Experiments

Synthesis of N-((5-Bromofuran-2-yl)methyl)-4-methylbenzenesulfonamide (II-37 ).

Scheme S8

To an ice cooled solution of 5-bromofuran-2-carbaldehyde (II-40) (3.500 g, 20.00 mmol) in MeOH (100.0 mL) was added NaBH₄ (0.756 g, 20.00 mmol) in small portions. The reaction mixture was warmed to room temperature and stirred for 1 h. The solvent was removed under reduced pressure. The residue was dissolved in DCM (100 mL) and washed subsequently with water (50 mL), brine (50 mL), and dried over MgSO₄, and concentrated under reduced pressure to give (5-bromofuran-2-yl)methanol (II-39) (3.522 g, 19.9 mmol, 99%) as a colorless oil.

To a flame-dried two-neck-flask were added triphenylphosphine (PPh₃, 6.295 g, 24.00 mmol), diisopropyl azodicarboxylate (DIAD, 4.8 mL, 24.00 mmol), NHTs(Boc) (5.426 g, 20.00 mmol), and anhydrous THF (60 mL). The mixture was warmed to room temperature and stirred for 0.5 h. The solution of

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(5-bromofuran-2-yl)methanol (II-39) (3.522 g, 19.9 mmol) in 40 mL THF was added to the flask. The reaction was stirred for an additional 1 h. The solvent was removed under reduced pressure. The residue was purified via flash column chromatography (silica gel, EtOAc/hexanes 1:15) to afford tert-butyl ((5-bromofuran-2-yl)methyl)(tosyl)carbamate (II-38) as a brown oil ( 7.573 g, 17.60 mmol, 88%).

The tert-butyl ((5-bromofuran-2-yl)methyl)(tosyl)carbamate (II-38) (7.573 g, 17.60 mmol) was dissolved in MeOH (176.0 mL). The solution was added K₂CO₃ (17.026 g, 123.2 mmol). The reaction mixture was stirred at 50 ^oC for 8 hours. The solvent was removed under reduced pressure and the reaction was quenched with HCl(aq) and diluted with CH₂Cl₂. The residue was extracted with CH₂Cl₂ (3 × 60 mL), dried over MgSO₄, and concentrated under reduced pressure to give the residue. The residue was purified via flash column chromatography over silica gel (EtOAc/hexanes 1:2) to give

N-((5-bromofuran-2-yl)methyl)-4-methylbenzenesulfonamide (II-37) as a

white solid (3.169 g, 9.60 mmol, 55%) (Scheme S1).

GP 2-1: Synthesis of 4-Methyl-N-((5-arylfuran-2-yl)methyl)benzene sulfonamide II-36 .

Scheme S2

Example for the Synthesis of II-36 . The appropriate arylboronic acid

(0.6078 g, 4.00 mmol) and Pd(PPh₃)₄ (0.116 g, 0.10 mmol) were added to a

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solution of

N-((5-Bromofuran-2-yl)methyl)-4-methylbenzenesulfonamide (II-37) (0.660 g, 2.00 mmol) in a 1:1 mixture of THF (6.0 mL) and 1 M

KOH_(aq) (6.0 mL). The reaction mixture was stirred under nitrogen atmosphere for 20 h at 65 ^oC, poured into water (40.0 mL), extracted with EtOAc (3 × 60 mL). The combined organic layer was washed with brine and dried over MgSO₄, and concentrated to give the residue. The residue was purified via flash column chromatography over silica gel (EtOAc/hexanes 1:2) to give

N-((5-(3-methoxyphenyl)furan-2-yl)methyl)-4-methylbenzenesulfonamide (II-36) as a white solid (0.686 g, 1.92 mmol, 96%) (Scheme S2).

GP 2-2: Synthesis of tert-Butyl ((5-(arylethynyl)furan-2-yl)methyl)(tosyl) carbamate II-43 .

Scheme S3

Example for the Synthesis of II-43. To a dry and nitrogen-flushed two-neck-flask, equipped with a magnetic stirring bar and a septum, were charged with Pd(PPh₃)₄ (0.116 g, 0.1 mmol), CuI (0.048 g, 0.25 mmol), Cs₂CO₃ (1.157 g, 6 mmol), tert-butyl ((5-bromofuran-2-yl)methyl)(tosyl) carbamate (II-38) (2.152 g, 5.00 mmol), acetonitrile (25.0 mL). The reaction mixture was kept in dark, stirred at room temperature for 30 min and then were added ethynylbenzene (II-45) (0.664 g, 6.50 mmol). The reaction stirred at 60

oC until starting material was used up which can be detected on TLC. Upon

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back to room temperature, the reaction mixture was filtered and concentrated.

