11:化合物 III-62 的推測反應機構

我們發展出一個利用三氟化硼進行高效率且實際可行的合成環外亞 甲基橋形雙環方法，在室溫，氮氣下，在 1 分鐘內，對具第三丁基二甲 基矽保護之環形 2,6-烯炔-1-醇化合物 III-51 來進行分子內環化反應，可 得到高產率、高立體選擇性的（E）-5-含氟亞甲基雙環[2.2.2]辛-2-烯衍生 物 III-61。

51

第四章 實驗部分

4.1 實驗操作及儀器分析

1. 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-d

₁

，

CDCl

₃

），化學位移（



, chemical shift）以 ppm 為單位；氫核磁共振光 譜（

¹

H NMR）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，單峰（singlet）；d，雙重峰（doublet）；t，三重峰（triplet）； q，四重峰（quartet）；quin，五重峰（quintet）；m，多重峰（multiplet）。

耦合常數（coupling constant）以 J 表示，單位是 Hz。光譜數據的記 錄依序為：化學位移（分裂形式，耦合常數，氫數）。碳核磁共振光 譜 （

¹³

C NMR ） 是 以 同 型 儀 器 操 作 ， 化 學 位 移 以 含 氘 - 氯 仿

（chloroform-d

₁

，CDCl

₃

）中間峰為內標準，定義其化學位移為 77.0 ppm。

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 Spectrometer (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

52

頂審老師代測，使用 Bruker apex II 作為測定儀器。CCDC number，

此 編 號 於 劍 橋 晶 體 數 據 中 心 免 費 索 取 ， 網 址 為

www.ccdc.cam.ac.uk/data_request/cif.。另附錄中附上 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 F

₂₅₄

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 的操作方法用加壓快速層析

（flash column chromatography）來分離。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。二氯甲烷（CH

₂

Cl

₂

）、甲苯（toluene）、四氫呋喃（THF）、

乙醚（ether）、乙腈（CH

₃

CN）均經過溶劑純化系統乾燥及純化（active alumina column）。

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。

53

4.2 起始物的合成

4.2.1 Procedure for the Synthesis of 3-Ethoxycyclohex-2-enone (II-91)

To a stirred solution of 1,3-cycloheaxanedione (5.61 g, 50.0 mmol) in ethanol (75mL), was added iodine (0.64 g, 5 mol%), The reaction was stirred at 30 ℃ and monitored by TLC. After the reaction was complete, the solvent was removed under reduced pressure. The residue was extracted with ethyl acetate (250 mL × 3) and washed with saturated aqueous sodium thiosulfate (250 mL × 3), and subsequently the combined organic layer extracts were washed with water (100× 3 mL) and brine (100 × 3 mL) and dried over anhydrous MgSO

₄

(10 g), and was concentrated in vacuo to give crude oil which was purified via flash chromatography over silica gel (1:8 ethyl acetate/hexanes) to afford 3-ethoxycyclohex-2-enone (5.26 g, 37.52 mmol, 75%).

4.2.2 Procedure for the Synthesis of

3-Ethoxy-6-(prop-2-yn-1-yl)cyclohex-2-enone (II-92)

To a flame-dried 250 mL round-bottom flask equipped with a stir bar containing diisopropylamine (3.04 g, 30.0 mmol) and THF (56 mL) at -78 ℃ was slowly added n-BuLi (18.75 mL of a 1.6 M solution in hexanes, 30 mmol). The mixture was stirred at -78 ℃ for 30 min before 3-ethoxycyclohex-2-enone (3.50 g , 25.0 mmol) was added dropwise via syringe. The resulting mixture was stirred at -78 ℃ for another 2 h and

54

propargyl bromide (2.6 mL of a 80% solution in toluene, 24.0 mmol) was added dropwise via syringe. The resulting brown solution was allowed to warm to ambient temperature and stirred overnight. The brown reaction mixture was quenched with saturated aqueous NH

₄

Cl solution and diluted with ethyl ether and water. Subsequently, the combined organic layer extracts with ethyl ether (150 mL × 3) were washed with water (150 × 3 mL) and brine (150 × 3 mL)and dried over anhydrous MgSO

₄

(15 g), and was concentrated in vacuo to give crude oil which was purified via flash chromatography over silica gel (1:9 ethyl acetate/hexanes) to afford 3-ethoxy-6-(prop-2-yn-1-yl)cyclohex-2-enone (3.33 g, 18.69 mmol, 75%).

4.2.3 Procedure for the Synthesis of 4-(Prop-2-yn-1-yl)cyclohex-2-enone (II-93)

To an ice cold suspension of LiAlH

₄

(0.38 g, 10.0 mmol) in 25 mL of THF was added dropwise via cannula a solution of 3-ethoxy-6-(2-propynyl)-2-cyclohexen-1-one (1.78 g, 10.0 mmol) in THF (20 mL). Following the addition, the reaction flask was removed from the ice bath, warmed to 29 ℃ and stirred for 2 h. The mixture was then cooled to 0 ℃ and 0.37 mL of H

₂

O was added dropwise over a 2 min period followed by the successive addition of 0.37 mL of 15% v/v aqueous NaOH, and 1.13 mL of H

₂

O. Caution: vigorous gas evolution ensues upon addition of H

₂

O and aqueous NaOH. The resulting white suspension was stirred vigorously for 12 h. The mixture was filtered through a bed pad of Celite and the flask and filter cake were rinsed with ethyl acetate (250 mL × 2). The filtrate was

55

concentrated under reduced pressure to afford a pale yellow oil. This material was dissolved in THF (40 mL) and to this solution was added slowly 5.0 M aqueous HCl (9.18 mL). The pale yellow mixture was stirred at 29 ℃ for 1h.

The reaction contents were then diluted with H

₂

O (200 mL) and extracted with ethyl acetate (250 mL × 2). The combined organic extracts were washed with water (50 × 3 mL) and brine (50 × 3 mL)and dried over anhydrous MgSO

₄

(10 g), and was concentrated in vacuo to give crude oil which was purified via flash chromatography over silica gel (1:5 ethyl acetate/hexanes) to afford 4-(prop-2-yn-1-yl)cyclohex-2-enone (1.11 g, 8.23 mmol, 83%).

4.3 synthesis of

(1S,4S,E)-5-(chloro(phenyl)methylene)bicyclo[2.2.2]oct-2-ene 4.3.1General Procedure I

Arylation of Terminal Alkynes Employing Sonogashira Reaction Condition : Synthesis of 4-(3-Phenylprop-2-yn-1-yl)cyclohex-2-enone (II-96)

To a stirred solution of 4-(prop-2-yn-1-yl)cyclohex-2-enone (0.246 g, 2.06 mmol) in Et3N (6.18 mL) were added Pd(PPh3)4 (0.048g, 0.04 mmol), CuI (0.016 g, 0.08 mmol), and iodobenzene (0.504 g, 2.47 mmol) under nitrogen.

The reaction mixture was stirred at 50 ℃ for 2 h before quenching with a saturated NH4Cl(aq) (30 mL). The resulting solution was extracted with CH2Cl2 (50 mL × 3). The combined organic solution was washed with water (30 × 3 mL) and brine (30 × 3 mL)and dried over anhydrous MgSO4 (5 g), and was concentrated in vacuo to give crude oil which was purified via flash chromatography over silica gel (1:10 ethyl acetate/hexanes) to afford 4-(3-phenylprop-2-yn-1-yl)cyclohex-2-enone (0.251 g, 1.19 mmol, 58%).

