14：推測合成吡咯衍生物 III-38 的環化反應機構

68

流程 III-14：推測合成吡咯衍生物 III-38 的環化反應機構

推測順式吡咯產物 III-38a 在酸性條件下，會經由酮‒烯醇互變異構性

（keto-enol tautomerism）隨反應時間轉換成熱力學穩定的反式吡咯產物

III-38a’ （表 III-3, entry 7）

，故反式結構可能為環化反應生成或經異構化 生成（式 III-21）。

式 III-21：順

‒

反吡咯衍生物 III-38a 與 III-38a’異構化

69

3.4 結論

本章節中，實驗室利用三氯化金催化 2‒炔醯胺呋喃化合物進行分子內 的環化反應，得到具有順式烯醛基團的吡咯化合物。在起始物的設計上，

不僅合成步驟短、易操作且產率高，而環化反應在溫和的條件下，不僅選 用對環境友善且毒性較低的甲苯為溶劑，且反應時間短可快速建立吡咯化 合物，加上具有良好的原子經濟學等優點，提供天然物全合成一個不同的 合成路徑選擇。

70

第四章 實驗部分

4.1 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）：

使用BRUKER AVANCE 500 NMR（500 MHz）、BRUKER AVANCE 400

NMR（400 MHz）核磁共振光譜儀所測定。樣品以氘化氯仿（CDCl

₃

）為

2. 紅外線光譜儀（Infrared Spectroscopy，簡稱 IR）：使用JASCOF/IR-5300 型光譜儀作為測定儀器。以 polystyrene之1601 cm

^-1

吸收作為內標準來校正。

光譜單位為波數（cm

^-1

）。

3. 質 譜 （ Mass Spectroscopy ， 簡 稱 MS ） ： 使 用 ThermoFinnigan LCQ Advantage 型質譜儀作為測定儀器。係委託黃岫妮老師於台灣師範大學貴 重儀器使用中心代測;高解析質譜（High Resolution Mass Spectroscopy，簡 稱HRMS）則是使用Waters XeV HMS G2-S TOF 型質譜儀作為測定儀器。

係委託黃岫妮老師於台灣師範大學貴重儀器使用中心代測。

4. X-光單晶繞射光譜：使用Bruker Enraf-Nonius Kappa CCD及Bruker Kappa APEX II 單晶繞射儀作為測定儀器。係委託郭頂審老師於台灣師範大學貴 重儀器使用中心代測。CCDC number，此編號於劍橋晶體數據中心得到，

71

網址為https://deposit.ccdc.cam.ac.uk/，且附上check cif的pdf檔案。

5. 熔點（melting point，簡稱mp）：係由Mel-Temp熔點測定儀器所測定。

此儀器並未校正。

6. 薄層色層分析（Thin Layer Chromatography，簡稱TLC）：使用Merck Silica gel 60 F254 0.2mm 厚度的鋁箔薄片展開後，以紫外燈來檢視薄層色層分析 片。

7. 管柱色層分析（Column Chromatography）：使用友和Silica gel 60，230-240 mesh ATSM 作為填充物，用加壓快速層析（flash column chromatography）

依Still的操作方法來分離。沖提液（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。

8. 所有反應物和溶劑皆為試藥級或分析級，若需進一步純化或乾燥，則依 標準處理手續。乙醚（ether）、四氫呋喃（THF）、二氯甲烷（CH

2

Cl

2

），

甲苯（toluene）皆經過溶劑純化系統乾燥（active alumina column）。

9. 除水反應均在氮氣下進行，並以磁石攪拌，在使用前須經過真空加熱並 填充氮氣（至少重複三次）。另外，反應時間的控制則是以薄層色層分析

（TLC）測定。

72

4.2 Iron(III) Chloride-Catalyzed Synthesis of Chlorinated Bicyclo[5.3.0]

γ-Lactams.

4.2.1 Experiments

Synthesis of Seven-Membered Ring 2-Enamine II-42.

To a flame-dried flask were added cycloheptanone II-48 (2.804 g, 25.00 mmol), 2-iodoxybenzoic acid (IBX, 16.801 g, 60.00 mmol), DMSO (20.0 mL) and toluene (40.0 mL) at 65

^o

C. The reaction was stirred for 8 h. Solvent was removed under reduced pressure. The crude product was then purified by flash column chromatography (silica gel, ethyl acetate/hexanes 1:25) to afford II-47 as a colorless liquid (0.736 g, 6.69 mmol, 27%)(Scheme S1).

To a solution of cyclohept-2-en-1-one II-47 (2.534 g, 23.02 mmol) in MeOH (57.6 mL) under air were added CeCl

3

.

7H

2

O (3.860 g, 10.36 mmol) and NaBH

4

(0.392 g, 10.36 mmol). The reaction mixture was stirred for 1 h at 0

^o

C. The reaction mixture was extracted with CH

2

Cl

2

(100.0 mL × 3) and NaCl

(aq)

(100.0 mL × 3), dried over anhydrous MgSO

₄

, and evaporated under reduced pressure to give the crude product (cyclohept-2-en-1-ol II-45 (2.041 g, 18.21 mmol, 79%)(Scheme S1).

73

To a flame-dried flask were added at 0

^o

C triphenylphosphine (PPh

3

, 4.739 g, 18.00 mmol), diisopropyl azodicarboxylate (DIAD, 3.5 mL, 18.00 mmol), NHTs(Boc) (4.070 g, 15.00 mmol), and THF (60.0 mL). After 30 mins, the solution of cyclohept-2-en-1-ol II-45 (1.693 g, 15.00 mmol) in 15.0 mL THF was added to the reaction mixture at 0

^o

C. The reaction was allowed to warm to room temperature and stirred for an additional 4 h. The solvent was removed under reduced pressure. The crude product was then purified by flash column chromatography (silica gel, ethyl acetate/hexanes 1:40) to afford II-44 as a white solid (3.347 g, 9.17 mmol, 61%)(Scheme S1).

To a sloution of II-44 (3.192 g, 8.74 mmol) in methanol (58.0 mL) was added K

2

CO

3

(8.457 g, 61.19 mmol). The reaction mixture was stirred at 50

^o

C for 24 h. Methanol was removed under reduced pressure and the reaction was quenched with HCl

(aq)

, and diluted with CH

2

Cl

2

. The mixture was extracted with CH

2

Cl

2

(3 × 50 mL). The combined organic solution was dried (MgSO

4

), and concentrated under reduced pressure to obtain II-42 as a white solid (2.206 g, 8.32 mmol, 95%)(Scheme S1).

GP 2-1：General Experimental Procedure for the Preparation of Alkyl- or

Aryl-substituted N-Tosyl-2-ynamidocycloheptenes II-40a‒m.

74

Example for the Synthesis of II-40a. To a dry and nitrogen-flushed 2-neck-flask,

equipped with a magnetic stirring bar and a septum were charged with bromoalkyne II-43 (0.679 g, 3.75 mmol), toluene (14.7 mL), cyclic 2-enamine

II-42 (0.663 g, 2.50 mmol), and Cs 2

CO

3

(1.629 g, 5.00 mmol). The reaction mixture was stirred at room temperature for 10 min and then were added CuI (0.101 g, 0.53 mmol) and DMEDA (0.208 g, 2.36 mmol). The reaction was stirred at 50

^o

C until no trace of the starting material was detected (monitored by TLC). Upon cooling to room temperature, the reaction mixture was filtered and concentrated. The resulting residue was purified by flash column chromatography (silica gel, ethyl acetate/hexanes 1:30) to give II-40a (0.815 g, 2.24 mmol, 89%) as a white solid (Scheme S2).

GP 2-2：General Experimental Procedure for the FeCl ₃ -mediated Synthesis of Chlorinated Bicyclo[5.3.0] γ-Lactams II-41a‒l.

Example for the Synthesis of II-41a and II-41a’. A dry 25-mL two-neck

round-bottom flask, equipped with a calcium chloride drying tube, a magnetic stirring bar, and a septum, were added II-40a (0.109 g, 0.30 mmol), dry THF (1.2 mL), and FeCl

3

(0.107 g, 0.66 mmol). The reaction mixture was heated at 40

^o

C until the starting material was consumed (monitored by TLC). The reaction mixture was quenched with NEt

3

(2.0 mL). The resulting mixture was

75

filtered through a pad of Celite/silica gel and concentrated under reduced pressure. The residue was separated using flash column chromatography over silica gel (ethyl acetate/hexanes 1:25) to give II-41a (0.052 g, 0.13 mmol, 42%) and II-41a’ (0.021 g, 0.05 mmol, 17%) as white solid (Scheme S3).

76

4.3 Gold(III)-Catalyzed Synthesis of Pyrrole Derivatives.

4.3.1 Experiments

Synthesis of N-(furan-2-ylmethyl)-4-methylbenzenesulfonamide III-39.

To a flame-dried flask were added triphenylphosphine (PPh

3

, 9.479 g, 36.00 mmol), diisopropyl azodicarboxylate (DIAD, 7.1 mL, 36.00 mmol), NHTs(Boc) (8.140 g, 30.00 mmol), and THF (120.0 mL), at 0

^o

C. After 30 mins, the solution of furan-2-ylmethanol III-41 (2.943 g, 30.00 mmol) in 30.0 mL THF was added to the reaction mixture at 0

^o

C. The reaction was allowed to warm to room temperature and stirred for an additional 2 h. The solvent was removed under reduced pressure. The crude product was then purified by flash column chromatography (silica gel, ethyl acetate/hexanes 1:15) to afford III-40 as a white solid (8.578 g, 24.42 mmol, 81%)(Scheme S4).

To a sloution of III-40 (10.535 g, 30.00 mmol) in methanol (150.0 mL) was added K

2

CO

3

(29.024 g, 210.00 mmol). The reaction mixture was stirred at 50

o

C for 24 h. Methanol was removed under reduced pressure and the reaction was quenched with HCl

(aq)

, and diluted with CH

2

Cl

2

. The mixture was extracted with CH

₂

Cl

₂

(3 × 100 mL). The combined organic solution was dried (MgSO

₄

), and concentrated under reduced pressure to obtain III-39 as a white solid (6.859 g, 27.32 mmol, 91%)(Scheme S4).

77

GP 3-1 ： General Experimental Procedure for the Preparation of N-(Arylethynyl)-N-(furan-2-ylmethyl)-4-methylbenzenesulfonamide

III-37a‒j.