The residue was purified by flash column chromatography (silica gel, EtOAc/hexanes 1:30) yielding II-43 (0.902 g, 2.00 mmol, 40%) (Scheme S3).

GP 2-3: Synthesis of N-((5-(Arylethynyl)furan-2-yl)methyl)-4-methyl benzenesulfonamide II-42.

Scheme S4

tert-Butyl ((5-(phenylethynyl)furan-2-yl)methyl)(tosyl)carbamate (II-43)

(0.902 g, 2.00 mmol) was dissolved in MeOH (20.0 mL). The solution was added K₂CO₃ (1.935 g, 14.0 mmol). The reaction mixture was stirred at 50 ^oC for 8 hours. The solvent was removed under reduced pressure and the reaction was quenched with HCl_(aq) and diluted with CH₂Cl₂. The residue was extracted with CH₂Cl₂ (3 × 60 mL), dried over MgSO₄, and concentrated under reduced pressure to give the residue. The residue was purified via flash column chromatography over silica gel (EtOAc/hexanes 1:1) to give 4-methyl-N-((5-(phenylethynyl)furan-2-yl)methyl)benzenesulfonamide (II-42) as a white solid (0.210 g, 1.2 mmol, 60%) (Scheme S4).

GP 2-4: Synthesis of Methyl 3-((5-(((4-methylphenyl)sulfonamido)methyl) furan-2-yl)ethynyl)benzoate II-42i.

Scheme S5

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To an ice cooled solution of methyl 3-((5-(((N-(tert-butoxycarbonyl) -4-methylphenyl)sulfonamido)methyl)furan-2-yl)ethynyl)benzoate (II-43i) (1.554 g, 3.05 mmol) in DCM (30.5 mL) was added trifluoroacetic acid (TFA, 4.7 mL, 61.0 mmol). The mixture was warmed to room temperature and stirred for 2.0 h. Saturated NaHCO_3(aq) was added to the reaction mixture stirring vigorously. The aqueous layer was extracted with DCM (30.0 mL × 3). The organic portion was washed with brine (30.0 mL × 3), dried over anhydrous MgSO₄, and finally evaporated under reduced pressure to give the crude product. The crude mixture was purified via flash column chromatography over silica gel (EtOAc/hexanes 1:4) to give methyl 3-((5-(((4-methylphenyl) sulfonamido)methyl)furan-2-yl)ethynyl)benzoate (II-42i) as a white solid (0.573 g, 1.40 mmol, 46%) (Scheme S4).

GP 2-5: General Experimental Procedure for the Preparation of Ynamide-Tethered Furan II-47.

Scheme S6

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Example for the Synthesis of II-47. To a dry and nitrogen-flushed

two-neck-flask, equipped with a magnetic stirring bar and a septum, were charged with (bromoethynyl)benzene II-36 (0.272 g, 1.50 mmol), toluene (6.0 mL), N-((5-(3-methox yphen yl)furan -2-yl)meth yl)-4-methylbenzene sulfonamide (II-46a) (0.3574 g, 1.00 mmol), and Cs₂CO₃ (0.652 g, 2.00 mmol).

The reaction mixture was stirred at room temperature for 5 min and then were added CuI (0.040 g, 0.21 mmol) and DMEDA (0.084 g, 0.95 mmol). The reaction was stirred at 50 ^oC until no trace of starting material can be detected on TLC. Upon cooling to room temperature, the reaction mixture was filtered and concentrated. The residue was purified by flash column chromatography (silica gel, EtOAc/hexanes 1:25) yielding II-47 (0.366 g, 0.8 mmol, 80%) (Scheme S6).

GP 2-6: General Experimental Procedure for the AuCl

₃

-Catalyzed Synthesis of (Z)-1-Aryl-3-(1H-pyrrol-3-yl)prop-2-en-1-one II-48 .

Scheme S7

Example for the Synthesis of II-48. A solution of AuCl

₃ (0.0038 g, 0.0125 mmol) in toluene (1.0 mL) in a dry and nitrogen-flushed two-neck-flask equipped with a stirring bar and capped with a rubber septum at room temperature was evacuated (oil pump) and filled with nitrogen three times. The

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solution were added to a solution of N-((5-(3-methoxyphenyl)furan-2-yl) methyl)-4-methyl-N-(phenylethynyl)benzenesulfonamide (II-47) (0.1144 g, 0.25 mmol) in toluene (1.5 mL). After starting material had been consumed (monitored by TLC), the reaction mixture was filtered through a pad of Celite/silica gel and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, EtOAc/hexanes 1:27) yielding II-48 (0.080 g, 0.16 mmol, 70%) as a yellow oil (Scheme S7).