56

4-(3-Phenylprop-2-yn-1-yl)cyclohex-2-enone (II-96)

In General Procedure I, to a solution of II-93 (0.276 g, 2.06 mmol) in 2.06 mL of Et

₃

N were added sequentially iodobenzene (0.504 g, 2.47 mmol), Pd(PPh

₃

)

₄

(0.005 mg, 0.004 mmol) and CuI (0.016 g, 0.08 mmol) at room temperature under an atmosphere of nitrogen. The reaction mixture was stirred for 3 h and the crude mixture was purified by flash column chromatography over silica gel (ethyl acetate/hexanes 1:10) to give II-96 (0.251 g, 1.19 mmol, 58%, R

_f

= 0.4 in 1:3 ethyl acetate/hexanes) as a tan oil:

1

H NMR (400 MHz, CDCl

₃

) δ 7.40−7.38 (m, 2H), 7.29−7.27 (m, 3H), 6.99 (d,

J = 10.2 Hz, 1H), 6.04 (dd, J = 10.2, 2.1 Hz, 1H), 2.75−2.66 (m, 1H),

2.61−2.49 (m, 3H), 2.38 (ddd, J = 16.8, 12.9, 4.9 Hz, 1H), 2.20 (dddd, J = 14.6, 9.5, 4.7, 1.4 Hz, 1H), 1.86 (tdd, J = 13.0, 9.8, 4.5 Hz, 1H);

¹³

C NMR (100 MHz, CDCl

₃

) δ 199.0, 152.7, 131.4 (2C), 129.6, 128.1 (2C), 127.8, 123.1, 86.6, 82.6, 36.6, 35.7, 28.4, 24.8; IR (CH

₂

Cl

₂

) 3046, 2916, 1680, 1489, 1249 cm

⁻¹

; MS (EI, 70 eV) m/e (%) 210.1 ([M]

⁺

, 20), 182.1 (63), 154.1 (32), 115.1 (100); HRMS (EI) calcd for C

₁₅

H

₁₄

O [M]

⁺

210.1045, found 210.1047.

57

4-(3-(m-Tolyl)prop-2-yn-1-yl)cyclohex-2-enone (II-97)

In General Procedure I, to a solution of II-93 (0.296 g, 2.20 mmol) in 2.20 mL of Et

₃

N were added sequentially iodobenzene (0.576 g, 2.64 mmol), Pd(PPh

₃

)

₄

(0.006 g, 0.004 mmol) and CuI (0.017 g, 0.09 mmol) at room temperature under an atmosphere of nitrogen. The reaction mixture was stirred for 3 h and the crude mixture was purified by flash column chromatography over silica gel (ethyl acetate/hexanes 1:10) to give II-97 (0.349 g, 1.56 mmol, 71%, R

_f = 0.43 in 1:3 ethyl acetate/hexanes) as a tan oil:

1

H NMR (400 MHz, CDCl

₃

) δ 7.22 (s, 1H), 7.21-7.16 (m, 2H), 7.11 (d, J = 6.6 Hz, 1H), 7.00 (dt, J = 10.2, 1.9 Hz, 1H), 6.06 (dd, J = 10.2, 2.5 Hz, 1H), 2.80-2.71 (m, 1H), 2.62-2.51 (m, 3H), 2.42 (ddd, J = 16.9, 12.9, 4.9 Hz, 1H), 2.32 (s, 3H), 2.25 (dddd, J = 13.4, 9.4, 4.7, 1.3 Hz, 1H), 1.91 (tdd, J = 13.1, 9.9, 4.5 Hz, 1H);

¹³

C NMR (100 MHz, CDCl

₃

) δ 199.3, 152.9, 138.0, 132.2, 129.9, 128.9, 128.6, 128.2, 123.1, 86.3, 82.9, 36.9, 36.0, 28.6, 25.0, 21.2; IR (CH

₂

Cl

₂

) 3027, 2921, 2230, 1678, 786 cm

⁻¹

; MS (EI) m/e (%) 224.1 ([M]

⁺

, 36), 223.1 (11), 196.1 (18), 168.1 (100), 165.1 (74); HRMS (EI) calcd for C

₁₆

H

₁₆

O [M]

⁺

224.1201, found 224.1198.

58

4-(3-(p-Tolyl)prop-2-yn-1-yl)cyclohex-2-enone (II-98)

In General Procedure I, to a solution of II-93 (0.537 g, 4.00 mmol) in 4.00 mL of Et

₃

N were added sequentially iodobenzene (1.047 g, 4.80 mmol), Pd(PPh

₃

)

₄

(0.009 mg, 0.008 mmol) and CuI (0.03 g, 0.16 mmol) at room temperature under an atmosphere of nitrogen. The reaction mixture was stirred for 3 h and the crude mixture was purified by flash column chromatography over silica gel (ethyl acetate/hexanes 1:10) to give II-98 (0.688 g, 3.10 mmol, 77%, R

_f

= 0.4 in 1:3 ethyl acetate/hexanes) as a tan oil:

1

H NMR (400 MHz, CDCl

₃

) δ 7.28 (d, J = 7.9 Hz, 2H), 7.09 (d, J = 7.8 Hz, 2H), 6.99 (d, J = 10.2 Hz, 1H), 6.05 (dd, J = 10.2, 1.9 Hz, 1H), 2.76−2.68 (m, 1H), 2.62−2.50 (m, 3H), 2.40 (ddd, J = 17.0, 13.0, 5.0 Hz, 1H), 2.33 (m, 3H), 2.26−2.19 (m, 1H), 1.88 (tdd, J = 13.0, 9.8, 4.3 Hz, 1H);

¹³

C NMR (100 MHz, CDCl

₃

) δ 199.2, 152.9, 137.9, 131.4 (2C), 129.7, 128.9 (2C), 120.1, 85.8, 82.7, 36.8, 35.9, 28.5, 24.9, 21.3; IR (CH

₂

Cl

₂

) 3029, 2921, 1682, 1451, 1388 cm

⁻¹

; MS (EI) m/e (%) 224.1 ([M]

⁺

, 27), 196.1 (19), 168.1 (13), 129.1 (100), 128.0 (15); HRMS (EI) calcd for C

₁₆

H

₁₆

O [M]

⁺

224.1201, found 224.1200.

59

4-(3-(Naphthalen-1-yl)prop-2-yn-1-yl)cyclohex-2-enone (II-99)

In General Procedure I, to a solution of II-93 (0.403 g, 3.00 mmol) in 3.0 mL of Et

₃

N were added sequentially iodobenzene (0.915 g, 3.6 mmol), Pd(PPh

₃

)

₄

(0.007 g, 0.006 mmol) and CuI (0.023 g, 0.12 mmol) at room temperature under an atmosphere of nitrogen. The reaction mixture was stirred for 1.5 h and the crude mixture was purified by flash column chromatography over silica gel (ethyl acetate/hexanes 1:10) to give II-99 (0.691 g, 2.65 mmol, 88%, R

_f

= 0.38 in 1:3 ethyl acetate/hexanes) as yellow solid: mp 55－56 ℃;

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.28 (d, J = 7.8 Hz,

1H), 7.83 (d, J = 7.8 Hz, 1H), 7.80 (d, J = 8.2 Hz, 1H), 7.63 (d, J = 7.1 Hz, 1H), 7.58−7.48 (m, 2H), 7.40 (dd, J = 8.4, 7.1 Hz, 1H), 7.06 (ddd, J = 10.2, 2.2, 1.6 Hz, 1H), 6.09 (dd, J = 10.2, 2.2 Hz, 1H), 2.87−2.80 (m, 1H), 2.78−2.67 (m, 2H), 2.58 (dt, J = 16.8, 4.5 Hz, 1H), 2.44 (ddd, J = 16.8, 13.0, 5.0 Hz, 1H), 2.33−2.26 (m, 1H), 1.98 (tdd, J = 13.2, 9.7, 4.5 Hz, 1H);

¹³ C

NMR (100 MHz, CDCl ₃ ) δ 199.2, 152.8, 133.3, 133.1, 130.3, 130.0, 128.4,

128.3, 126.7, 126.3, 126.0, 125.1, 120.9, 91.6, 80.8, 36.9, 36.1, 28.6, 25.3; IR

(CH ₂ Cl ₂ ) 3053, 2948, 2221, 1682, 1396 cm ⁻¹

; MS (EI) m/e (%) 260.1 ([M]

⁺

, 25), 227.0 (13), 204.1 (8), 165.0 (100), 160.0 (12); HRMS (EI) calcd for C

₁₉

H

₁₆

O [M]

⁺

260.1201, found 260.1202.