Example for the Synthesis of III-37a. To a dry and nitrogen-flushed

2-neck-flask, equipped with a magnetic stirring bar and a septum, were charged with bromoalkyne II-43 (1.350 g, 7.50 mmol), toluene (29.4 mL),

N-(furan-2-ylmethyl)-4-methylbenzenesulfonamide III-39 (1.255 g, 5.00

mmol), and Cs

2

CO

3

(3.258 g, 10.00 mmol). The reaction mixture was stirred at room temperature for 10 min and then were added CuI (0.202 g, 1.06 mmol) and DMEDA (0.420 g, 4.76 mmol). The reaction was stirred at 50

^o

C until no trace of the starting material was detected (monitored by TLC). Upon cooling to room temperature, the reaction mixture was filtered and concentrated. The resulting residue was purified by flash column chromatography (silica gel, ethyl acetate/hexanes 1:20) to give II-37a (1.629 g, 4.64 mmol, 92%) as a white solid (Scheme S5).

78

GP 3-2 ： General Experimental Procedure for the Cyclization of (Z)-3-(4-Aryl-1-tosyl-1H-pyrrol-3-yl)acrylaldehyde III-38a‒j.

Example for the Synthesis of III-38a. To a solution of III-37a (105.3 mg, 0.30

mmol) in toluene (3.0 mL) at room temperature under nitrogen was added AuCl

3

(4.6 mg, 0.015 mmol). The reaction mixture was stirred for 15 min until no III-37a was detected by TLC. The solvent was removed under reduced pressure. The crude product was then purified by flash column chromatography (silica gel, ethyl acetate/hexanes 1:15) to give III-38a (0.077 g, 0.22 mmol, 73%) as a white solid (Scheme S6).

79

4.4 Synthesis of N-Tosyl-2-ynamidocycloheptenes.

N-(Cyclohept-2-en-1-yl)-4-methyl-N-(phenylethynyl)benzenesulfonamide (II-40a)

According to GP 2-1 using (bromoethynyl)benzene (0.679 g, 3.75 mmol), toluene (14.7 mL), Seven-membered Ring 2-Enamine II-42 (0.663 g, 2.50 mmol), Cs

2

CO

3

(1.629 g, 5.00 mmol), CuI (0.101 g, 0.53 mmol), and DMEDA (0.208 g, 2.36 mmol). The mixture was stirred at 50

^o

C for 12 h. The crude mixture was purified via flash column chromatography over silica gel (ethyl acetate/hexanes = 1:24) to give II-40a as a colorless oil (0.828 g, 2.23 mmol, 89%): R

_f

= 0.35 (ethyl acetate/hexanes = 1:10);

¹ H NMR (400 MHz, CDCl ₃ ) δ

7.83 (d, J = 8.3 Hz, 2H), 7.39–7.26 (m, 7H), 5.80–5.72 (m, 1H), 5.48–5.42 (m, 1H), 4.73–4.66 (m, 1H), 2.44 (s, 3H), 2.26–2.14 (m, 1H), 2.12–2.02 (m, 1H), 1.99–1.77 (m, 3H), 1.74–1.54 (m, 2H), 1.36–1.25 (m, 1H);

¹³ C NMR (100

MHz, CDCl ₃ ) δ 144.4, 135.7, 132.5, 132.3, 131.3, 129.7, 128.2, 127.6, 123.1

(2C), 80.6, 72.1, 61.7, 33.3, 28.4, 27.6, 26.1, 21.6; IR (CH

₂ Cl ₂ ) 2929, 2235,

1597, 1444, 1365, 1169, 1092, 994, 813, 755, 665, 592, 548 cm

^-1

; MS (ESI)

m/e (%) 388.0 ([M+Na] ⁺

, 100); HRMS (ESI) m/e calcd for C

₂₂

H

₂₄

NO

₂

S [M+H]

⁺

366.1528, found 366.1534.

80

N-(Cyclohept-2-en-1-yl)-4-methyl-N-(o-tolylethynyl)benzenesulfonamide (II-40b)

According to GP 2-1 using 1-(bromoethynyl)-2-methylbenzene (0.320 g, 1.65 mmol), toluene (6.5 mL), Seven-membered Ring 2-Enamine II-42 (0.291 g, 1.10 mmol), Cs

2

CO

3

(0.717 g, 2.20 mmol), CuI (0.044 g, 0.233 mmol), and DMEDA (0.092 g, 1.04 mmol). The mixture was stirred at 50

^o

C for 12 h. The crude mixture was purified via flash column chromatography over silica gel (ethyl acetate/hexanes = 1:24) to give II-40b as a colorless oil (0.390 g, 1.02 mmol, 93%): R

_f

= 0.35 (ethyl acetate/hexanes = 1:10);

¹ H NMR (400 MHz,

CDCl ₃ ) δ 7.83 (d, J = 8.3 Hz, 2H), 7.36–7.29 (m, 3H), 7.18–7.17 (m, 3H),

5.80–5.71 (m, 1H), 5.50–5.42 (m, 1H), 4.76–4.69 (m, 1H), 2.44 (s, 3H), 2.36 (s, 3H), 2.24–2.14 (m, 1H), 2.12–2.02 (m, 1H), 2.00–1.81 (m, 3H), 1.74–1.56 (m, 2H), 1.37–1.25 (m, 1H);

¹³ C NMR (100 MHz, CDCl ₃ ) δ 144.4, 139.6, 135.9,

132.5, 132.4, 131.3, 129.7, 129.3, 127.6, 127.5, 125.4, 123.0, 84.5, 71.1, 61.8, 33.4, 28.4, 27.6, 26.2, 21.6, 20.8; IR (CH

₂ Cl ₂ ) 2927, 2233, 1598, 1446, 1366,

1170, 1092, 997, 814, 758, 665, 594, 548 cm

^-1

; MS (ESI) m/e (%) 402.3 ([M+Na]

⁺

, 100); HRMS (ESI) m/e calcd for C

₂₃

H

₂₅

NO

₂

NaS [M+Na]

⁺

402.1504, found 402.1503.

81

N-(Cyclohept-2-en-1-yl)-4-methyl-N-(m-tolylethynyl)benzenesulfonamide (II-40c)

According to GP 2-1 using 1-(bromoethynyl)-3-methylbenzene (0.320 g, 1.65 mmol), toluene (6.5 mL), Seven-membered Ring 2-Enamine II-42 (0.291 g, 1.10 mmol), Cs

2

CO

3

(0.717 g, 2.20 mmol), CuI (0.044 g, 0.233 mmol), and DMEDA (0.092 g, 1.04 mmol). The mixture was stirred at 50

^o

C for 10 h. The crude mixture was purified via flash column chromatography over silica gel (ethyl acetate/hexanes = 1:24) to give II-40c as a colorless oil (0.297 g, 0.77 mmol, 70%): R

_f

= 0.35 (ethyl acetate/hexanes = 1:10);

¹ H NMR (400 MHz,

CDCl ₃ ) δ 7.86–7.80 (m, 2H), 7.33 (d, J = 8.1 Hz, 2H), 7.21–7.13 (m, 3H),

7.11–7.04 (m, 1H), 5.80–5.71 (m, 1H), 5.49–5.41 (m, 1H), 4.73–4.64 (m, 1H), 2.44 (s, 3H), 2.31 (s, 3H), 2.25–2.14 (m, 1H), 2.13–2.01 (m, 1H), 2.00–1.77 (m, 3H), 1.75–1.59 (m, 2H), 1.38–1.24 (m, 1H);

¹³ C NMR (100 MHz, CDCl ₃ ) δ

144.4, 137.9, 135.8, 132.5, 132.4, 131.9, 129.7, 128.5, 128.4, 128.1, 127.6, 122.9, 80.4, 72.2, 61.7, 33.3, 28.4, 27.7, 26.1, 21.6, 21.2; IR (CH

₂ Cl ₂ ) 2930,

2234, 1598, 1446, 1366, 1170, 1091, 1000, 814, 784, 666, 594, 548 cm

^-1

; MS

(ESI) m/e (%) 402.6 ([M+Na] ⁺

, 100); HRMS (ESI) m/e calcd for C

23

H

25

NO

2

NaS [M+Na]

⁺

402.1504, found 402.1500.

82

N-(Cyclohept-2-en-1-yl)-4-methyl-N-(p-tolylethynyl)benzenesulfonamide (II-40d)

According to GP 2-1 using 1-(bromoethynyl)-4-methylbenzene (0.410 g, 2.10 mmol), toluene (8.5 mL), Seven-membered Ring 2-Enamine II-42 (0.371 g, 1.40 mmol), Cs

2

CO

3

(0.912 g, 2.80 mmol), CuI (0.058 g, 0.30 mmol), and DMEDA (0.117 g, 1.33 mmol). The mixture was stirred at 50

^o

C for 12 h. The crude mixture was purified via flash column chromatography over silica gel (ethyl acetate/hexanes = 1:24) to give II-40d as a colorless oil (0.387 g, 1.01 mmol, 72%): R

_f

= 0.35 (ethyl acetate/hexanes = 1:10);

¹ H NMR (400 MHz,

CDCl ₃ ) δ 7.83 (d, J = 8.4 Hz, 2H), 7.32 (d, J = 8.1 Hz, 2H), 7.29–7.24 (m, 2H),

7.12–7.06 (m, 2H), 5.81–5.69 (m, 1H), 5.50–5.40 (m, 1H), 4.75–4.63 (m, 1H), 2.44 (s, 3H), 2.33 (s, 3H), 2.25–2.14 (m, 1H), 2.13–2.00 (m, 1H), 1.99–1.77 (m, 3H), 1.74–1.58 (m, 2H), 1.37–1.25 (m, 1H);

¹³ C NMR (100 MHz, CDCl ₃ ) δ

144.3, 137.8, 135.8, 132.4 (2C), 131.4, 129.7, 128.9, 127.6, 120.0, 80.0, 72.1, 61.7, 33.3, 28.4, 27.7, 26.1, 21.6, 21.4; IR (CH

₂ Cl ₂ ) 2927, 2236, 1598, 1446,

1365, 1169, 1092, 996, 815, 663, 589, 547 cm

^-1

; MS (ESI) m/e (%) 402.3 ([M+Na]

⁺

, 100); HRMS (ESI) m/e calcd for C

₂₃

H

₂₅

NO

₂

NaS [M+Na]

⁺

402.1504, found 402.1505.