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3.3 Synthesis of N-((5-(Aryl)furan-2-yl)methyl)-4-methylbenzene sulfonamide II-36.

4-Methyl-N-((5-(p-tolyl)furan-2-yl)methyl)benzenesulfonamide (II-36a)

According to GP 2-1, II-37 (0.660 g, 2.00 mmol), THF (6.0 mL), KOH_(aq) (6.0 mL), p-tolylboronic acid (0.5443 g, 4.00 mmol), Pd(PPh₃)₄ (0.1156 g, 0.10 mmol) were employed. The mixture was stirred at 65 ℃ for 19 h. The crude mixture was purified via flash column chromatography over silica gel (ethyl acetate/hexanes = 1:3) to give II-36a as a white solid (0.423 g, 1.24 mmol, 62%) : R_f 0.18 (ethyl acetate /hexanes = 1:3), m.p. 161－162 ^oC.

1

H NMR (400 MHz, CDCl

₃): δ 7.73 – 7.68 (m, 2H), 7.39 – 7.34 (m, 2H), 7.21 (d, J = 8.1 Hz, 2H), 7.14 (d, J = 8.0 Hz, 2H), 6.37 (d, J = 3.3 Hz, 1H), 6.14 (d,

J = 3.2 Hz, 1H), 4.91 (s, 1H), 4.24 (s, 2H), 2.35 (s, 3H), 2.31 (s, 3H) ppm.

13

C NMR (100 MHz, CDCl

₃): δ 154.2, 148.5, 143.4, 137.4, 137.0, 129.6, 129.2, 127.6, 127.0, 123.6, 110.3, 104.7, 40.3, 21.4, 21.2 ppm.

IR (CH

₂Cl₂): ν 3301, 2363, 1620, 1436, 1316, 1159, 1064, 795, 658, 560 cm^-1.

MS (ESI) m/e (%) 364.3 ([M+Na]

⁺, 100).

HRMS (ESI) m/e calcd for C

₁₉H₁₉NO₃NaS [M+Na]⁺ 364.0983, found 364.0984.

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N-((5-(3-Methoxyphenyl)furan-2-yl)methyl)-4-methylbenzenesulfonamide (II-36b)

According to GP 2-1, II-37 (0.660 g, 2.00 mmol), THF (6.0 mL), KOH_(aq) (6.0 mL), (3-methoxyphenyl)boronic acid (0.6078 g, 4.00 mmol), Pd(PPh₃)₄ (0.1156 g, 0.10 mmol) were employed. The mixture was stirred at 65 ℃ for 20 h. The crude mixture was purified via flash column chromatography over silica gel (ethyl acetate/hexanes = 1:2) to give II-36b as a white solid (0.684 g, 1.91 mmol, 96%) : R_f 0.23 (ethyl acetate /hexanes = 1:3), m.p. 98－99 ^oC.

1

H NMR (400 MHz, CDCl

₃): δ 7.69 (d, J = 8.1 Hz, 2H), 7.26 (t, J = 8.0 Hz, 1H), 7.16 (d, J = 7.8 Hz, 2H), 7.06 (d, J = 7.8 Hz, 1H), 7.02 – 7.00 (m, 1H), 6.78 (dd, J = 8.2, 2.4 Hz, 1H), 6.40 (d, J = 3.3 Hz, 1H), 6.15 (d, J = 3.2 Hz, 1H), 5.32 – 5.20 (m, 1H), 4.22 (d, J = 6.1 Hz, 2H) ppm.

13

C NMR (100 MHz, CDCl

₃): δ 159.7, 153.6, 149.1, 143.3, 136.8, 131.5, 129.5, 129.4, 126.9, 116.2, 113.0, 110.3, 109.1, 105.8, 77.3, 77.0, 76.7, 55.2, 41.2, 21.2 ppm.

IR (CH

₂Cl₂): ν 3286, 2364, 1605, 1430, 1317, 1219, 1155, 1048, 810, 663, 545 cm^-1.

MS (ESI) m/e (%) 380.2 ([M+Na]

⁺, 100).

HRMS (ESI) m/e calcd for C

₁₉H₁₉NO₄NaS [M+Na]⁺ 380.0932, found 380.0934.