60

4-(3-(4-Bromophenyl)prop-2-yn-1-yl)cyclohex-2-enone (II-100)

In General Procedure I, to a solution of II-93 (0.671 g, 5.00 mmol) in 2.06 mL of Et

₃

N were added sequentially iodobenzene (1.697 g, 6.00 mmol), Pd(PPh

₃

)

₄

(0.012 g, 0.01 mmol) and CuI (0.038 g, 0.2 mmol) at room temperature under an atmosphere of nitrogen. The reaction mixture was stirred for 1.5 h and the crude mixture was purified by flash column chromatography over silica gel (ethyl acetate/hexanes 1:10) to give II-100 (1.191 g, 4.12 mmol, 85%, R

_f

= 0.38 in 1:3 ethyl acetate/hexanes) as a yellow solid: mp 55－56 ℃;

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.42 (d, J = 8.5 Hz,

2H), 7.25 (d, J = 8.5 Hz, 2H), 6.97 (dt, J = 10.2, 2.0 Hz, 1H), 6.06 (dd, J = 10.2, 2.4 Hz, 1H), 2.79−2.71 (m, 1H), 2.63−2.51 (m, 3H), 2.41 (ddd, J = 16.8, 12.9, 4.9 Hz, 1H), 2.24 (dddd, J = 14.4, 9.7, 4.7, 1.3 Hz, 1H), 1.89 (tdd, J = 14.1, 9.8, 4.5 Hz, 1H);

¹³ C NMR (100 MHz, CDCl ₃ ) δ 199.1, 152.6, 133.0

(2C), 131.5 (2C), 129.9, 122.2, 122.1, 88.0, 81.8, 36.8, 35.8, 28.5, 25.0; IR

(CH ₂ Cl ₂ ) 3030, 2920, 2231, 1682, 1485 cm ⁻¹

; MS (EI) m/e (%) 290.0 ([M + 2]

⁺

, 19), 288.0 ([M]

⁺

, 19), 260.0 (25), 234.0 (13), 193.0 (100), 181.1 (13), 152.0 (8); HRMS (EI) calcd for C

₁₅

H

₁₃

O

⁷⁹

Br [M]

⁺

288.0150, found 288.0156.

61

4-(3-(2-Bromophenyl)prop-2-yn-1-yl)cyclohex-2-enone (II-101)

In General Procedure I, to a solution of II-93 (0.336 g, 2.50 mmol) in 2.5 mL of Et

₃

N were added sequentially iodobenzene (0.846 g, 3.00 mmol), Pd(PPh

₃

)

₄

(0.007 g, 0.005 mmol) and CuI (0.019 g, 0.01 mmol) at room temperature under an atmosphere of nitrogen. The reaction mixture was stirred for 3 h and the crude mixture was purified by flash column chromatography over silica gel (ethyl acetate/hexanes 1:10) to give II-101 (0.321 g, 1.11 mmol, 45%, R

_f = 0.35 in 1:3 ethyl acetate/hexanes) as a yellow

oil:

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.57 (dd, J = 8.0, 0.9 Hz, 1H), 7.43 (dd, J

= 7.5, 1.8 Hz, 1H), 7.24 (dd, J = 8.0, 1.3 Hz, 1H), 7.15 (td, J = 8.0, 0.6 Hz,

1H), 7.06 (dt, J = 10.2, 1.9 Hz, 1H), 6.08 (dd, J = 10.2, 2.4 Hz, 1H), 2.85−2.77 (m, 1H), 2.72−2.54 (m, 3H), 2.43 (ddd, J = 16.8, 12.9, 4.9 Hz, 1H), 2.33−2.24 (m, 1H), 1.96 (tdd, J = 13.2, 10.1, 4.4 Hz 1H);

¹³ C NMR (100 MHz, CDCl ₃ ) δ 199.2, 152.7, 133.3, 132.3, 130.0, 129.1, 127.0, 125.5, 125.3,

91.7, 81.4, 36.8, 35.9, 28.6, 25.2; IR (CH

₂ Cl ₂ ) 2916, 2229, 1678, 1467 cm ⁻¹

;

MS (ESI) m/e (%) 311 ([M+Na] ⁺

, 49), 247 (13), 190 (5), 143 (7); HRMS (EI) calcd for C

₁₅

H

₁₃

ONa

⁷⁹

Br [M+Na]

⁺

311.0047, found 311.0046.

4-(3-(3-Methoxyphenyl)prop-2-yn-1-yl)cyclohex-2-enone (II-102)

62

In General Procedure I, to a solution of II-93 (0.450 g, 3.35 mmol) in 3.4 mL of Et

₃

N were added sequentially iodobenzene (0.942 g, 4.03 mmol), Pd(PPh

₃

)

₄

(0.009 g, 0.007 mmol) and CuI (0.026 g, 0.13 mmol) at room temperature under an atmosphere of nitrogen. The reaction mixture was stirred for 3 h and the crude mixture was purified by flash column chromatography over silica gel (ethyl acetate/hexanes 1:10) to give II-102 (0.490 g, 2.04 mmol, 61%, R

_f

= 0.35 in 1:3 ethyl acetate/hexanes) as a tan oil:

1 H NMR (400 MHz, CDCl ₃ ) δ 7.20 (t, J = 7.9 Hz, 1H), 7.03-6.98 (m, 2H),

6.86 (dd, J = 8.4, 2.6 Hz, 1H), 6.07 (dd, J = 10.1, 2.6 Hz, 1H), 3.80 (s, 3H), 2.80-2.71 (m, 1H), 2.61-2.52 (m, 3H), 2.42 (ddd, J = 16.8, 12.9, 4.9 Hz, 1H), 2.25 (dddd, J = 13.3, 9.5, 4.7, 1.4 Hz, 1H), 1.90 (tdd, J = 13.1, 10.0, 4.5 Hz, 1H);

¹³ C NMR (100 MHz, CDCl ₃ ) δ 199.2, 159.3, 152.8, 129.9, 129.3, 124.3,

124.1, 166.6, 114.5, 86.3, 82.7, 55.3, 36.8, 36.0, 28.6, 25.0; IR (CH

₂ Cl ₂ )

2941, 1678, 1165, 785 cm

⁻¹

; MS (ESI) m/e (%) 263 ([M+Na]

⁺

, 100), 258 (5), 202 (7); HRMS (ESI) calcd for C

₁₆

H

₁₆

O

₂

Na [M+Na]

⁺

263.1048, found 263.1051.

63

4-(3-(4-Methoxyphenyl)prop-2-yn-1-yl)cyclohex-2-enone (II-103)

In General Procedure I, to a solution of II-93 (0.403 g, 3.00 mmol) in 3.0 mL of Et

₃

N were added sequentially iodobenzene (0.842 g, 3.60 mmol), Pd(PPh

₃

)

₄

(0.008 g, 0.006 mmol) and CuI (0.023 g, 0.12 mmol) at room temperature under an atmosphere of nitrogen. The reaction mixture was stirred for 3 h and the crude mixture was purified by flash column chromatography over silica gel (ethyl acetate/hexanes 1:10) to give II-103 (0.631 g, 2.62 mmol, 88%, R

_f

= 0.35 in 1:3 ethyl acetate/hexanes) as a tan oil:

1 H NMR (400 MHz, CDCl ₃ ) δ 7.33 (dt, J = 9.3, 2.3 Hz, 2H), 7.00 (dd, J =

10.2, 2.2 Hz, 1H), 6.82 (dt, J = 9.3, 2.4 Hz, 2H), 6.06 (dd, J = 10.2, 2.3 Hz, 1H), 3.80 (s, 3H), 2.79-2.69 (m, 1H), 2.60-2.52 (m, 3H), 2.41 (ddd, J = 16.8, 12.9, 4.9 Hz, 1H), 2.24 (dqd, J = 13.3, 4.8, 1.3 Hz, 1H), 1.90 (tdd, J = 26.2, 9.9, 4.5 Hz, 1H);

¹³ C NMR (100 MHz, CDCl ₃ ) δ 199.3, 159.3, 153.0, 132.9

(2C), 129.8, 115.4, 113.9 (2C), 85.1, 82.5, 55.3, 36.8, 36.1, 28.6, 25.0; IR

(CH ₂ Cl ₂ ) 2935, 1678, 1607, 1247, 833 cm ⁻¹

; MS (ESI) m/e (%) 263 ([M+Na]

⁺

, 100), 247 (3), 202 (3), 190 (3), 143 (3); HRMS (ESI) calcd for C

₁₆

H

₁₆

O

₂

Na [M+Na]

⁺

263.1048, found 263.1046.