83

N-([1,1'-Biphenyl]-4-ylethynyl)-N-(cyclohept-2-en-1-yl)-4-methylbenzenesu lfonamide (II-40e)

According to GP 2-1 using 4-(bromoethynyl)-1,1'-biphenyl (0.230 g, 0.90 mmol), toluene (3.5 mL), Seven-membered Ring 2-Enamine II-42 (0.160 g, 0.60 mmol), Cs

2

CO

3

(0.391 g, 1.20 mmol), CuI (0.025 g, 0.13 mmol), and DMEDA (0.050 g, 0.57 mmol). The mixture was stirred at 50

^o

C for 10 h. The crude mixture was purified via flash column chromatography over silica gel (ethyl acetate/hexanes = 1:24) to give II-40e as a white solid (0.206 g, 0.46 mmol, 77%): R

_f

= 0.20 (ethyl acetate/hexanes = 1:20); mp 99‒100

^o

C;

¹ H

NMR (400 MHz, CDCl ₃ ) δ 7.89–7.82 (m, 2H), 7.60–7.49 (m, 4H), 7.47–7.40

(m, 4H), 7.37–7.31 (m, 3H), 5.83–5.73 (m, 1H), 5.51–5.44 (m, 1H), 4.76–4.68 (m, 1H), 2.44 (s, 3H), 2.26–2.15 (m, 1H), 2.15–2.02 (m, 1H), 2.02–1.77 (m, 3H), 1.74–1.56 (m, 2H), 1.39–1.25 (m, 1H);

¹³ C NMR (100 MHz, CDCl ₃ ) δ

144.5, 140.3, 135.7, 132.5, 132.3, 131.7, 129.7, 128.8, 127.6, 127.5 (2C), 126.9, 126.8, 122.0, 81.4, 72.0, 61.7, 33.3, 28.4, 27.6, 26.1, 21.6; IR (CH

₂ Cl ₂ ) 2931,

2234, 1598, 1366, 1169, 1100, 999, 814, 764, 666, 594, 547 cm

^-1

; MS (ESI)

m/e (%) 464.0 ([M+Na] ⁺

, 100); HRMS (ESI) m/e calcd for C

₂₈

H

₂₈

NO

₂

S [M+H]

⁺

442.1841, found 442.1841.

84

N-(Cyclohept-2-en-1-yl)-4-methyl-N-(naphthalen-1-ylethynyl)benzenesulfo namide (II-40f)

According to GP 2-1 using 1-(bromoethynyl)naphthalene (0.207 g, 0.90 mmol), toluene (3.5 mL), Seven-membered Ring 2-Enamine II-42 (0.160 g, 0.60 mmol), Cs

2

CO

3

(0.391 g, 1.20 mmol), CuI (0.025 g, 0.13 mmol), and DMEDA (0.050 g, 0.57 mmol). The mixture was stirred at 50

^o

C for 12 h. The crude mixture was purified via flash column chromatography over silica gel (ethyl acetate/hexanes = 1:24) to give II-40f as a colorless oil (0.217 g, 0.52 mmol, 87%): R

_f

= 0.25 (ethyl acetate/hexanes = 1:20);

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.26–8.20 (m, 1H), 7.88 (d, J = 8.2 Hz, 2H), 7.85–7.74 (m, 2H),

7.60–7.46 (m, 3H), 7.42–7.28 (m, 3H), 5.86–5.77 (m, 1H), 5.59–5.52 (m, 1H), 4.82–4.74 (m, 1H), 2.43 (s, 3H), 2.28–2.18 (m, 1H), 2.15–2.04 (m, 1H), 2.03–

1.84 (m, 3H), 1.78–1.59 (m, 2H), 1.42–1.29 (m, 1H);

¹³ C NMR (100 MHz,

CDCl ₃ ) δ 144.5, 135.7, 133.2, 132.8, 132.3, 129.8, 129.5, 128.2, 127.9, 127.6,

126.6, 126.3, 125.2, 120.9, 85.4, 70.6, 61.9, 33.5, 28.4, 27.5, 26.2, 21.6; IR

(CH ₂ Cl ₂ ) 2929, 2230, 1702, 1446, 1361, 1170, 1091, 989, 800, 775, 666, 594,

548 cm

^-1

; MS (ESI) m/e (%) 438.0 ([M+Na]

⁺

, 100); HRMS (ESI) m/e calcd for C

26

H

26

NO

2

S [M+H]

⁺

416.1684, found 416.1686.

85

N-(Cyclohept-2-en-1-yl)-N-((3-methoxyphenyl)ethynyl)-4-methylbenzenesu lfonamide (II-40g)

According to GP 2-1 using 1-(bromoethynyl)-3-methoxybenzene (0.189 g, 0.90 mmol), toluene (3.5 mL), Seven-membered Ring 2-Enamine II-42 (0.160 g, 0.60 mmol), Cs

2

CO

3

(0.391 g, 1.20 mmol), CuI (0.025 g, 0.13 mmol), and DMEDA (0.050 g, 0.57 mmol). The mixture was stirred at 50

^o

C for 12 h. The crude mixture was purified via flash column chromatography over silica gel (ethyl acetate/hexanes = 1:15) to give II-40g as a colorless oil (0.204 g, 0.51 mmol, 85%): R

_f

= 0.20 (ethyl acetate/hexanes = 1:10);

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.86–7.80 (m, 2H), 7.37–7.31 (m, 2H), 7.23–7.16 (m, 1H), 6.99–6.93

(m, 1H), 6.91–6.88 (m, 1H), 6.86–6.80 (m, 1H), 5.80–5.71 (m, 1H), 5.48–5.42 (m, 1H), 4.73–4.66 (m, 1H), 3.80 (s, 3H), 2.44 (s, 3H), 2.25–2.14 (m, 1H), 2.13–2.02 (m, 1H), 2.00–1.76 (m, 3H), 1.75–1.57 (m, 2H), 1.38–1.27 (m, 1H);

13 C NMR (100 MHz, CDCl ₃ ) δ 159.3, 144.5, 135.7, 132.5, 132.3, 129.7, 129.2,

127.6, 124.2, 123.8, 116.3, 114.0, 80.7, 72.2, 61.8, 55.3, 33.4, 28.4, 27.6, 26.1, 21.7; IR (CH

₂ Cl ₂ ) 2930, 2234, 1598, 1365, 1169, 1092, 999, 814, 665, 593,

549 cm

^-1

; MS (ESI) m/e (%) 418.4 ([M+Na]

⁺

, 100); HRMS (ESI) m/e calcd for C

23

H

25

NO

3

NaS [M+Na]

⁺

418.1453, found 418.1455.

86

N-(Cyclohept-2-en-1-yl)-N-((4-methoxyphenyl)ethynyl)-4-methylbenzenesu lfonamide (II-40h)

According to GP 2-1 using 1-(bromoethynyl)-4-methoxybenzene (0.189 g, 0.90 mmol), toluene (3.5 mL), Seven-membered Ring 2-Enamine II-42 (0.160 g, 0.60 mmol), Cs

2

CO

3

(0.391 g, 1.20 mmol), CuI (0.025 g, 0.13 mmol), and DMEDA (0.050 g, 0.57 mmol). The mixture was stirred at 50

^o

C for 12 h. The crude mixture was purified via flash column chromatography over silica gel (ethyl acetate/hexanes = 1:15) to give II-40h as a colorless oil (0.177 g, 0.44 mmol, 74%): R

_f

= 0.20 (ethyl acetate/hexanes = 1:10);

¹ H NMR (400 MHz,

CDCl ₃ ) δ 7.83 (d, J = 8.3 Hz, 2H), 7.37–7.29 (m, 4H), 6.82 (d, J = 8.8 Hz, 2H),

5.79–5.70 (m, 1H), 5.49–5.42 (m, 1H), 4.73–4.66 (m, 1H), 3.80 (s, 3H), 2.44 (s, 3H), 2.24–2.13 (m, 1H), 2.11–2.01 (m, 1H), 1.99–1.77 (m, 3H), 1.73–1.55 (m, 2H), 1.36–1.24 (m, 1H);

¹³ C NMR (100 MHz, CDCl ₃ ) δ 159.4, 144.3, 135.8,

133.3, 132.4, 132.3, 129.6, 127.6, 115.0, 113.8, 79.1, 71.7, 61.7, 55.3, 33.3, 28.4, 27.7, 26.1, 21.6; IR (CH

₂ Cl ₂ ) 2932, 2236, 1606, 1362, 1169, 1091, 997,

814, 663, 589, 547 cm

^-1

; MS (ESI) m/e (%) 418.0 ([M+Na]

⁺

, 100); HRMS

(ESI) m/e calcd for C ₂₃

H

₂₆

NO

₃

S [M+H]

⁺

396.1633, found 396.1636.

87

Methyl

3-(((N-(Cyclohept-2-en-1-yl)-4-methylphenyl)sulfonamido)ethynyl)benzoat e (II-40i)

According to GP 2-1 using methyl 3-(bromoethynyl)benzoate (0.214 g, 0.90 mmol), toluene (3.5 mL), Seven-membered Ring 2-Enamine II-42 (0.160 g, 0.60 mmol), Cs

2

CO

3

(0.391 g, 1.20 mmol), CuI (0.025 g, 0.13 mmol), and DMEDA (0.050 g, 0.57 mmol). The mixture was stirred at 50

^o

C for 10 h. The crude mixture was purified via flash column chromatography over silica gel (ethyl acetate/hexanes = 1:20) to give II-40i as a colorless oil (0.159 g, 0.38 mmol, 63%): R

_f

= 0.18 (ethyl acetate/hexanes = 1:10);

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.03–7.99 (m, 1H), 7.95–7.89 (m, 1H), 7.87–7.81 (m, 2H), 7.57–7.52

(m, 1H), 7.41–7.32 (m, 3H), 5.82–5.74 (m, 1H), 5.48–5.41 (m, 1H), 4.74–4.66 (m, 1H), 3.93 (s, 3H), 2.45 (s, 3H), 2.26–2.16 (m, 1H), 2.13–2.00 (m, 1H), 2.00–1.78 (m, 3H), 1.76–1.59 (m, 2H), 1.40–1.24 (m, 1H);

¹³ C NMR (100 MHz, CDCl ₃ ) δ 166.5, 144.6, 135.7, 135.4, 132.7, 132.2, 132.2, 130.3, 129.8,

128.5, 128.4, 127.6, 123.7, 81.8, 71.4, 61.8, 52.2, 33.4, 28.4, 27.6, 26.1, 21.7;

IR (CH ₂ Cl ₂ ) 2929, 2234, 1726, 1442, 1367, 1253, 1170, 1093, 1001, 812, 755,

665, 593, 548 cm

^-1

; MS (ESI) m/e (%) 446.6 ([M+Na]

⁺

, 100); HRMS (ESI)

m/e calcd for C ₂₄

H

₂₅

NO

₄

NaS [M+H]

⁺

446.1402, found 446.1400.

