131.4 (2C), 129.4 (2C), 128.3, 128.0, 127.8 (2C), 127.1, 122.3, 85.5, 82.4, 70.6, 47.9, 36.0, 32.7, 27.7, 25.8 (3C), 21.3, 18.7, 18.1, 16.0, -4.2, -4.7; IR (CH₂Cl₂) 3446, 2935, 2859, 2363, 2343, 1636, 1350, 1256, 1164, 1077, 837, 757, 661, 550 cm^-1; MS (ESI) m/e (%) 546.2 ([M + Na]⁺, 100); HRMS (ESI) calc. for C₃₀H₄₁NO₃SSiNa [M + Na]⁺ 546.2474; found 546.2476.

111

5.2.3 BF₃-Promoted to Synthesis of Azaspiro[4.5]dec-6-enes (II-69)

(Z)-4-(Fluoro-(phenyl)methylene)-2-tosyl-2-azaspiro[4.5]dec-6-ene (II-69a)

In General Procedure II-4, to a solution of II-35a (0.130 g, 0.25 mmol) in CH₂Cl₂ (101.1 ml) at room temperature under an atmosphere of nitrogen was added BF₃．OEt₂ (0.062 mL, 0.51 mmol). The reaction mixture was stirred for 1 min and the crude mixture was purified by flash column chromatography (sil i-ca gel, 1:30 ethyl acetate/hexanes) to give II-69a (0.073 g, 0.18 mmol, 73%, R_f

= 0.38 in 17% ethyl acetate/83% hexanes) as a colorless powder: mp 146‒147

℃; ¹H NMR (500 MHz, CDCl₃) δ 7.74 (d, J = 8.2 Hz, 2H), 7.37‒7.33 (m, 4H),

112

(Z)-4-((4-Bromophenyl)fluoromethylene)-2-tosyl-2-azaspiro[4.5]dec-6-ene (II-69b)

In General Procedure II-4, to a solution of II-35b (0.150 g, 0.25 mmol) in CH₂Cl₂ (101.1 ml) at room temperature under an atmosphere of nitrogen was added BF₃·OEt₂ (0.062 mL, 0.51 mmol). The reaction mixture was stirred for 1 min and the crude mixture was purified by flash column chromatography over silica gel (1:30 ethyl acetate/hexanes) to give II-69b (0.054 g, 0.11 mmol, 45%, R_f = 0.35 in 17% ethyl acetate/83% hexanes) as a white powder: mp 147‒148

113

(Z)-4-(Fluoro(p-tolyl)methylene)-2-tosyl-2-azaspiro[4.5]dec-6-ene (II-69c)

In General Procedure II-4, to a solution of II-35c (0.130 g, 0.25 mmol) in CH₂Cl₂ (101.1 ml) at room temperature under an atmosphere of nitrogen was added BF₃·OEt₂ (0.062 mL, 0.51 mmol). The reaction mixture was stirred for 1 min and the crude mixture was purified by flash column chromatography (sil i-ca gel, 1:30 ethyl acetate/hexanes) to give II-69c (0.08 g, 0.20 mmol, 77%, R_f

= 0.38 in 17% ethyl acetate/83% hexanes) as a colorless powder: mp 133‒134

℃; ¹H NMR (400 MHz, CDCl₃) δ 7.74 (d, J = 8.2 Hz, 2H), 7.36 (d, J = 8.1 Hz,

114

(Z)-4-(Fluoro(m-tolyl)methylene)-2-tosyl-2-azaspiro[4.5]dec-6-ene (II-69d)

In General Procedure II-4, to a solution of II-35d (0.137 g, 0.25 mmol) in CH₂Cl₂ (101.1 ml) at room temperature under an atmosphere of nitrogen was added BF₃·OEt₂ (0.062 mL, 0.51 mmol). The reaction mixture was stirred for 1 min and the crude mixture was purified by flash column chromatograph y over silica gel (1:30 ethyl acetate/hexanes) to give II-69d (0.091 g, 0.22 mmol, 87%, R_f = 0.41 in 17% ethyl acetate/83% hexanes) as a white powder: mp 135‒137