64

4-(3-(3-Nitrophenyl)prop-2-yn-1-yl)cyclohex-2-enone (II-104)

In General Procedure I, to a solution of II-93 (0.403 g, 3.00 mmol) in 2.06 mL of Et

₃

N were added sequentially iodobenzene (0.896 g, 3.60 mmol), Pd(PPh

₃

)

₄

(0.008 g, 0.006 mmol) and CuI (0.023 g, 0.12 mmol) at room temperature under an atmosphere of nitrogen. The reaction mixture was stirred for 3 h and the crude mixture was purified by flash column chromatography over silica gel (ethyl acetate/hexanes 1:10) to give II-104 (0.330 g, 1.30 mmol, 43%, R

_f = 0.21 in 1:3 ethyl acetate/hexanes) as a yellow

oil:

¹

H NMR (400 MHz, CDCl

₃

) δ 8.24 (s, 1H), 8.15 (dt, J = 8.4, 1.1 Hz, 1H), 7.70 (d, J = 7.5 Hz, 1H), 7.49 (t, J = 8.0 Hz, 1H), 6.98 (dt, J = 10.2, 2.0 Hz, 1H), 6.09 (dd, J = 10.2, 2.6 Hz, 1H), 2.87−2.73 (m, 1H), 2.70−2.53 (m, 3H), 2.44 (ddd, J = 21.6, 12.8, 4.8 Hz, 1H), 2.34−2.21 (m, 1H), 1.92 (tdd, J = 13.3, 9.7, 4.4 Hz, 1H);

¹³

C NMR (100 MHz, CDCl

₃

) δ 199.0, 152.2, 148.0, 137.3, 130.1, 129.2, 126.4, 125.0, 122.7, 89.7, 80.6, 36.7, 35.7, 28.6, 24.9; IR (CH

₂

Cl

₂

) 2925, 2229, 1679, 1530, 1351 cm

⁻¹

; MS (ESI) m/e 278 (%) ([M+Na]

⁺

, 51); HRMS (ESI) calcd for Chemical Formula: C

₁₅

H

₁₃

NO

₃

Na [M+Na]

⁺

278.0793, found 278.0795.

65

4-(3-(4-Nitrophenyl)prop-2-yn-1-yl)cyclohex-2-enone (II-105)

In General Procedure I, to a solution of II-93 (0.537 g, 4.00 mmol) in 4.00 mL of Et

₃

N were added sequentially iodobenzene (1.195 g, 4.8 mmol), Pd(PPh

₃

)

₄

(0.009 g, 0.008 mmol) and CuI (0.03 g, 0.16 mmol) at room temperature under an atmosphere of nitrogen. The reaction mixture was stirred for 2 h and the crude mixture was purified by flash column chromatography over silica gel (ethyl acetate/hexanes 1:10) to give II-105 (0.727 g, 2.80 mmol, 71 %, R

_f

= 0.2 in 1:3 ethyl acetate/hexanes) as a tan oil:

1

H NMR (400 MHz, CDCl

₃

) δ 8.17 (d, J = 8.7 Hz, 2H), 7.53 (d, J = 8.7 Hz, 2H), 6.97 (d, J = 10.2 Hz, 1H), 6.09 (dd, J = 10.2, 1.6 Hz, 1H), 2.84−2.76 (m, 1H), 2.71−2.55 (m, 3H), 2.44 (ddd, J = 17.4, 13.0, 4.9 Hz, 1H), 2.30−2.23 (m, 1H), 1.92 (tdd, J = 13.0, 9.7, 4.4 Hz, 1H);

¹³

C NMR (100 MHz, CDCl

₃

) δ 198.9, 152.1, 146.9, 132.3 (2C), 130.2, 130.1, 123.5 (2C), 92.7, 81.3, 36.7, 35.6, 28.6, 25.1; IR (CH

₂

Cl

₂

) 2933, 2227, 1682, 1594, 1344 cm

⁻¹

; MS (EI)

m/e (%) 255.1 ([M] ⁺

, 12), 227.0 (100), 181.1 (13), 160.0 (57), 152.0 (23), 114.0 (21); HRMS (EI) calcd for C

₁₅

H

₁₃

O

₃

N [M]

⁺

255.0895, found 255.0893.

66

Ethyl 3-(3-(4-oxocyclohex-2-en-1-yl)prop-1-yn-1-yl)benzoate (II-106)

In General Procedure I, to a solution of II-93 (0.246 g, 1.83 mmol) in 1.9 mL of Et

₃

N were added sequentially iodobenzene (0.607 g, 2.20 mmol), Pd(PPh

₃

)

₄

(0.005 g, 0.004 mmol) and CuI (0.014 g, 0.08 mmol) at room temperature under an atmosphere of nitrogen. The reaction mixture was stirred for 3 h and the crude mixture was purified by flash column chromatography over silica gel (ethyl acetate/hexanes 1:10) to give II-106 (0.449 g, 1.59 mmol, 87%, R

_f

= 0.33 in 1:3 ethyl acetate/hexanes) as a yellow oil:

¹

H NMR (400 MHz, CDCl

₃

) δ 8.07 (s, 1H), 7.97 (d, J = 7.8 Hz, 1H), 7.57 (d, J = 7.7 Hz, 1H), 7.38 (t, J = 7.7 Hz, 1H), 7.00 (d, J = 10.2 Hz, 1H), 6.08 (dd, J = 10.2, 2.3 Hz, 1H), 4.38 (q, J = 7.1 Hz, 2H), 2.82-2.73 (m, 1H), 2.63-2.53 (m, 3H), 2.43 (ddd, J = 16.8, 12.9, 4.9 Hz, 1H), 2.26 (dddd, J = 13.7, 4.7, 4.7, 4.7 Hz, 1H), 1.91 (tdd, J = 13.1, 10.0, 4.5 Hz, 1H), 1.40 (t, J = 7.1, 3H);

¹³

C NMR (100 MHz, CDCl

₃

) δ 199.1, 165.9, 152.6, 135.6, 132.6, 130.7, 130.0, 129.0, 128.4, 123.6, 87.7, 81.9, 61.2, 36.8, 35.9, 28.6, 25.0, 14.3;

IR (CH

₂

Cl

₂

) 3030, 2981, 2234, 1715, 1684, 1228, 755 cm

⁻¹

; MS (EI, 70 eV)

m/e (%) 282.1 ([M] ⁺

, 100), 277.1 (13); HRMS (EI) calcd for C

₁₈

H

₁₈

O

₃

[M]

⁺

282.1256, found 282.1254.

67

Ethyl 4-(3-(4-oxocyclohex-2-en-1-yl)prop-1-yn-1-yl)benzoate (II-107)

In General Procedure I, to a solution of II-93 (0.268 g, 2.00 mmol) in 2.0 mL of Et

₃

N were added sequentially iodobenzene (0.662 g, 2.40 mmol), Pd(PPh

₃

)

₄

(0.005 g, 0.004 mmol) and CuI (0.015 g, 0.08 mmol) at room temperature under an atmosphere of nitrogen. The reaction mixture was stirred for 3 h and the crude mixture was purified by flash column chromatography over silica gel (ethyl acetate/hexanes 1:10) to give II-107 (0.511 g, 1.81 mmol, 91%, R

_f

= 0.3 in 1:3 ethyl acetate/hexanes) as a tan oil:

1

H NMR (400 MHz, CDCl

₃

) δ 7.97 (dt, J = 8.4, 1.7 Hz, 2H), 7.45 (dt, J = 8.3, 1.7 Hz, 2H), 6.99 (ddd, J = 10.2, 2.4, 1.6 Hz, 1H), 6.08 (dd, J = 10.1, 2.5 Hz, 1H), 4.37 (q, J = 7.1 Hz, 2H), 2.82-2.73 (m, 1H), 2.68-2.53 (m, 3H), 2.43 (ddd, J = 16.8, 12.9, 4.9 Hz, 1H), 2.26 (dqd, J = 13.2, 4.7, 1.5 Hz, 1H), 1.91 (tdd, J = 26.2, 9.8, 4.5 Hz, 1H), 1.39 (t, J = 7.1, 3H);

¹³

C NMR (100 MHz, CDCl

₃

) δ 199.0, 166.0, 152.5, 131.4 (2C), 130.0, 129.7, 129.4 (2C), 127.8, 89.9, 82.2, 61.1, 36.8, 35.8, 28.6, 25.1, 14.3; IR (CH

₂

Cl

₂

) 2981, 2229, 1716, 1681, 1607, 1273, 858, 770, 697 cm

⁻¹

; MS (ESI) m/e (%) 305 ([M+Na]

⁺

, 100), 300 (5), 223 (4); HRMS (ESI) calcd for C

₁₈

H

₁₈

O

₃

Na [M+Na]

⁺

305.1154, found 305.1157.