88

N-(Cyclohept-2-en-1-yl)-4-methyl-N-((3-(trifluoromethyl)phenyl)ethynyl)b enzenesulfonamide (II-40j)

According to GP 2-1 using 1-(bromoethynyl)-3-(trifluoromethyl)benzene (0.223 g, 0.90 mmol), toluene (3.5 mL), Seven-membered Ring 2-Enamine

II-42 (0.160 g, 0.60 mmol), Cs ₂

CO

₃

(0.391 g, 1.20 mmol), CuI (0.025 g, 0.13 mmol), and DMEDA (0.050 g, 0.57 mmol). The mixture was stirred at 50

^o

C for 10 h. The crude mixture was purified via flash column chromatography over silica gel (ethyl acetate/hexanes = 1:30) to give II-40j as a white solid (0.210 g, 0.49 mmol, 81%): R

f

= 0.30 (ethyl acetate/hexanes = 1:20); mp 52‒53

o

C;

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.86–7.80 (m, 2H), 7.59–7.48 (m, 3H),

7.44–7.38 (m, 1H), 7.37–7.32 (m, 2H), 5.83–5.75 (m, 1H), 5.48–5.41 (m, 1H), 4.74–4.66 (m, 1H), 2.46 (s, 3H), 2.27–2.16 (m, 1H), 2.14–2.02 (m, 1H), 2.01–

1.78 (m, 3H), 1.75–1.57 (m, 2H), 1.40–1.28 (m, 1H);

¹³ C NMR (100 MHz, CDCl ₃ ) δ 146.9, 137.4, 136.0, 134.5, 133.8, 131.7 (2C), 131.3, 129.3 (2C),

128.7 (q, J = 15.4 Hz), 126.0 (2C), 125.8 (q, J = 13.8 Hz), 84.6, 72.5, 63.3, 34.9, 29.6, 27.6, 22.3; IR (CH

₂ Cl ₂ ) 2929, 2236, 1598, 1444, 1369, 1169, 1091,

1000, 850, 763, 664, 593, 547 cm

^-1

; MS (ESI) m/e (%) 456.8 ([M+Na]

⁺

, 100);

HRMS (ESI) m/e calcd for C ₂₃

H

₂₃

NO

₂

SF

₃

[M+H]

⁺

434.1402, found 434.1404.

89

N-((4-Chlorophenyl)ethynyl)-N-(cyclohept-2-en-1-yl)-4-methylbenzenesulf onamide (II-40k)

According to GP 2-1 using 1-(bromoethynyl)-4-chlorobenzene (0.193 g, 0.90 mmol), toluene (3.5 mL), Seven-membered Ring 2-Enamine II-42 (0.160 g, 0.60 mmol), Cs

2

CO

3

(0.391 g, 1.20 mmol), CuI (0.025 g, 0.13 mmol), and DMEDA (0.050 g, 0.57 mmol). The mixture was stirred at 50

^o

C for 12 h. The crude mixture was purified via flash column chromatography over silica gel (ethyl acetate/hexanes = 1:24) to give II-40k as a white solid (0.202 g, 0.50 mmol, 84%): R

_f

= 0.30 (ethyl acetate/hexanes = 1:10); mp 89‒90

^o

C;

¹ H NMR

(400 MHz, CDCl ₃ ) δ 7.77–7.72 (m, 2H), 7.26 (d, J = 8.3 Hz, 2H), 7.23–7.15

(m, 4H), 5.73–5.61 (m, 1H), 5.39–5.32 (m, 1H), 4.65–4.58 (m, 1H), 2.37 (s, 3H), 2.17–2.07 (m, 1H), 2.05–1.93 (m, 1H), 1.93–1.71 (m, 3H), 1.67–1.50 (m, 2H), 1.31–1.17 (m, 1H);

¹³ C NMR (100 MHz, CDCl ₃ ) δ 144.6, 135.7, 133.5,

132.7, 132.4, 132.2, 129.8, 128.5, 127.6, 121.7, 81.8, 71.2, 61.8, 33.4, 28.4, 27.6, 26.1, 21.7;

IR (CH ₂ Cl ₂ ) 2928, 2236, 1597, 1366, 1169, 1091, 995, 814,

755, 665, 598, 546 cm

^-1

; MS (ESI) m/e (%) 422.3 ([M+Na]

⁺

, 100); HRMS

(ESI) m/e calcd for C ₂₂

H

₂₃

NO

₂

SCl [M+H]

⁺

400.1138, found 400.1140.

90

N-(Cyclohept-2-en-1-yl)-4-methyl-N-(thiophen-3-ylethynyl)benzenesulfona mide (II-40l)

According to GP 2-1 using 3-(bromoethynyl)thiophene (0.167 g, 0.90 mmol), toluene (3.5 mL), Seven-membered Ring 2-Enamine II-42 (0.160 g, 0.60 mmol), Cs

2

CO

3

(0.391 g, 1.20 mmol), CuI (0.025 g, 0.13 mmol), and DMEDA (0.050 g, 0.57 mmol). The mixture was stirred at 50

^o

C for 10 h. The crude mixture was purified via flash column chromatography over silica gel (ethyl acetate/hexanes = 1:24) to give II-40l as a white solid (0.166 g, 0.45 mmol, 75%): R

_f

= 0.30 (ethyl acetate/hexanes = 1:10); mp 99‒100

^o

C;

¹ H NMR (400 MHz, CDCl 3 ) δ 7.82 (d, J = 8.3 Hz, 2H), 7.40–7.31 (m, 3H), 7.25–

7.22 (m, 1H), 7.09–7.02 (m, 1H), 5.80–5.71 (m, 1H), 5.48–5.42 (m, 1H), 4.73–

4.64 (m, 1H), 2.45 (s, 3H), 2.25–2.13 (m, 1H), 2.12–2.00 (m, 1H), 1.99–1.74 (m, 3H), 1.74–1.57 (m, 2H), 1.37–1.24 (m, 1H);

¹³ C NMR (100 MHz, CDCl ₃ )

δ 144.4, 135.8, 132.5, 132.4, 130.3, 129.7, 128.5, 127.6, 125.0, 121.8, 80.0, 67.1, 61.7, 33.3, 28.4, 27.7, 26.1, 21.7; IR (CH

₂ Cl ₂ ) 2932, 2236, 1597, 1365,

1168, 1091, 784, 666, 592 cm

^-1

; MS (ESI) m/e (%) 394.5 ([M+Na]

⁺

, 100);

HRMS (ESI) m/e calcd for C ₂₀

H

₂₂

NO

₂

S

₂

[M+H]

⁺

372.1092, found 372.1097.

91

N-(Cyclohept-2-en-1-yl)-N-(cyclopropylethynyl)-4-methylbenzenesulfonam ide (II-40m)

According to GP 2-1 using (bromoethynyl)cyclopropane (0.131 g, 0.90 mmol), toluene (3.5 mL), Seven-membered Ring 2-Enamine II-42 (0.160 g, 0.60 mmol), Cs

2

CO

3

(0.391 g, 1.20 mmol), CuI (0.025 g, 0.13 mmol), and DMEDA (0.050 g, 0.57 mmol). The mixture was stirred at 50

^o

C for 12 h. The crude mixture was purified via flash column chromatography over silica gel (ethyl acetate/hexanes = 1:30) to give II-40m as a white solid (0.164 g, 0.50 mmol, 83%): R

_f

= 0.35 (ethyl acetate/hexanes = 1:10); mp 87‒88

^o

C;

¹ H NMR (400 MHz, CDCl 3 ) δ 7.76 (d, J = 8.3 Hz, 2H), 7.31 (d, J = 8.0 Hz, 2H), 5.76–

5.67 (m, 1H), 5.37–5.31 (m, 1H), 4.60–4.53 (m, 1H), 2.44 (s, 3H), 2.22–2.11 (m, 1H), 2.10–2.00 (m, 1H), 2.00–1.83 (m, 1H), 1.76–1.50 (m, 4H), 1.40–1.22 (m, 2H), 0.82–0.72 (m, 2H), 0.66–0.56 (m, 2H);

¹³ C NMR (100 MHz, CDCl ₃ )

δ 144.1, 135.9, 132.7, 132.0, 129.5, 127.6, 76.2, 66.6, 61.2, 33.2, 28.4, 27.8, 26.1, 21.6, 9.0, 8.9, -0.6; IR (CH

₂ Cl ₂ ) 2930, 2246, 1598, 1446, 1366, 1167,

1092, 1008, 814, 665, 590, 548 cm

^-1

; MS (ESI) m/e (%) 352.1 ([M+Na]

⁺

, 100);

HRMS (ESI) m/e calcd for C ₁₉

H

₂₄

NO

₂

S [M+H]

⁺

330.1528, found 330.1531.

92

4.5 Synthesis of Chlorinated Bicyclo[5.3.0]-γ-lactams.

(3S*,3aR*,4R*,8aR*)-4-Chloro-3-phenyl-1-tosyloctahydrocyclohepta[b]pyr rol-2(1H)-one (II-41a)

According to GP 2-2 using seven-membered ring 2-enynamide II-40a (0.110 g, 0.30 mmol), FeCl

3

(0.107 g, 0.66 mmol), and THF (1.2 mL). The mixture was stirred at 40

^o

C for 2 h. The crude mixture was purified via flash column chromatography over silica gel (ethyl acetate/hexanes = 1:10) to give

II-41a as a white solid (0.052 g, 0.13 mmol, 42%):

R

f

= 0.30 (ethyl acetate/hexanes = 1:5); mp 166‒167

^o

C;

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.00–

7.95 (m, 2H), 7.33 (d, J = 8.1 Hz, 2H), 7.30–7.22 (m, 4H), 7.02–6.96 (m, 2H), 4.70–4.63 (m, 1H), 4.10–4.03 (m, 1H), 3.68 (d, J = 12.2 Hz, 1H), 3.17–3.07 (m, 1H), 2.44 (s, 3H), 2.37–2.27 (m, 1H), 2.22–2.13 (m, 1H), 2.05–1.75 (m, 4H), 1.71–1.57 (m, 2H);

¹³ C NMR (100 MHz, CDCl ₃ ) δ 172.0, 145.2, 136.3, 135.8,

129.6, 128.8, 128.7, 128.5, 127.9, 61.9, 61.3, 54.1, 53.4, 34.6, 31.1, 26.8, 24.7, 21.7; IR (CH

₂ Cl ₂ ) 2933, 1737, 1356, 1169, 1101, 963, 912, 732, 668, 586, 550

cm

^-1

; MS (ESI) m/e (%) 440.4 ([M+Na]

⁺

, 100); HRMS (ESI) m/e calcd for C

₂₂

H

₂₄

NO

₃

NaSCl [M+Na]

⁺

440.1063, found 440.1066. Crystals suitable for X-ray diffraction analysis were grown from acetone and hexanes