℃; ¹H NMR (400 MHz, CDCl₃) δ 7.74 (d, J = 8.1 Hz, 2H), 7.36 (d, J = 8.0 Hz, 2H), 7.21‒7.09 (m, 4H), 5.57‒5.48 (m, 1H), 5.03 (d, J = 9.7 Hz, 1H), 4.27 (dd, J = 14.7, 2.7 Hz, 1H), 3.95 (dd, J = 14.7, 3.3 Hz, 1H), 3.39 (dd, J = 9.3, 2.3 Hz, 1H), 2.78 (d, J = 9.3 Hz, 1H), 2.46 (s, 3H), 2.30 (s, 3H), 2.03 ‒1.92 (m, 2H), 1.88‒1.77 (m, 1H), 1.76‒1.60 (m, 2H), 1.57‒1.45 (m, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 152.0 (d, J = 242 Hz), 143.7, 137.0, 132.3, 131.1 (d, J = 28 Hz), 130.0, 129.7 (2C), 129.4, 129.3, 129.2, 1 28.0 (2C), 127.4, 125.6 (d, J = 5 Hz), 122.9 (d, J = 19 Hz), 59.4, 49.8 (d, J = 11 Hz), 44.6 (d, J = 5 Hz), 32.1 (d, J = 2 Hz), 24.5, 21.6, 21.2, 20.0; ¹⁹F NMR (CDCl₃, 376 MHz) δ −90.40; IR (CH₂Cl₂) 3033, 2944, 2872, 2338, 1693, 1598, 1456, 1341, 1156, 109 4, 1050, 818, 795, 702, 667, 550 cm^-1; MS (ESI) m/e (%) 412.2 ([M + H]⁺, 40), 360.3 (5); HRMS (ESI) calc. for C₂₄H₂₇NO₂SF [M + H]⁺ 412.1747; found 412.1743.

115

(Z)-4-(Fluoro(naphthalen-1-yl)methylene)-2-tosyl-2-azaspiro[4.5]dec-6-ene (II-69e)

In General Procedure II-4, to a solution of II-35e (0.11 g, 0.25 mmol) in CH₂Cl₂ (101.1 ml) at room temperature under an atmosphere of nitrogen was added BF₃·OEt₂ (0.062 mL, 0.51 mmol). The reaction mixture was stirred for 1 min and the crude mixture was purified by flash column chromatography over silica gel (1:30 ethyl acetate/hexanes) to give II-69e (0.068 g, 0.15 mmol, 60%, R_f = 0.33 in 17% ethyl acetate/83% hexanes) as a colorless powder: mp 193‒ 2934, 2341, 1717, 1597, 1447, 1348, 1163, 1093, 910, 781, 733, 668, 581, 550 cm^-1; MS (ESI) m/e (%) 446.2 ([M - H]^-, 100), 96.9 (75); HRMS (ESI) calc. for C₂₇H₂₅NO₂SF [M - H]^- 446.1590; found 446.1594. Crysatals suitable for X-ray diffraction analysis were grown from CH₂Cl₂ and hexanes. CCDC number:

1010690.

116

(Z)-4-([1,1'-Biphenyl]-4-ylfluoromethylene)-2-tosyl-2-azaspiro[4.5]dec-6-en e (II-69f)

In General Procedure II-4, to a solution of II-35f (0.148 g, 0.25 mmol) in CH₂Cl₂ (101.1 ml) at room temperature under an atmosphere of nitrogen was added BF₃·OEt₂ (0.062 mL, 0.51 mmol). The reaction mixture was stirred for 1 min and the crude mixture was purified by flash column chromatography over silica gel (1:30 ethyl acetate/hexanes) to give II-69f (0.068 g, 0.14 mmol, 57%, R_f = 0.38 in 17% ethyl acetate/83% hexanes) as a white powder: mp 164‒165

117

(Z)-4-(Fluoro(4-methoxyphenyl)methylene)-2-tosyl-2-azaspiro[4.5]dec-6-en e (II-69g)

In General Procedure II-4, to a solution of II-35g (0.137 g, 0.25 mmol) in CH₂Cl₂ (101.1 ml) at room temperature under an atmosphere of nitrogen was added BF₃·OEt₂ (0.062 mL, 0.51 mmol). The reaction mixture was stirred for 1 min and the crude mixture was purified by flash column chromatography over silica gel (1:30 ethyl acetate/hexanes) to give II-69g (0.041 g, 0.01 mmol, 38%, R_f = 0.30 in 17% ethyl acetate/83% hexanes) as a pale yellow powder: mp 126‒

128 ℃; ¹H NMR (400 MHz, CDCl₃) δ 7.74 (d, J = 8.2 Hz, 2H), 7.36 (d, J =

118

(Z)-4-(Fluoro(3-methoxyphenyl)methylene)-2-tosyl-2-azaspiro[4.5]dec-6-en

在文檔中一、路易士酸輔佐矽保護3-(3-芳香基丙炔基甲苯磺醯胺基)甲基環己-2-烯-1-醇化合物分子內環化反應－含氮螺旋[4.5]癸-6-烯衍生物之合成二、布忍司特酸催化與路易士酸輔佐2-甲基-2,3-環氧基-4-(3-芳香基丙炔基)環己-1-酮化合物分子內環化反應－7-苯甲醯基雙環[3.2.1]辛-2-酮與芳香基含鹵亞甲基雙環[3.2.1]辛-2-酮衍生物之合成 (頁 99-200)

第 五章 實驗部分

第五章實驗部分