68

4.3.2 General Procedure II

Reduction of α,β-unsaturated ketone Employing Luche Reduction Reaction Condition for the Synthesis of 1a

To a 50 mL round-bottom flask equipped with a stirrer bar was added 4-(3-phenylprop-2-yn-1-yl)cyclohex-2-enone (1.154 g, 5.49 mmol), CeCl3‧7 H2O (2.251 g, 6.04 mmol) and methanol (27.0 mL). The reaction mixture was stirred at 0 ℃ for 5 min. Subsequently, The reaction mixture was added NaBH4 (0.208 g, 5.49 mmol) slowly. After the reaction was completed, the solvent was removed under reduced pressure. The mixture was added a saturated NH4Cl(aq) (30 mL). The resulting mixture was extracted with ethyl acetate (30 × 3 mL), and the combined extracts were washed with water (30 × 3 mL) and brine (30 × 3 mL), and dried over anhydrous MgSO4 (5 g), and was concentrated in vacuo to give crude oil which was purified via flash chromatography over silica gel to give 4-(3-phenylprop-2-yn-1-yl)cyclohex-2-enol (0.952 g, 4.49 mmol, 82%).

69

4-(3-Phenylprop-2-yn-1-yl)cyclohex-2-enol (II-110)

In General Procedure II, to a 50 mL round-bottom flask were added II-96 (1.154 g, 5.49 mmol)、CeCl

₃

‧7 H

₂

O (2.250 g, 6.04 mmol) and methanol (27.0 mL), then NaBH

₄

(0.208 g, 5.49 mmol) was added at 0 ℃, and the mixture was stirred for 1 h. The crude mixture was purified by flash column chromatography over silica gel (ethyl acetate/hexanes 1:10) to give II-110 (0.952g, 4.49 mmol, 82%, R

_f

= 0.28, (ethyl acetate/hexanes 1:3)) as a pale yellow oil:

¹

H NMR (400 MHz, CDCl

₃

) δ 7.40‒7.37 (m, 2H), 7.30‒7.26 (m, 3H), 5.81 (d, J = 10.8 Hz, 1H), 5.76 (d, J = 10.5 Hz, 1H), 4.24 (s, 1H), 2.45‒

2.30 (m, 3H), 2.13‒2.08 (m, 1H), 2.04‒2.00 (m, 1H), 1.63‒1.37 (m, 2H);

¹³

C NMR (100 MHz, CDCl

₃

) δ 132.6, 131.6, 131.5 (2C), 128.1 (2C), 127.6, 123.7, 88.1, 81.9, 66.7, 35.2, 31.6, 26.6, 25.8; IR (CH

₂

Cl

₂

) 3346, 3021, 1598, 1488, 1265 cm

⁻¹

; MS (EI, 70 eV) m/e (%) 212.1 ([M]

⁺

, 63), 194.1 (24), 184.1 (82), 168.1 (100), 167.1 (12); HRMS (EI) calcd for C

₁₅

H

₁₆

O [M]

⁺

212.1201, found 212.1206.

70

4-(3-(m-Tolyl)prop-2-yn-1-yl)cyclohex-2-enol (II-111)

In General Procedure II, to a 50 mL round-bottom flask were added II-97 (0.160 g, 0.71 mmol)、CeCl

₃

‧7 H

₂

O (0.321 g, 0.78 mmol) and methanol (3.5 mL), then NaBH

₄

(0.027 g, 0.71 mmol) was added at 0 ℃, and the mixture was stirred for 1 h. The crude mixture was purified by flash column chromatography over silica gel (ethyl acetate/hexanes 1:10) to give II-111 (0.098 g, 0.43 mmol, 61%, R

_f

= 0.28, (ethyl acetate/hexanes 1:3)) as colorless oil:

¹

H NMR (400 MHz, CDCl

₃

) δ 7.22 (s, 1H), 7.17 (t, J = 7.6 Hz, 2H), 7.08 (d, J =7.0 Hz, 1H), 5.82 (d, J = 10.6 Hz, 1H), 5.77 (d, J = 10.3 Hz, 1H), 4.26 (s, 1H), 2.48‒2.33 (m, 2H), 2.31 (s, 3H), 2.17‒2.08 (m, 1H), 2.06‒1.97 (m, 1H), 1.64‒1.54 (m, 1H), 1.56‒1.35 (m, 1H);

¹³

C NMR (100 MHz, CDCl

₃

) δ 137.9, 132.8, 132.2, 131.5, 128.6, 128.5, 128.1, 123.6, 87.7, 82.0, 66.8, 35.3, 31.7, 26.6, 25.8, 21.2; IR (CH

₂

Cl

₂

) 3339, 3022, 1602, 1485, 1282 cm

⁻¹

; MS (ESI) m/e (%) 249.1 ([M + Na]

⁺

, 100), 244.2 (4), 209.1 (3); HRMS (ESI) calcd for C

₁₆

H

₁₈

ONa [M + Na]

⁺

249.1255, found 249.1248.

71

4-(3-(p-Tolyl)prop-2-yn-1-yl)cyclohex-2-enol (II-112)

In General Procedure II, to a 50 mL round-bottom flask were added II-98 (0.100 g, 0.45 mmol)、CeCl

₃

‧7 H

₂

O (0.184 g, 0.50 mmol) and methanol (2.25 mL), then NaBH

₄

(0.017 g, 0.45 mmol) was added at 0 ℃, and the mixture was stirred for 1 h. The crude mixture was purified by flash column chromatography over silica gel (ethyl acetate/hexanes 1:10) to give II-112 (0.087g, 0.39 mmol, 86%, R

_f

= 0.33, (ethyl acetate/hexanes 1:3)) pale yellow solid, mp 56‒57 ℃:

¹

H NMR (400 MHz, CDCl

₃

) δ 7.28 (d, J = 8.0 Hz, 2H), 7.08 (d, J = 8.0 Hz, 2H), 5.81 (d, J = 10.6 Hz, 1H), 5.77 (d, J = 10.7 Hz, 1H), 4.25 (s, 1H), 2.39‒2.34 (m, 3H), 2.33 (s, 3H), 2.16‒2.07 (m, 1H), 2.06‒1.97 (m, 1H) , 1.56‒1.47 (m, 2H);

¹³

C NMR (100 MHz, CDCl

₃

) δ 137.6, 134.1, 131.4 (2C), 129.8, 128.9 (2C), 120.7, 87.3, 81.9, 66.8, 35.3, 31.6, 26.6, 25.8 21.3; IR (CH

₂

Cl

₂

) 3346, 3024, 2924, 1510, 1055 cm

⁻¹

; MS (EI, 70 eV) m/e (%) 226.1 ([M]

⁺

, 100), 25.1 (26), 208.1 (25), 198.1 (20), 169.1 (31), 167.1 (17); HRMS (EI) calcd for C

₁₆

H

₁₈

O [M]

⁺

226.1358, found 226.1362.

72

4-(3-(Naphthalen-1-yl)prop-2-yn-1-yl)cyclohex-2-enol (II-113)

In General Procedure II, to a 50 mL round-bottom flask were added II-99 (0.260 g, 1.0 mmol)、CeCl

₃

‧7 H

₂

O (0.410g, 1.1 mmol) and methanol (5.0 mL), then NaBH

₄

(0.038 g, 1.0 mmol) was added at 0 ℃, and the mixture was stirred for 1 h. The crude mixture was purified by flash column chromatography over silica gel (ethyl acetate/hexanes 1:10) to give II-113 (0.226 g, 0.86 mmol, 86%, R

_f

= 0.25, (ethyl acetate/hexanes 1:3)) pale yellow solid: mp 56‒57 ℃;

¹

H NMR (400 MHz, CDCl

₃

) δ 8.32 (d, J = 8.2 Hz, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.76 (d, J = 8.2 Hz, 1H), 7.61 (d, J = 7.1 Hz, 1H), 7.54 (t, J = 7.5 Hz, 1H), 7.48 (t, J = 7.3 Hz, 1H), 7.38 (t, J = 7.8 Hz, 1H), 5.91‒5.78 (m, 2H), 4.27 (s, 1H), 2.56‒2.49 (m, 3H), 2.19‒1.99 (m, 2H), 1.57‒

1.46 (m, 2H);

¹³

C NMR (100 MHz, CDCl

₃

) δ 137.9, 132.8, 132.2, 131.5, 128.6, 128.5, 128.1, 123.6, 87.7, 82.0, 66.8, 35.3, 31.7, 26.6, 25.8, 21.2; IR (CH

₂

Cl

₂

) 3347, 3053, 2930, 1585, 1397, 1054 cm

⁻¹

; MS (EI, 70 eV) m/e (%) 262.1 ([M]

⁺

, 100), 244.1 (44), 229.1 (25), 228.1 (10); HRMS (EI) calcd for C

₁₉

H

₁₈

O [M]

⁺

262.1358, found 262.1354.