93

(3S*,3aR*,4S*,8aR*)-4-Chloro-3-phenyl-1-tosyloctahydrocyclohepta[b]pyr rol-2(1H)-one (II-41a')

According to GP 2-2 using seven-membered ring 2-enynamide II-40a (0.110 g, 0.30 mmol), FeCl

3

(0.107 g, 0.66 mmol), and THF (1.2 mL). The mixture was stirred at 40

^o

C for 2 h. The crude mixture was purified via flash column chromatography over silica gel (ethyl acetate/hexanes = 1:10) to give

II-41a' as a white solid (0.021 g, 0.05 mmol, 17%):

R

_f

= 0.30 (ethyl acetate/hexanes = 1:5); mp 147‒148

^o

C;

¹ H NMR (400 MHz, CDCl 3 ) δ 7.97 (d,

J = 8.4 Hz, 2H), 7.35–7.24 (m, 5H), 7.14–7.08 (m, 2H), 4.57–4.47 (m, 1H),

4.42–4.35 (m, 1H), 4.23 (d, J = 11.6 Hz, 1H), 3.02 (ddd, J = 11.6, 8.8, 5.2 Hz, 1H), 2.44 (s, 3H), 2.28–2.17 (m, 3H), 2.16–1.91 (m, 2H), 1.85–1.65 m(m, 2H), 1.59–1.44 (m, 1H);

¹³ C NMR (100 MHz, CDCl ₃ ) δ 172.7, 145.2, 136.2, 135.9,

129.5, 128.9, 128.7, 128.5, 127.8, 63.0, 60.6, 52.1, 51.1, 33.2, 29.6, 26.8, 23.3, 21.7; IR (CH

₂ Cl ₂ ) 2936, 1736, 1356, 1170, 1105, 969, 912, 728, 666, 574, 547

cm

^-1

; MS (ESI) m/e (%) 440.3 ([M+Na]

⁺

, 100); HRMS (ESI) m/e calcd for C

22

H

24

NO

3

NaSCl [M+Na]

⁺

440.1063, found 440.1064.

94

(3S*,3aR*,4R*,8aR*)-4-Chloro-3-(o-tolyl)-1-tosyloctahydrocyclohepta[b]py rrol-2(1H)-one (II-41b)

According to GP 2-2 using seven-membered ring 2-enynamide II-40b (0.114 g, 0.30 mmol), FeCl

3

(0.107 g, 0.66 mmol), and THF (1.2 mL). The mixture was stirred at 40

^o

C for 4 h. The crude mixture was purified via flash column chromatography over silica gel (ethyl acetate/hexanes = 1:10) to give

II-41b as a colorless oil (0.036 g, 0.08 mmol, 28%):

R

_f

= 0.30 (ethyl acetate/hexanes = 1:5);

¹ H NMR (400 MHz, CDCl 3 ) δ 7.97 (d, J = 8.4 Hz, 2H),

7.32 (d, J = 8.2 Hz, 2H), 7.16–7.03 (m, 3H), 6.84–6.76 (m, 1H), 4.69–4.61 (m, 1H), 4.06–3.99 (m, 1H), 3.92 (d, J = 11.8 Hz, 1H), 3.21–3.11 (m, 1H), 2.44 (s, 3H), 2.38–2.29 (m, 1H), 2.25–2.05 (m, 4H), 2.05–1.83 (m, 4H), 1.74–1.55 (m, 2H);

¹³ C NMR (100 MHz, CDCl ₃ ) δ 172.0, 145.2, 135.7, 130.8 (2C), 129.5

(2C), 128.6 (2C), 127.7, 126.3, 62.1 (2C), 62.0 (2C), 35.7, 31.3, 27.3, 25.3, 21.7, 19.9; IR (CH

₂ Cl ₂ ) 2936, 2361, 1736, 1356, 1170, 1093, 965, 912, 734,

668, 589, 549 cm

^-1

; MS (ESI) m/e (%) 454.4 ([M+Na]

⁺

, 100); HRMS (ESI)

m/e calcd for C 23

H

26

NO

3

NaSCl [M+Na]

⁺

454.1220, found 454.1223.

95

(3S*,3aR*,4R*,8aR*)-4-Chloro-3-(m-tolyl)-1-tosyloctahydrocyclohepta[b]p yrrol-2(1H)-one (II-41c)

According to GP 2-2 using seven-membered ring 2-enynamide II-40c (0.114 g, 0.30 mmol), FeCl

3

(0.107 g, 0.66 mmol), and THF (1.2 mL). The mixture was stirred at 40

^o

C for 2 h. The crude mixture was purified via flash column chromatography over silica gel (ethyl acetate/hexanes = 1:10) to give

II-41c as a colorless oil (0.033 g, 0.08 mmol, 27%):

R

_f

= 0.30 (ethyl acetate/hexanes = 1:5);

¹ H NMR (400 MHz, CDCl 3 ) δ 7.97 (d, J = 8.3 Hz, 2H),

7.32 (d, J = 8.3 Hz, 2H), 7.18–7.11 (m, 1H), 7.08–7.02 (m, 1H), 6.82–6.72 (m, 2H), 4.72–4.62 (m, 1H), 4.10–4.02 (m, 1H), 3.63 (d, J = 12.1 Hz, 1H), 3.16–

3.06 (m, 1H), 2.43 (s, 3H), 2.36–2.23 (m, 4H), 2.22–2.10 (m, 1H), 2.06–1.85 (m, 3H), 1.84–1.54 (m, 3H);

¹³ C NMR (100 MHz, CDCl ₃ ) δ 172.1, 145.2,

138.4, 136.3, 135.8, 129.5, 129.2, 128.7, 128.6, 128.5, 125.8, 61.9, 61.2, 54.0, 53.3, 34.3, 31.2, 26.6, 24.5, 21.6, 21.3; IR (CH

₂ Cl ₂ ) 2938, 1738, 1306, 1038,

963, 912, 732, 668, 580 cm

^-1

; MS (ESI) m/e (%) 454.4 ([M+Na]

⁺

, 100);

HRMS (ESI) m/e calcd for C ₂₃

H

₂₇

NO

₃

SCl [M+H]

⁺

432.1400, found 432.1404.

96

(3S*,3aR*,4R*,8aR*)-4-Chloro-3-(p-tolyl)-1-tosyloctahydrocyclohepta[b]py rrol-2(1H)-one (II-41d)

According to GP 2-2 using seven-membered ring 2-enynamide II-40d (0.114 g, 0.30 mmol), FeCl

3

(0.107 g, 0.66 mmol), and THF (1.2 mL). The mixture was stirred at 40

^o

C for 2 h. The crude mixture was purified via flash column chromatography over silica gel (ethyl acetate/hexanes = 1:10) to give

II-41d as a white solid (0.054 g, 0.13 mmol, 42%):

R

_f

= 0.30 (ethyl acetate/hexanes = 1:5); mp 178‒179

^o

C;

¹ H NMR (400 MHz, CDCl 3 ) δ 7.96 (d, J = 8.3 Hz, 2H), 7.32 (d, J = 8.3 Hz, 2H), 7.07 (d, J = 7.9 Hz, 2H), 6.88 (d, J =

8.0 Hz, 2H), 4.70–4.61 (m, 1H), 4.11–4.02 (m, 1H), 3.64 (d, J = 12.2 Hz, 1H), 3.14–3.04 (m, 1H), 2.44 (s, 3H), 2.37–2.25 (m, 4H), 2.21–2.11 (m, 1H), 2.05–

1.85 (m, 3H), 1.84–1.57 (m, 3H);

¹³ C NMR (100 MHz, CDCl ₃ ) δ 172.2, 145.2,

137.6, 135.8, 133.2, 129.5, 129.5, 61.9, 61.2, 53.7, 53.3, 34.4, 31.1, 26.7, 24.6, 21.7, 21.1; IR (CH

₂ Cl ₂ ) 2937, 1738, 1356, 1170, 1102, 964, 912, 734, 667, 580,

550 cm

^-1

; MS (ESI) m/e (%) 454.3 ([M+Na]

⁺

, 100); HRMS (ESI) m/e calcd for C

23

H

26

NO

3

NaSCl [M+Na]

⁺

454.1220, found 454.1222. Crystals suitable for X-ray diffraction analysis were grown from acetone and hexanes

97

(3S*,3aR*,4S*,8aR*)-4-Chloro-3-(p-tolyl)-1-tosyloctahydrocyclohepta[b]py rrol-2(1H)-one (II-41d')

According to GP 2-2 using seven-membered ring 2-enynamide II-40d (0.114 g, 0.30 mmol), FeCl

3

(0.107 g, 0.66 mmol), and THF (1.2 mL). The mixture was stirred at 40

^o

C for 2 h. The crude mixture was purified via flash column chromatography over silica gel (ethyl acetate/hexanes = 1:10) to give

II-41d' as a white solid (0.022 g, 0.05 mmol, 17%):

R

_f

= 0.30 (ethyl acetate/hexanes = 1:5); mp 152‒153

^o

C;

¹ H NMR (400 MHz, CDCl 3 ) δ 7.97 (d,

J = 8.4 Hz, 2H), 7.32 (d, J = 8.2 Hz, 2H), 7.10 (d, J = 8.0 Hz, 2H), 7.03–6.96

(m, 2H), 4.55–4.47 (m, 1H), 4.41–4.35 (m, 1H), 4.18 (d, J = 11.6 Hz, 1H), 3.12 (ddd, J = 11.6, 8.8, 5.2 Hz, 1H), 2.44 (s, 3H), 2.30 (s, 3H), 2.27–2.15 (m, 3H), 2.15–1.91 (m, 2H), 1.85–1.64 (m, 2H), 1.55–1.43 (m, 1H);

¹³ C NMR (100

MHz, CDCl ₃ ) δ 172.9, 145.1, 137.6, 135.9, 133.0, 129.6, 129.5, 128.6, 128.5,

62.9, 60.6, 51.7, 51.1, 33.2, 29.6, 26.8, 23.3, 21.7, 21.1; IR (CH

₂ Cl ₂ ) 2934,

1735, 1355, 1170, 1106, 970, 813, 666, 578, 548 cm

^-1

; MS (ESI) m/e (%) 454.3 ([M+Na]

⁺

, 100); HRMS (ESI) m/e calcd for C

₂₃

H

₂₆

NO

₃

NaSCl [M+Na]

⁺

454.1220, found 454.1221.