73

4-(3-(4-Bromophenyl)prop-2-yn-1-yl)cyclohex-2-enol (II-114)

In General Procedure II, to a 50 mL round-bottom flask were added II-100 (0.400 g, 1.38 mmol)、CeCl

₃

‧7 H

₂

O (0.566 g, 1.52 mmol) and methanol (7.0 mL), then NaBH

₄

(0.052 g, 1.38 mmol) was added at 0 ℃, and the mixture was stirred for 1 h. The crude mixture was purified by flash column chromatography over silica gel (ethyl acetate/hexanes 1:10) to give II-114 (0.356 g, 1.22 mmol, 89%, R

_f

= 0.25, (ethyl acetate/hexanes 1:3)) white solid:

mp 55‒57

^o

C;

¹

H NMR (400 MHz, CDCl

₃

) δ 7.40 (d, J = 8.4 Hz, 2H), 7.24 (d,

J = 8.4 Hz, 2H), 5.82‒5.74 (m, 2H), 4.25 (s, 1H), 2.46‒2.33 (m, 3H), 2.15‒

2.06 (m, 1H), 2.05‒1.96 (m, 1H), 1.57‒1.35 (m, 2H);

¹³

C NMR (100 MHz, CDCl

₃

) δ 133.0 (2C), 132.4, 131.7, 131.4 (2C), 122.7, 121.7, 89.5, 80.9, 66.7, 35.1, 31.6, 26.6, 25.8; IR (CH

₂

Cl

₂

) 3342, 2933, 1486, 1269 cm

⁻¹

; MS (EI, 70 eV) m/e (%) 292.0 ([M + 2]

⁺

, 89), 290.0 ([M]

⁺

, 96), 272.0 (34); HRMS (EI) calcd for C

₁₅

H

₁₅

O

⁷⁹

Br [M]

⁺

290.0306, found 292.0298.

74

4-(3-(2-Bromophenyl)prop-2-yn-1-yl)cyclohex-2-enol (II-115)

In General Procedure II, to a 50 mL round-bottom flask were added II-101 (0.248 g, 0.87 mmol)、CeCl

₃

‧7 H

₂

O (0.356 g, 0.95 mmol) and methanol (6.5 mL), then NaBH

₄

(0.033 g, 0.87 mmol) was added at 0 ℃, and the mixture was stirred for 1 h. The crude mixture was purified by flash column chromatography over silica gel (ethyl acetate/hexanes 1:10) to give II-115 (0.187 g, 0.65 mmol, 74%, R

_f

= 0.33, (ethyl acetate/hexanes 1:3)) colorless oil:

1

H NMR (400 MHz, CDCl

₃

) δ 7.56 (dd, J =8.0, 0.9 Hz, 2H), 7.37 (dd, J = 7.7, 1.6 Hz, 1H), 7.23 (td, J = 7.7, 1.0 Hz, 1H), 7.12 (td, J = 7.7, 1.6 Hz, 1H), 5.89‒5.75 (m, 2H), 4.27(s, 1H), 2.55‒2.37 (m, 3H), 2.18‒2.01 (m, 2H), 1.55‒

1.42 (m, 2H);

¹³

C NMR (100 MHz, CDCl

₃

) δ 133.3, 132.6, 132.3, 131.7, 128.8, 126.9, 125.8, 125.4, 93.3, 80.6, 66.8, 35.2, 31.7, 26.6, 26.0; IR (CH

₂

Cl

₂

) 3351, 2924, 1463, 1429, 750 cm

⁻¹

; MS (ESI) m/e (%) 315.0 ([M + Na + 2]

⁺

, 78), 313.0 ([M + Na]

⁺

, 100) , 311.0 (10), 266.1 (8); HRMS (ESI) calcd for C

₁₅

H

₁₅

ONa

⁷⁹

Br [M + Na]

⁺

313.0204, found 292.0207.

75

4-(3-(3-Methoxyphenyl)prop-2-yn-1-yl)cyclohex-2-enol (II-116)

In General Procedure II, to a 50 mL round-bottom flask were added II-102 (0.452 g, 1.88 mmol)、CeCl

₃

‧7H

₂

O (0.770 g, 2.07 mmol) and methanol (9.5 mL), then NaBH

₄

(0.071 g, 1.88 mmol) was added at 0 ℃, and the mixture was stirred for 1 h. The crude mixture was purified by flash column chromatography over silica gel (ethyl acetate/hexanes 1:10) to give II-116 (0.331 g, 1.36 mmol, 73%, R

_f

= 0.23, (ethyl acetate/hexanes 1:3)) colorless oil:

1

H NMR (400 MHz, CDCl

₃

) δ 7.19 (t, J =7.9 Hz, 1H), 6.99 (d, J = 7.6 Hz, 1H), 6.94‒6.91 (m, 1H), 6.84 (dd, J = 8.1, 2.4 Hz, 1H), 5.82 (d, J = 10.8 Hz, 1H), 5.78 (d, J = 10.6 Hz, 1H), 4.26 (s, 1H), 3.79 (s, 3H), 2.48‒2.30 (m, 3H), 2.16‒2.08 (m, 1H), 2.07‒1.98 (m, 1H), 1.54‒1.38 (m, 2H);

¹³

C NMR (100 MHz, CDCl

₃

) δ 159.3, 132.7, 131.6, 129.3, 124.8, 124.1, 116.5, 114.2, 88.0, 81.8, 66.8, 55.2, 35.2, 31.7, 26.6, 25.8; IR (CH

₂

Cl

₂

) 3353, 2936, 1598, 1576, 854, 784 cm

⁻¹

; MS (ESI) m/e (%) 265.1 ([M + Na]

⁺

, 100), 260.2 (4), 247.1 (2), 143.1 (2); HRMS (ESI) calcd for C

₁₆

H

₁₈

O

₂

Na [M + Na]

⁺

265.1204, found 265.1203.

76

4-(3-(4-Methoxyphenyl)prop-2-yn-1-yl)cyclohex-2-enol (II-117)

In General Procedure II, to a 50 mL round-bottom flask were added II-103 (0.320 g, 1.33 mmol)、CeCl

₃

‧7H

₂

O (0.546 g, 1.47 mmol) and methanol (6.5 mL), then NaBH

₄

(0.050 g, 1.33 mmol) was added at 0 ℃, and the mixture was stirred for 1 h. The crude mixture was purified by flash column chromatography over silica gel (ethyl acetate/hexanes 1:10) to give II-117 (0.169 g, 0.699 mmol, 73%, R

_f

= 0.2, (ethyl acetate/hexanes 1:3)) colorless oil:

1

H NMR (400 MHz, CDCl

₃

) δ 7.32 (d, J = 8.7 Hz, 2H), 6.81 (d, J = 8.8 Hz, 2H), 5.82 (d, J = 10.6 Hz, 1H), 5.77 (d, J = 10.3 Hz, 1H), 4.24 (s, 1H), 3.79 (s, 3H), 2.46‒2.30 (m, 3H), 2.15‒2.06 (m, 1H), 2.06‒1.96 (m, 1H) 1.86‒1.66 (m, 1H), 1.55‒1.34 (m, 2H);

¹³

C NMR (100 MHz, CDCl

₃

) δ 159.1, 132.8(2C), 131.5, 115.9, 113.8(2C), 86.5, 81.6, 66.7, 55.2, 35.3, 31.6, 26.6, 25.8; IR (CH

₂

Cl

₂

) 3366, 2934, 1607, 1510, 832 cm

⁻¹

; MS (ESI) m/e (%) 265 ([M + Na]

⁺

, 100), 263 (41), 260 (5), 243 (4); HRMS (ESI) calcd for C

₁₆

H

₁₈

O

₂

Na [M + Na]

⁺

265.1204, found 265.1208.