98

(3S*,3aR*,4R*,8aR*)-3-([1,1'-Biphenyl]-4-yl)-4-chloro-1-tosyloctahydrocyc lohepta[b]pyrrol-2(1H)-one (II-41e)

According to GP 2-2 using seven-membered ring 2-enynamide II-40e (0.148 g, 0.30 mmol), FeCl

3

(0.107 g, 0.66 mmol), and THF (1.2 mL). The mixture was stirred at 40

^o

C for 2 h. The crude mixture was purified via flash column chromatography over silica gel (ethyl acetate/hexanes = 1:10) to give

II-41e as a white solid (0.047 g, 0.10 mmol, 32%):

R

_f

= 0.30 (ethyl acetate/hexanes = 1:5); mp 203‒204

^o

C;

¹ H NMR (400 MHz, CDCl 3 ) δ 7.98 (d,

J = 8.4 Hz, 2H), 7.56–7.46 (m, 4H), 7.44–7.38 (m, 2H), 7.36–7.29 (m, 3H),

7.09–7.03 (m, 2H), 4.72–4.64 (m, 1H), 4.14–4.05 (m, 1H), 3.73 (d, J = 12.1 Hz, 1H), 3.21–3.11 (m, 1H), 2.44 (s, 3H), 2.39–2.29 (m, 1H), 2.25–2.14 (m, 1H), 2.08–1.75 (m, 4H), 1.74–1.58 (m, 2H);

¹³ C NMR (100 MHz, CDCl ₃ ) δ 172.0,

145.3, 140.8, 140.6, 135.8, 135.3, 129.6, 129.1, 128.7, 128.5, 127.5, 127.3, 127.1, 62.0, 61.3, 53.8, 53.4, 34.7, 31.1, 26.8, 24.8, 21.7; IR (CH

₂ Cl ₂ ) 2935,

1738, 1598, 1356, 1170, 1099, 964, 916, 733, 668, 588, 549 cm

^-1

; MS (ESI)

m/e (%) 516.5 ([M+Na] ⁺

, 100); HRMS (ESI) m/e calcd for C

₂₈

H

₂₉

NO

₃

SCl [M+H]

⁺

494.1557, found 494.1555.

99

(3S*,3aR*,4S*,8aR*)-3-([1,1'-Biphenyl]-4-yl)-4-chloro-1-tosyloctahydrocyc lohepta[b]pyrrol-2(1H)-one (II-41e')

According to GP 2-2 using seven-membered ring 2-enynamide II-40e (0.148 g, 0.30 mmol), FeCl

3

(0.107 g, 0.66 mmol), and THF (1.2 mL). The mixture was stirred at 40

^o

C for 2 h. The crude mixture was purified via flash column chromatography over silica gel (ethyl acetate/hexanes = 1:10) to give

II-41e' as a white solid (0.019 g, 0.04 mmol, 12%):

R

_f

= 0.30 (ethyl acetate/hexanes = 1:5); mp 172‒173

^o

C;

¹ H NMR (400 MHz, CDCl 3 ) δ 7.99 (d, J = 8.3 Hz, 2H), 7.57–7.48 (m, 4H), 7.46–7.38 (m, 2H), 7.37–7.31 (m, 3H),

7.19 (d, J = 8.2 Hz, 2H), 4.59–4.51 (m, 1H), 4.48–4.40 (m, 1H), 4.28 (d, J = 11.6 Hz, 1H), 3.07 (ddd, J = 11.6, 8.8, 5.5 Hz, 1H), 2.44 (s, 3H), 2.32–2.17 (m, 3H), 2.17–1.92 (m, 2H), 1.88–1.67 (m, 2H), 1.62–1.45 (m, 1H);

¹³ C NMR (100 MHz, CDCl ₃ ) δ 172.7, 145.2, 140.9, 140.6, 135.9, 135.1, 129.5, 129.1, 128.8,

128.6, 127.7, 127.4, 127.1, 63.0, 60.6, 51.8, 51.1, 33.2, 29.7, 26.8, 23.3, 21.7;

IR (CH ₂ Cl ₂ ) 2943, 1734, 1597, 1357, 1171, 1110, 970, 847, 734, 666, 576, 548

cm

^-1

; MS (ESI) m/e (%) 516.3 ([M+Na]

⁺

, 100); HRMS (ESI) m/e calcd for C

₂₈

H

₂₉

NO

₃

SCl [M+H]

⁺

494.1557, found 494.1558.

100

(3S*,3aR*,4R*,8aR*)-4-Chloro-3-(naphthalen-1-yl)-1-tosyloctahydrocycloh epta[b]pyrrol-2(1H)-one (II-41f)

According to GP 2-2 using seven-membered ring 2-enynamide II-40f (0.140 g, 0.30 mmol), FeCl

3

(0.107 g, 0.66 mmol), and THF (1.2 mL). The mixture was stirred at 40

^o

C for 3 h. The crude mixture was purified via flash column chromatography over silica gel (ethyl acetate/hexanes = 1:10) to give

II-41f as a white solid (0.031 g, 0.07 mmol, 22%):

R

_f

= 0.30 (ethyl acetate/hexanes = 1:5); mp 215‒216

^o

C;

¹ H NMR (400 MHz, CDCl 3 ) δ 8.26–

8.18 (m, 1H), 8.03 (d, J = 8.3 Hz, 2H), 7.87–7.79 (m, 2H), 7.53–7.45 (m, 2H), 7.41–7.34 (m, 3H), 7.33–7.28 (m, 1H), 4.78 (d, J = 9.3 Hz, 1H), 4.64–4.56 (m, 1H), 3.47–3.26 (m, 2H), 2.59–2.50 (m, 1H), 2.47 (s, 3H), 2.14–1.85 (m, 4H), 1.83–1.72 (m, 1H), 1.51–1.36 (m, 1H), 1.16–1.00 (m, 1H);

¹³ C NMR (100

MHz, CDCl ₃ ) δ 173.5, 145.4, 135.7, 134.0, 132.8, 131.7, 129.6, 129.1, 128.7,

128.6, 126.8, 126.1, 125.9, 124.9, 124.8, 64.5, 60.4, 51.1, 47.4, 38.8, 32.9, 28.8, 27.8, 21.7; IR (CH

₂ Cl ₂ ) 2934, 1733, 1598, 1358, 1173, 1108, 972, 734, 666,

577, 548 cm

^-1

; MS (ESI) m/e (%) 490.4 ([M+Na]

⁺

, 100); HRMS (ESI) m/e calcd for C

₂₆

H

₂₇

NO

₃

SCl [M+H]

⁺

468.1400, found 468.1403.

101

(3S*,3aR*,4R*,8aR*)-4-Chloro-3-(3-methoxyphenyl)-1-tosyloctahydrocycl ohepta[b]pyrrol-2(1H)-one (II-41g)

According to GP 2-2 using seven-membered ring 2-enynamide II-40g (0.134 g, 0.30 mmol), FeCl

3

(0.107 g, 0.66 mmol), and THF (1.2 mL). The mixture was stirred at 40

^o

C for 2 h. The crude mixture was purified via flash column chromatography over silica gel (ethyl acetate/hexanes = 1:7) to give

II-41g as a colorless oil (0.048 g, 0.11 mmol, 36%):

R

_f

= 0.20 (ethyl acetate/hexanes = 1:5);

¹ H NMR (400 MHz, CDCl 3 ) δ 7.97 (d, J = 8.2 Hz, 2H),

7.32 (d, J = 8.2 Hz, 2H), 7.22–7.15 (m, 1H), 6.83–6.75 (m, 1H), 6.61–6.55 (m, 1H), 6.52–6.46 (m, 1H), 4.70–4.61 (m, 1H), 4.11–4.03 (m, 1H), 3.72 (s, 3H), 3.65 (d, J = 12.1 Hz, 1H), 3.16–3.06 (m, 1H), 2.43 (s, 3H), 2.37–2.27 (m, 1H), 2.23–2.11 (m, 1H), 2.05–1.85 (m, 3H), 1.85–1.54 (m, 3H);

¹³ C NMR (100

MHz, CDCl ₃ ) δ 171.8, 159.7, 145.2, 137.8, 135.8, 129.8, 129.5, 128.5, 121.0,

114.6, 113.1, 61.9, 61.2, 55.1, 54.1, 53.3, 34.4, 31.2, 26.7, 24.6, 21.7; IR

(CH ₂ Cl ₂ ) 2936, 1738, 1600, 1359, 1173, 1106, 970, 910, 736, 667, 573, 548

cm

^-1

; MS (ESI) m/e (%) 470.4 ([M+Na]

⁺

, 100); HRMS (ESI) m/e calcd for C

₂₃

H

₂₇

NO

₄

SCl [M+H]

⁺

448.1349, found 448.1351.

102

(3S*,3aR*,4R*,8aR*)-4-Chloro-3-(4-methoxyphenyl)-1-tosyloctahydrocycl ohepta[b]pyrrol-2(1H)-one (II-41h)

According to GP 2-2 using seven-membered ring 2-enynamide II-40h (0.134 g, 0.30 mmol), FeCl

3

(0.107 g, 0.66 mmol), and THF (1.2 mL). The mixture was stirred at 40

^o

C for 2 h. The crude mixture was purified via flash column chromatography over silica gel (ethyl acetate/hexanes = 1:7) to give

II-41h as a colorless oil (0.045 g, 0.10 mmol, 33%): R _f

= 0.20 (ethyl acetate/hexanes = 1:5);

¹ H NMR (400 MHz, CDCl 3 ) δ 7.96 (d, J = 8.4 Hz, 2H),

7.32 (d, J = 8.2 Hz, 2H), 6.93–6.87 (m, 2H), 6.84–6.76 (m, 2H), 4.69–4.59 (m, 1H), 4.09–4.02 (m, 1H), 3.75 (s, 3H), 3.63 (d, J = 12.2 Hz, 1H), 3.11–3.00 (m, 1H), 2.43 (s, 3H), 2.35–2.26 (m, 1H), 2.21–2.11 (m, 1H), 2.05–1.75 (m, 4H), 1.72–1.53 (m, 2H);

¹³ C NMR (100 MHz, CDCl ₃ ) δ 172.3, 159.2, 145.2, 135.8,

129.7, 129.5, 128.5, 128.2, 114.2, 61.8, 61.2, 55.2, 53.4, 53.3, 34.5, 31.0, 26.8, 24.7, 21.7; IR (CH

₂ Cl ₂ ) 2934, 1738, 1614, 1516, 1354, 1172, 964, 827, 735,

667, 583, 550 cm

^-1

; MS (ESI) m/e (%) 470.2 ([M+Na]

⁺

, 100); HRMS (ESI)

m/e calcd for C 23

H

27

NO

4

SCl [M+H]

⁺

448.1349, found 448.1347.

103

3-((3S*,3aR*,4R*,8aR*)-4-Chloro-2-oxo-1-tosyldecahydrocyclohepta[b]pyr rol-3-yl)benzoate (II-41i)

According to GP 2-2 using seven-membered ring 2-enynamide II-40i (0.143 g, 0.30 mmol), FeCl

3

(0.107 g, 0.66 mmol), and THF (1.2 mL). The mixture was stirred at 40

^o

C for 3 h. The crude mixture was purified via flash column chromatography over silica gel (ethyl acetate/hexanes = 1:7) to give

II-41i as a colorless oil (0.053 g, 0.11 mmol, 37%):

R

_f

= 0.20 (ethyl acetate/hexanes = 1:5);

¹ H NMR (400 MHz, CDCl 3 ) δ 8.00–7.91 (m, 3H),

7.73–7.65 (m, 1H), 7.39–7.31 (m, 3H), 7.24–7.17 (m, 1H), 4.71–4.62 (m, 1H), 4.07–3.99 (m, 1H), 3.89 (s, 3H), 3.74 (d, J = 12.0 Hz, 1H), 3.21–3.11 (m, 1H), 2.44 (s, 3H), 2.39–2.29 (m, 1H), 2.25–2.13 (m, 1H), 2.07–1.81 (m, 4H), 1.71–

1.56 (m, 2H);

¹³ C NMR (100 MHz, CDCl ₃ ) δ 171.5, 166.5, 145.4, 137.0, 135.6,

133.3, 130.6, 130.0, 129.6, 129.1, 128.8, 128.5, 62.1, 61.7, 54.4, 53.4, 52.1, 35.9, 31.1, 27.4, 25.5, 21.7; IR (CH

₂ Cl ₂ ) 2947, 1738, 1597, 1360, 1204, 1112,

963, 815, 738, 667, 589, 550 cm

^-1

; MS (ESI) m/e (%) 498.5 ([M+Na]

⁺

, 100);

HRMS (ESI) m/e calcd for C ₂₄

H

₂₇

NO

₅

SCl [M+H]

⁺

476.1298, found 476.1306.

104

(3S*,3aR*,4R*,8aR*)-4-Chloro-1-tosyl-3-(3-(trifluoromethyl)phenyl)octahy drocyclohepta[b]pyrrol-2(1H)-one (II-41j)

According to GP 2-2 using seven-membered ring 2-enynamide II-40j (0.146 g, 0.30 mmol), FeCl

3

(0.107 g, 0.66 mmol), and THF (1.2 mL). The mixture was stirred at 40

^o

C for 3 h. The crude mixture was purified via flash column chromatography over silica gel (ethyl acetate/hexanes = 1:10) to give

II-41j as a colorless oil (0.034 g, 0.07 mmol, 23%):

R

_f

= 0.30 (ethyl acetate/hexanes = 1:5);

¹ H NMR (400 MHz, CDCl 3 ) δ 7.96 (d, J = 8.4 Hz, 2H),

7.53–7.48 (m, 1H), 7.42–7.37 (m, 1H), 7.34 (d, J = 8.1 Hz, 2H), 7.24–7.20 (m, 1H), 7.15–7.12 (m, 1H), 4.69–4.61 (m, 1H), 4.06–3.99 (m, 1H), 3.74 (d, J = 11.8 Hz, 1H), 3.14–3.05 (m, 1H), 2.44 (s, 3H), 2.38–2.29 (m, 1H), 2.23–2.14 (m, 1H), 2.06–1.80 (m, 4H), 1.71–1.57 (m, 2H);

¹³ C NMR (100 MHz, CDCl ₃ )

δ 171.3, 145.6, 137.9, 1.35.5, 132.3, 131.0 (q, J = 32.3 Hz), 129.6, 129.2, 128.4, 125.5 (q, J = 3.7 Hz), 124.7 (q, J = 3.6 Hz), 123.8 (q, J = 271 Hz), 62.1, 62.0, 54.6, 53.8, 36.5, 31.4, 27.7, 25.7, 21.7; IR (CH

₂ Cl ₂ ) 2934, 1738, 1598, 1329,

1178, 968, 814, 737, 702, 668, 550 cm

^-1

; MS (ESI) m/e (%) 508.1 ([M+Na]

⁺

, 100); HRMS (ESI) m/e calcd for C

₂₃

H

₂₃

NO

₃

F

₃

NaSCl [M+Na]

⁺

508.0937, found 508.0937.

105

(3S*,3aR*,4R*,8aR*)-4-Chloro-3-(4-chlorophenyl)-1-tosyloctahydrocycloh epta[b]pyrrol-2(1H)-one (II-41k)

According to GP 2-2 using seven-membered ring 2-enynamide II-40k (0.135 g, 0.30 mmol), FeCl

3

(0.107 g, 0.66 mmol), and THF (1.2 mL). The mixture was stirred at 40

^o

C for 4 h. The crude mixture was purified via flash column chromatography over silica gel (ethyl acetate/hexanes = 1:10) to give

II-41k as a white solid (0.037 g, 0.08 mmol, 27%):

R

_f

= 0.30 (ethyl acetate/hexanes = 1:5); mp 183‒184

^o

C;

¹ H NMR (400 MHz, CDCl 3 ) δ 7.96 (d, J = 8.4 Hz, 2H), 7.33 (d, J = 8.0 Hz, 2H), 7.26–7.22 (m, 2H), 6.93 (d, J = 8.5

Hz, 2H), 4.69–4.60 (m, 1H), 4.06–3.98 (m, 1H), 3.65 (d, J = 12.0 Hz, 1H), 3.11–3.02 (m, 1H), 2.44 (s, 3H), 2.36–2.26 (m, 1H), 2.21–2.11 (m, 1H), 2.05–

1.78 (m, 4H), 1.70–1.50 (m, 2H);

¹³ C NMR (100 MHz, CDCl ₃ ) δ 171.5, 145.4,

135.7, 135.1, 133.8, 130.1, 129.6, 128.9, 128.5, 62.0, 61.7, 53.9, 53.5, 35.7, 31.1, 27.3, 25.4, 21.7; IR (CH

₂ Cl ₂ ) 2936, 1736, 1357, 1170, 1093, 964, 911,

731, 666, 589, 547 cm

^-1

; MS (ESI) m/e (%) 474.1 ([M+Na]

⁺

, 100); HRMS

(ESI) m/e calcd for C ₂₂

H

₂₃

NO

₃

NaSCl

₂

[M+Na]

⁺

474.0673, found 474.0677.

106

(3S*,3aR*,4R*,8aR*)-4-Chloro-3-(thiophen-3-yl)-1-tosyloctahydrocyclohep ta[b]pyrrol-2(1H)-one (II-41l)

According to GP 2-2 using seven-membered ring 2-enynamide II-40l (0.127 g, 0.30 mmol), FeCl

3

(0.107 g, 0.66 mmol), and THF (1.2 mL). The mixture was stirred at 40

^o

C for 2 h. The crude mixture was purified via flash column chromatography over silica gel (ethyl acetate/hexanes = 1:10) to give

II-41l as a colorless oil (0.040 g, 0.10 mmol, 32%):

R

_f

= 0.30 (ethyl acetate/hexanes = 1:5);

¹ H NMR (400 MHz, CDCl 3 ) δ 7.96 (d, J = 8.3 Hz, 2H),

7.32 (d, J = 8.2 Hz, 2H), 7.29–7.24 (m, 1H), 7.05–7.00 (m, 1H), 6.78–6.73 (m, 1H), 4.69–4.61 (m, 1H), 4.13–4.07 (m, 1H), 3.85 (d, J = 12.2 Hz, 1H), 3.14–

3.03 (m, 1H), 2.44 (s, 3H), 2.36–2.26 (m, 1H), 2.21–2.11 (m, 1H), 2.06–1.83 (m, 3H), 1.83–1.53 (m, 3H);

¹³ C NMR (100 MHz, CDCl ₃ ) δ 171.3, 145.3,

135.7, 135.7, 129.6, 128.5, 126.6, 126.4, 123.8, 61.8, 61.1, 52.8, 49.0, 34.3, 31.0, 26.7, 24.6, 21.7; IR (CH

₂ Cl ₂ ) 3298, 2932, 1734, 1332, 1166, 813, 572

cm

^-1

; MS (ESI) m/e (%) 446.3 ([M+Na]

⁺

, 100); HRMS (ESI) m/e calcd for C

20

H

23

NO

3

S

2

Cl [M+H]

⁺

424.0808, found 424.0812.

107

4.6 Synthesis of Ynamide-tethered Furans.

N-(Furan-2-ylmethyl)-4-methyl-N-(phenylethynyl)benzenesulfonamide (III-37a)

According to GP 3-1 using (bromoethynyl)benzene (1.350 g, 7.50 mmol), toluene (29.4 mL), amide-tethered furan III-39 (1.255 g, 5.00 mmol), Cs

₂

CO

₃

(3.258 g, 10.00 mmol), CuI (0.210 g, 1.06 mmol), and DMEDA (0.420 g, 4.73 mmol). The mixture was stirred at 50

^o

C for 10 h. The crude mixture was purified via flash column chromatography over silica gel (ethyl acetate/hexanes

= 1:15) to give III-37a as a white solid (1.629 g, 4.64 mmol, 92%): R

_f

= 0.25 (ethyl acetate/hexanes = 1:10); mp 47‒48

^o

C;

¹ H NMR (400 MHz, CDCl ₃ ) δ

7.80 (d, J = 8.3 Hz, 2H), 7.32‒7.24 (m, 8H), 6.32‒6.28 (m, 2H), 4.65 (s, 2H), 2.44 (s, 3H);

¹³ C NMR (100 MHz, CDCl ₃ ) δ 147.9, 144.6, 143.1, 134.6, 131.2,

129.6, 128.2, 127.8, 127.7, 122.8, 110.5, 110.5, 82.1, 71.3, 48.3, 21.6; IR

(CH ₂ Cl ₂ ) 2925, 2240, 1598, 1443, 1367, 1170, 1007, 934, 814, 756, 574 cm ^-1

;

MS (ESI) m/e (%) 374.0 ([M+Na] ⁺

, 100); HRMS (ESI) m/e calcd for C

20

H

18

NO

3

S [M+H]

⁺

352.1007, found 352.1010.