77

4-(3-(3-Nitrophenyl)prop-2-yn-1-yl)cyclohex-2-enol (II-118)

In General Procedure II, to a 50 mL round-bottom flask were added II-104 (0.220 g, 0.86 mmol)、CeCl

₃

‧7 H

₂

O (0.410 g, 0.95 mmol) and methanol (4.3 mL), then NaBH

₄

(0.033 g, 0.86 mmol) was added at 0 ℃, and the mixture was stirred for 1 h. The crude mixture was purified by flash column chromatography over silica gel (ethyl acetate/hexanes 1:10) to give II-118 (0.190 g, 0.74 mmol, 86%, R

_f

= 0.15, (ethyl acetate/hexanes 1:3)) light yellow oil:

¹

H NMR (400 MHz, CDCl

₃

) δ 8.23 (d, J = 1.8 Hz, 1H), 8.12 (ddd, J = 8.3, 2.2, 1.0 Hz, 1H), 7.68 (dt, J = 7.5, 1.2 Hz, 1H), 7.46 (t, J = 8.0 Hz, 1H), 5.84‒

5.77 (m, 2H), 4.27 (s, 1H), 2.51‒2.35 (m, 3H), 2.18‒2.09 (m, 1H) 2.08‒1.99 (m, 1H), 1.58‒1.38 (m, 2H);

¹³

C NMR (100 MHz, CDCl

₃

) δ 148.0, 137.3, 132.2, 131.9, 129.1, 126.4, 125.6, 122.4, 91.3, 79.7, 66.7, 35.0, 31.6, 26.6, 25.7; IR (CH

₂

Cl

₂

) 3375, 2926, 2227, 1530, 1351, 1054, 736 cm

⁻¹

; MS (ESI)

m/e (%) 280.1 ([M + Na] ⁺

, 26), 278.1 (2), 240.1 (1); HRMS (ESI) calcd for C

₁₅

H

₁₅

NO

₃

Na [M + Na]

⁺

280.0950, found 280.0953.

78

4-(3-(4-Nitrophenyl)prop-2-yn-1-yl)cyclohex-2-enol (II-119)

In General Procedure II, to a 50 mL round-bottom flask were added II-105 (0.229 g, 0.9 mmol)、CeCl

₃

‧7 H

₂

O (0.369 g, 0.99 mmol) and methanol (4.5 mL), then NaBH

₄

(0.034 g, 0.9 mmol) was added at 0 ℃, and the mixture was stirred for 1 h. The crude mixture was purified by flash column chromatography over silica gel (ethyl acetate/hexanes 1:10) to give II-119 (0.159 g, 0.62 mmol, 69%, R

_f

= 0.2, (ethyl acetate/hexanes 1:3)) deep yellow solid: mp 64–65

^o

C;

¹

H NMR (400 MHz, CDCl

₃

) δ 8.15 (d, J = 8.7 Hz, 2H), 7.52 (d, J = 8.7 Hz, 2H), 5.84‒5.76 (m, 2H), 4.30‒4.23 (m, 1H), 2.48‒2.41 (m, 3H), 2.17‒2.09 (m, 1H), 2.08‒1.98 (m, 1H) 1.56‒1.38 (m, 2H);

¹³

C NMR (100 MHz, CDCl

₃

) δ 146.7, 133.6, 132.3 (2C), 130.8, 130.2, 123.5 (2C), 94.4, 80.5, 66.7, 35.0, 31.6, 26.6, 25.9; IR (CH

₂

Cl

₂

) 3362, 2931, 2221, 1593, 1515, 1343, 853 cm

⁻¹

; MS (EI, 70 eV) m/e (%) 257.1 ([M]

⁺

, 100), 213.0 (78), 161.0 (78), 114 (43); HRMS (ESI) calcd for C

₁₅

H

₁₅

NO

₃

[M]

⁺

257.1052, found 257.1049.

79

Ethyl 3-(3-(4-hydroxycyclohex-2-en-1-yl)prop-1-yn-1-yl)benzoate (II-120)

In General Procedure II, to a 50 mL round-bottom flask were added II-106 (0.340 g, 1.20 mmol)、CeCl

₃

‧7 H

₂

O (0.493 g, 1.32 mmol) and methanol (6.0 mL), then NaBH

₄

(0.046 g, 1.20 mmol) was added at 0 ℃, and the mixture was stirred for 1 h. The crude mixture was purified by flash column chromatography over silica gel (ethyl acetate/hexanes 1:10) to give II-120 (0.213 g, 0.75 mmol, 62%, R

_f

= 0.23, (ethyl acetate/hexanes 1:3)) pale yellow oil:

¹

H NMR (400 MHz, CDCl

₃

) δ 8.06 (s, 1H), 7.94 (d, J = 7.7 Hz, 1H), 7.56 (d, J = 7.7 Hz, 1H), 7.36 (t, J = 7.8 Hz, 1H), 5.85–5.75 (m, 2H), 4.38 (q, J = 7.1 Hz, 2H), 4.26 (s, 1H), 2.49‒2.34 (m, 3H), 2.18‒2.09 (m, 1H) 2.08‒1.99 (m, 1H), 1.58‒1.44 (m, 2H), 1.40 (t, J = 7.1 Hz);

¹³

C NMR (100 MHz, CDCl

₃

) δ 166.0, 135.6, 132.6, 132.6, 131.7, 128.7, 128.3, 124.2, 89.2, 81.0, 66.8, 61.1, 35.2, 31.7, 26.6, 25.8, 14.3; IR (CH

₂

Cl

₂

) 3380, 2937, 2224, 1720, 1296, 1228, 912, 754 cm

⁻¹

; MS (ESI) m/e (%) 307.1 ([M + Na]

⁺

, 56), 302.2 (1); HRMS (ESI) calcd for C

₁₈

H

₂₀

O

₃

Na[M + Na]

⁺

307.1310, found 307.1306.

80

Ethyl 4-(3-(4-hydroxycyclohex-2-en-1-yl)prop-1-yn-1-yl)benzoate (II-121)

In General Procedure II, to a 50 mL round-bottom flask were added II-107 (0.486 g, 1.72 mmol)、CeCl

₃

‧7 H

₂

O (0.708 g, 1.90 mmol) and methanol (8.5 mL), then NaBH

₄

(0.065 g, 1.72 mmol) was added at 0 ℃, and the mixture was stirred for 1 h. The crude mixture was purified by flash column chromatography over silica gel (ethyl acetate/hexanes 1:10) to give II-121 (0.475 g, 1.67 mmol, 97%, R

_f

= 0.2, (ethyl acetate/hexanes 1:3)) pale yellow oil:

¹

H NMR (400 MHz, CDCl

₃

) δ 7.96 (d, J = 8.2 Hz, 2H), 7.43 (d, J = 8.2 Hz, 2H), 5.80 (t, J = 11.4 Hz, 2H), 4.37 (q, J = 7.1 Hz, 2H), 4.26 (s, 1H), 2.50‒2.34 (m, 3H), 2.18‒2.08 (m, 1H), 2.07‒1.98 (m, 1H), 1.55‒1.46 (m, 2H), 1.39 (t, J = 7.2 Hz, 3H);

¹³

C NMR (100 MHz, CDCl

₃

) δ 146.7, 133.6, 132.3 (2C), 130.8, 130.2, 123.5 (2C), 94.4, 80.5, 66.7, 35.0, 31.6, 26.6, 25.9; IR (CH

₂

Cl

₂

) 3419, 2937, 2224, 1716, 1274, 858 cm

⁻¹

; MS (EI) m/e (%) 284.1 ([M]

⁺

, 100), 282.1 (25), 270.1 (2); HRMS (EI) calcd for C

₁₈

H

₂₀

O

₃

[M]

⁺

284.1412, found 284.1405.

81

4-(Prop-2-yn-1-yl)cyclohex-2-enol (II-122)

In General Procedure II, to a 50 mL round-bottom flask were added II-93 (0.340 g, 2.53 mmol)、CeCl

₃

‧7H

₂

O (1.04 g, 2.79 mmol) and methanol (12.5 mL), then NaBH

₄

(0.096 g, 2.53 mmol) was added at 0 ℃, and the mixture was stirred for 1 h. The crude mixture was purified by flash column chromatography over silica gel (ethyl acetate/hexanes 1:10) to give II-122 ((0.277g, 2.04 mmol, 80%, R

_f

= 0.28, (ethyl acetate/hexanes 1:3))colorless oil:

1

H NMR (400 MHz, CDCl

₃

) δ 5.80‒5.71 (m, 2H), 4.23 (s, 1H), 2.40‒2.30 (m, 1H), 2.17 (dd, J = 7.0, 2.6 Hz, 2H), 2.14‒2.05 (m, 1H), 2.02‒1.92 (m, 2H), 1.85‒1.67 (m, 1H), 1.57‒1.31 (m, 2H);

¹³

C NMR (100 MHz, CDCl

₃

) δ 132.3, 131.7, 82.5, 69.5, 66.7, 34.9, 31.6, 26.4, 24.8; IR (CH

₂

Cl

₂

) 3290, 2924, 2855, 2107, 1645 cm

⁻¹

; MS (ESI) m/e (%) 159.1 ([M + Na]

⁺

, 7), 158.1(2), 100.1(2);

HRMS (ESI) calcd for C

₉

H

₁₂

ONa [M + Na]

⁺

159.0786, found 159.0782.