108

N-(Furan-2-ylmethyl)-4-methyl-N-(p-tolylethynyl)benzenesulfonamide (III-37b)

According to GP 3-1 using 1-(bromoethynyl)-4-methylbenzene (0.243 g, 1.26 mmol), toluene (4.9 mL), amide-tethered furan III-39 (0.210 g, 0.84 mmol), Cs

2

CO

3

(0.545 g, 1.67 mmol), CuI (0.034 g, 0.18 mmol), and DMEDA (0.070 g, 0.79 mmol). The mixture was stirred at 50

^o

C for 10 h. The crude mixture was purified via flash column chromatography over silica gel (ethyl acetate/hexanes = 1:15) to give III-37b as a white solid (0.298 g, 0.81 mmol, 97%): R

_f

= 0.25 (ethyl acetate/hexanes = 1:10); mp 52‒53

^o

C;

¹ H NMR (400

MHz, CDCl ₃ ) δ 7.79 (d, J = 8.3 Hz, 2H), 7.31‒7.29 (m, 3H), 7.20‒7.18 (m,

2H), 7.08‒7.06 (m, 2H), 6.30‒6.27 (m, 2H), 4.64 (s, 2H), 2.43 (s, 3H), 2.32 (s, 3H);

¹³ C NMR (100 MHz, CDCl ₃ ) δ 148.0, 144.5, 143.0, 137.9, 134.5, 131.3,

129.5, 128.9, 127.8, 119.6, 110.5, 110.4, 81.3, 71.2, 48.3, 21.6, 21.4; IR

(CH ₂ Cl ₂ ) 2928, 2240, 1598, 1366, 1170, 1007, 934, 815, 718, 663, 573 cm ^-1

;

MS (ESI) m/e (%) 388.0 ([M+Na] ⁺

, 100); HRMS (ESI) m/e calcd for C

21

H

20

NO

3

S [M+H]

⁺

366.1164, found 366.1169.

109

N-([1,1'-Biphenyl]-4-ylethynyl)-N-(furan-2-ylmethyl)-4-methylbenzenesulf onamide (III-37c)

According to GP 3-1 using 4-(bromoethynyl)-1,1'-biphenyl (0.500 g, 1.95 mmol), toluene (7.6 mL), amide-tethered furan III-39 (0.0.326 g, 1.30 mmol), Cs

2

CO

3

(0.847 g, 2.60 mmol), CuI (0.053 g, 0.28 mmol), and DMEDA (0.108 g, 1.23 mmol). The mixture was stirred at 50

^o

C for 10 h. The crude mixture was purified via flash column chromatography over silica gel (ethyl acetate/hexanes = 1:15) to give III-37c as a white solid (0.484 g, 1.13 mmol, 87%): R

_f

= 0.25 (ethyl acetate/hexanes = 1:10); mp 117‒118

^o

C;

¹ H NMR (400

MHz, CDCl ₃ ) δ 7.81 (d, J = 8.3 Hz, 2H), 7.57‒7.55 (m, 2H), 7.51‒7.49 (m,

2H), 7.45‒7.41 (m, 2H), 7.37‒7.31 (m, 6H), 6.33‒6.29 (m, 2H), 4.67 (s, 2H), 2.44 (s, 3H);

¹³ C NMR (100 MHz, CDCl ₃ ) δ 147.9, 144.6, 143.1, 140.5, 140.3,

134.5, 131.6, 129.6, 128.8, 127.8, 127.5, 126.9, 126.8, 121.6, 110.6, 110.5, 82.7, 71.2, 48.3, 21.6; IR (CH

₂ Cl ₂ ) 3030, 2236, 1598, 1488, 1366, 1170, 1007, 934,

814, 764, 574 cm

^-1

; MS (ESI) m/e (%) 450.1 ([M+Na]

⁺

, 100); HRMS (ESI)

m/e calcd for C 26

H

21

NO

3

NaS [M+Na]

⁺

450.1140, found 450.1141.

110

N-(Furan-2-ylmethyl)-N-((4-methoxyphenyl)ethynyl)-4-methylbenzenesulf onamide (III-37d)

According to GP 3-1 using 1-(bromoethynyl)-4-methoxybenzene (0.409 g, 1.95 mmol), toluene (7.6 mL), amide-tethered furan III-39 (0.326 g, 1.30 mmol), Cs

2

CO

3

(0.847 g, 2.60 mmol), CuI (0.053 g, 0.28 mmol), and DMEDA (0.108 g, 1.23 mmol). The mixture was stirred at 50

^o

C for 10 h. The crude mixture was purified via flash column chromatography over silica gel (ethyl acetate/hexanes = 1:10) to give III-37d as a white solid (0.473 g, 1.23 mmol, 95%): R

_f

= 0.15 (ethyl acetate/hexanes = 1:10); mp 57‒58

^o

C;

¹ H NMR (400

MHz, CDCl ₃ ) δ 7.78 (d, J = 8.3 Hz, 2H), 7.31‒7.29 (m, 3H), 7.25‒7.22 (m,

2H), 6.81‒6.78 (m, 2H), 6.30‒6.26 (m, 2H), 4.63 (s, 2H), 3.78 (s, 3H), 2.43 (s, 3H);

¹³ C NMR (100 MHz, CDCl ₃ ) δ 159.4, 148.1, 144.5, 142.9, 134.6, 133.3,

129.5, 127.8, 114.7, 113.8, 110.4, 110.4, 80.6, 70.9, 55.3, 48.3, 21.6; IR

(CH ₂ Cl ₂ ) 2935, 2241, 1606, 1513, 1366, 1249, 1169, 1030, 933, 832, 717, 663,

573 cm

^-1

; MS (ESI) m/e (%) 404.5 ([M+Na]

⁺

, 100); HRMS (ESI) m/e calcd for C

21

H

20

NO

4

S [M+H]

⁺

382.1113, found 382.1113.

111

Methyl

4-((N-(furan-2-ylmethyl)-4-methylphenylsulfonamido)ethynyl)benzoate (III-37e)

According to GP 3-1 using methyl 4-(bromoethynyl)benzoate (0.464 g, 1.95 mmol), toluene (7.6 mL), amide-tethered furan III-39 (0.326 g, 1.30 mmol), Cs

2

CO

3

(0.847 g, 2.60 mmol), CuI (0.053 g, 0.28 mmol), and DMEDA (0.108 g, 1.23 mmol). The mixture was stirred at 50

^o

C for 9 h. The crude mixture was purified via flash column chromatography over silica gel (ethyl acetate/hexanes = 1:5) to give III-37e as a white solid (0.407 g, 0.99 mmol, 77%): R

_f

= 0.13 (ethyl acetate/hexanes = 1:5); mp 104‒105

^o

C;

¹ H NMR (400

MHz, CDCl ₃ ) δ 7.93 (d, J = 8.2 Hz, 2H), 7.79 (d, J = 8.3 Hz, 2H), 7.34‒7.28

(m, 5H), 6.34‒6.28 (m, 2H), 4.67 (s, 2H), 3.90 (s, 3H), 2.44 (s, 3H);

¹³ C NMR

(100 MHz, CDCl ₃ ) δ 147.6, 144.8, 143.2, 134.4, 130.4, 129.7, 129.3, 128.6,

127.8, 127.7, 110.7, 110.5, 85.4, 71.4, 52.1, 48.1, 21.6; IR (CH

₂ Cl ₂ ) 2952,

2234, 1722, 1606, 1436, 1368, 1276, 1169, 1118, 1005, 933, 768, 577 cm

^-1

; MS

(ESI) m/e (%) 432.4 ([M+Na] ⁺

, 100); HRMS (ESI) m/e calcd for C

₂₂

H

₂₀

NO

₅

S [M+H]

⁺

410.1062, found 410.1060.

112

N-(Furan-2-ylmethyl)-4-methyl-N-((3-nitrophenyl)ethynyl)benzenesulfona mide (III-37f)

According to GP 3-1 using 1-(bromoethynyl)-3-nitrobenzene (0.439 g, 1.95 mmol), toluene (7.6 mL), amide-tethered furan III-39 (0.326 g, 1.30 mmol), Cs

2

CO

3

(0.847 g, 2.60 mmol), CuI (0.053 g, 0.28 mmol), and DMEDA (0.108 g, 1.23 mmol). The mixture was stirred at 50

^o

C for 9 h. The crude mixture was purified via flash column chromatography over silica gel (ethyl acetate/hexanes = 1:5) to give III-37f as a white solid (0.397 g, 0.99 mmol, 77%): R

_f

= 0.13 (ethyl acetate/hexanes = 1:5); mp 68‒69

^o

C;

¹ H NMR (400

MHz, CDCl ₃ ) δ 8.10‒8.04 (m, 2H), 7.82‒7.77 (m, 2H), 7.59‒7.53 (m, 1H),

7.44 (t, J = 7.9 Hz, 1H), 7.38‒7.32 (m, 3H), 6.36‒6.31 (m, 2H), 4.68 (s, 2H), 2.45 (s, 3H);

¹³ C NMR (100 MHz, CDCl ₃ ) δ 148.0, 147.5, 145.0, 143.3, 136.4,

134.3, 129.7, 129.2, 127.7, 125.4, 124.7, 122.1, 110.8, 110.5, 84.8, 69.8, 48.1, 21.6; IR (CH

₂ Cl ₂ ) 3085, 2238, 1704, 1598, 1532, 1353, 1299, 1170, 1007, 942,

812, 736, 666, 576 cm

^-1

; MS (ESI) m/e (%) 419.3 ([M+Na]

⁺

, 100); HRMS

(ESI) m/e calcd for C ₂₀

H

₁₇

N

₂

O

₅

S [M+H]

⁺

397.0858, found 397.0859.

113

N-((4-Bromophenyl)ethynyl)-N-(furan-2-ylmethyl)-4-methylbenzenesulfon amide (III-37g)

According to GP 3-1 using 1-(bromoethynyl)-4-bromobenzene (0.503 g, 1.95 mmol), toluene (7.6 mL), amide-tethered furan III-39 (0.326 g, 1.30 mmol), Cs

2

CO

3

(0.847 g, 2.60 mmol), CuI (0.053 g, 0.28 mmol), and DMEDA (0.108 g, 1.23 mmol). The mixture was stirred at 50

^o

C for 9 h. The crude mixture was purified via flash column chromatography over silica gel (ethyl acetate/hexanes = 1:15) to give III-37g as a white solid (0.434 g, 1.02 mmol,

According to GP 3-1 using 1-(bromoethynyl)-4-bromobenzene (0.503 g, 1.95 mmol), toluene (7.6 mL), amide-tethered furan III-39 (0.326 g, 1.30 mmol), Cs

2

CO

3

(0.847 g, 2.60 mmol), CuI (0.053 g, 0.28 mmol), and DMEDA (0.108 g, 1.23 mmol). The mixture was stirred at 50

^o

C for 9 h. The crude mixture was purified via flash column chromatography over silica gel (ethyl acetate/hexanes = 1:15) to give III-37g as a white solid (0.434 g, 1.02 mmol,

在文檔中 路易斯酸輔佐七員環2-烯炔醯胺及呋喃炔醯胺化合物的環化反應：稠雙環γ-內醯胺與吡咯衍生物的合成 (頁 80-200)