82

4-(But-2-yn-1-yl)cyclohex-2-enol (II-123)

In General Procedure II, to a 50 mL round-bottom flask were added II-109 (1.154 g, 5.49 mmol)、CeCl

₃

‧7 H

₂

O (2.250 g, 6.04 mmol) and methanol (33.5 mL), then NaBH

₄

(0.208 g, 5.49 mmol) was added at 0 ℃, and the mixture was stirred for 1 h. The crude mixture was purified by flash column chromatography over silica gel (ethyl acetate/hexanes 1:10) to give II-123 (0.952g, 0.2 mmol, 82%, R

_f

= 0.34, (ethyl acetate/hexanes 1:3)) colorless oil:

1

H NMR (400 MHz, CDCl

₃

) δ 5.74‒5.70 (m, 2H), 4.23 (s, 1H), 2.33‒2.22 (m, 1H), 2.21‒2.04 (m, 3H), 2.02‒1.90 (m, 1H), 1.79 (t, J = 2.5 Hz, 3H), 1.97 (t, J

= 2.5 Hz, 3H);

¹³

C NMR (100 MHz, CDCl

₃

) δ 133.0, 131.2, 77.2, 76.8, 66.8, 35.3, 31.7, 26.5, 25.2, 3.4; IR (CH

₂

Cl

₂

) 3353, 3020, 2860, 2232, 1649 cm

⁻¹

; MS (APCI) m/e (%) 151 ([M + H]

⁺

, 88), 133 (100), 105 (4); HRMS (APCI) calcd for C

₁₀

H

₁₅

O [M + H]

⁺

151.1123, found 151.1124.

83

4-(Hept-2-yn-1-yl)cyclohex-2-enol (II-124)

The n-BuLi (3.32 mL of a 1.6 M solution in hexane, 5.31 mmol) was added dropwise over 20 min to a stirred solution of 4-(prop-2-yn-1-yl)cyclohex-2-enol II-122 (0.345 g, 2.53 mmol) in anhydrous THF (12 mL) at ‒78 ℃ under nitrogen. The reaction mixture was stirred for 1 h at this temperature. After that, 1-bromobutane (0.3 ml, 2.8 mmol) in HMPA (1.14 mL, 6.58 mmol) was added to the reaction mixture at ‒78 ℃ and the reaction mixture was stirred for 5 h at room temperature. The mixture was quenched with a saturated NaHCO

_3(aq)

(30 mL) and extracted with diethyl ether (50 mL × 4). The combined organic layers were dried over MgSO

₄

(10 g) and concentrated under vacuum. The crude mixture was purified by flash column chromatography over silica gel (ethyl acetate/hexanes 1:10) yielding 4-(hept-2-yn-1-yl)cyclohex-2-enol (II-124) (0.279 g, 1.45 mmol, 57%, R

_f

= 0.36, (ethyl acetate/hexanes 1:3)) as a colorless oil:

¹

H NMR (400 MHz, CDCl

₃

) δ 5.79‒5.70 (m, 2H), 4.22 (s, 1H), 2.33‒2.23 (m, 1H), 2.20‒2.10 (m, 5H), 1.98‒1.89 (m, 1H), 1.53‒1.29 (m, 8H), 0.91 (t, J = 7.2 Hz, 1H);

¹³

C NMR (100 MHz, CDCl

₃

) δ 133.1, 131.2, 81.6, 78.0, 66.9, 35.4, 31.8, 31.2, 26.5, 25.2, 21.9, 18.4, 13.6; IR (CH

₂

Cl

₂

) 3336, 2924, 2855, 1650, 1448 cm

⁻¹

; MS (ESI) m/e (%) 215.1 ([M + Na]

⁺

, 67), 199.0 (7), 190.0 (7), 143.1 (19) , 138.6 (11); HRMS (ESI) calcd for C

₁₅

H

₁₆

ONa [M + Na]

⁺

215.1412, found 215.1407.

84

4.3.3 General Procedure IV

FeCl3-Promoted Cabohalogenation Reaction of 4-(3-Arylpropargyl)-Tethered Cyclohex-2-en-1-ols:

To an oven-dried 10 mL round-bottom flask equipped with a stirrer bar were added 4-(3-phenylprop-2-yn-1-yl)- cyclohex-2-en-1-ol (0.064 g, 0.3 mmol), DCM (3.0 mL) and FeCl3 (0.096 mg, 0.6 mmol) at room temperature under air. The reaction mixture was stirred until no trace of 1a, as monitored by TLC. The mixture was added 3.0 mL of water. The resulting mixture was extracted with diethyl ether (10 × 3 mL), and the combined extracts were washed with water (50 × 3 mL) and brine (50 × 3 mL), and dried over anhydrous MgSO4 (5 g), and was concentrated in vacuo to give crude oil which was purified via flash chromatography over silica gel (heaxanes) to give (1S,4S,E)-5-(chloro(phenyl)methylene)bicyclo[2.2.2]oct-2-ene as a yellow oil; yield: 0.060 g (0.26 mmol, 86%).

85

(1S,4S,E)-5-(Chloro(phenyl)methylene)bicyclo[2.2.2]oct-2-ene (II-125)

In General Procedure IV, to a solution of II-110 (0.064 g, 0.3 mmol) in 3.0 mL of CH

₂

Cl

₂

at room temperature under an air was added FeCl

₃

(0.096 mg, 0.6 mmol). The reaction mixture was stirred for 2 min, and the crude mixture was purified by flash column chromatography over silica gel (heaxanes) to give II-125 (0.060 g, 0.26 mmol, 86%, R

_f

= 0.68 (ethyl acetate/hexanes 1:3)) as a yellow oil:

¹

H NMR (500 MHz, CDCl

₃

) δ 7.38−7.28 (m, 5H, C-11−15), 6.39 (t, J = 7.3 Hz, 1H, C-3), 6.17 (t, J = 7.3 Hz, 1H, C-2), 3.37−3.31 (m, 1H, C-1), 2.86−2.79 (m, 1H, C-4), 2.37 (dd, J = 17.4, 2.5 Hz, 1H), 2.24 (dt, J = 17.4, 2.8 Hz, 1H, C-5), 1.70−1.58 (m, 2H, C-8 and C-7), 1.42−1.30 (m, 2H, C-7 and C-8);

¹³

C NMR (125 MHz, CDCl

₃

) δ 140.1, 138.7, 135.7, 131.7, 129.2 (2C), 128.2 (2C), 127.8, 122.5, 36.9, 36.3, 31.2, 25.5, 24.8; IR (CH

₂

Cl

₂

) 3047, 2947, 1637, 1364, 1178, 1101 cm

⁻¹

; MS (FAB) m/e 230.1 ([M]

⁺

, 25), 229.1 (10), 195.1 (41), 193.1 (41), 167.1 (100), 165.1 (81); HRMS (FAB) calcd for C

₁₅

H

₁₅ ³⁵

Cl [M]

⁺

230.0862, found 230.0867.

86

(1S,4S,E)-5-(Chloro(m-tolyl)methylene)bicyclo[2.2.2]oct-2-ene (II-126)

In General procedure IV, to a solution of II-111 (0.068 g, 0.3 mmol) in 3.0 mL of CH

₂

Cl

₂

at room temperature under an air was added FeCl

₃

(0.096 mg,

In General procedure IV, to a solution of II-111 (0.068 g, 0.3 mmol) in 3.0 mL of CH

₂

Cl

₂

at room temperature under an air was added FeCl

₃

(0.096 mg,

在文檔中 路易士酸輔佐之分子內環化反應:（E）-5-含鹵亞甲基雙環[2.2.2]辛-2-烯衍生物的簡易合成 (頁 61-200)