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N-((5-(4-Methoxyphenyl)furan-2-yl)methyl)-4-methylbenzenesulfonamide (II-36c)

According to GP 2-1, II-37 (0.660 g, 2.00 mmol), THF (6.0 mL), KOH_(aq) (6.0 mL), (4-methoxyphenyl)boronic acid (0.6078 g, 4.00 mmol), Pd(PPh₃)₄ (0.1156 g, 0.10 mmol) were employed. The mixture was stirred at 65 ℃ for 24 h. The crude mixture was purified via flash column chromatography over silica gel (ethyl acetate/hexanes = 1:2) to give II-36c as a white solid (0.608 g, 1.70 mmol, 85%) : R_f 0.18 (ethyl acetate /hexanes = 1:3), m.p. 140－141 ^oC.

1

H NMR (400 MHz, CDCl

₃): δ 7.73 – 7.69 (m, 2H), 7.43 – 7.38 (m, 2H), 7.22 (d, J = 8.1 Hz, 2H), 6.91 – 6.85 (m, 2H), 6.30 (d, J = 3.4 Hz, 1H), 6.14 (d, J = 3.4 Hz, 1H), 4.80 (s, 1H), 4.24 (d, J = 5.4 Hz, 2H), 3.83 (s, 3H), 2.33 (s, 3H) ppm.

13

C NMR (100 MHz, CDCl

₃): δ 159.2, 154.1, 148.2, 143.4, 137.0, 130.0, 127.1, 125.1, 123.4, 114.0, 110.4, 103.9, 55.3, 40.4, 21.4 ppm.

IR (CH

₂Cl₂): ν 3297, 2363, 1601, 1318, 1255, 1157, 1032, 787, 659, 546 cm^-1.

MS (ESI) m/e (%) 380.4 ([M+Na]

⁺, 100).

HRMS (ESI) m/e calcd for C

₁₉H₁₉NO₄NaS [M+Na]⁺ 380.0932, found 380.0929.

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4-Methyl-N-((5-(4-nitrophenyl)furan-2-yl)methyl)benzenesulfonamide (II-36d)

According to GP 2-1, II-37 (0.660 g, 2.00 mmol), THF (6.0 mL), KOH_(aq) (6.0 mL), (4-nitrophenyl)boronic acid (0.6660 g, 4.00 mmol), Pd(PPh₃)₄ (0.1156 g, 0.10 mmol) were employed. The mixture was stirred at 65 ℃ for 11 h. The crude mixture was purified via flash column chromatography over silica gel (ethyl acetate/hexanes = 1:1) to give II-36d as a orange solid (0.383 g, 1.02 mmol, 51%) : R_f 0.10 (ethyl acetate /hexanes = 1:3), m.p. 186－187 ^oC.

1

H NMR (400 MHz, CDCl

₃): δ 8.24 – 8.18 (m, 2H), 7.73 (d, J = 8.2 Hz, 2H), 7.64 – 7.58 (m, 2H), 7.24 (d, J = 8.1 Hz, 2H), 6.70 (d, J = 3.4 Hz, 1H), 6.29 (d,

J = 3.4 Hz, 1H), 4.94 (m, 1H), 4.29 (d, J = 6.2 Hz, 2H), 2.33 (s, 3H) ppm.

13

C NMR (100 MHz, CDCl

₃): δ 151.6, 151.5, 146.5, 143.6, 136.9, 135.8, 129.7, 127.1, 124.2, 123.8, 111.1, 109.6, 40.2, 21.4 ppm.

IR (CH

₂Cl₂): ν 3301, 2363, 1620, 1436, 1316, 1159, 1064, 795, 658, 560 cm^-1.

MS (ESI) m/e (%) 371.3 ([M－H]

^－, 100).

HRMS (ESI) m/e calcd for C

₁₈H₁₅N₂O₅S [M－H]^－ 371.0702, found 371.0703.

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N-((5-(4-Cyanophenyl)furan-2-yl)methyl)-4-methylbenzenesulfonamide (II-36e)

According to GP 2-1, II-37 (0.660 g, 2.00 mmol), THF (6.0 mL), KOH_(aq) (6.0 mL), (4-cyanophenyl)boronic acid (0.5878 g, 4.00 mmol), Pd(PPh₃)₄ (0.1156 g, 0.10 mmol) were employed. The mixture was stirred at 65 ℃ for 20 h. The crude mixture was purified via flash column chromatography over silica gel (ethyl acetate/hexanes = 1:2) to give II-36e as a yellow solid (0.486 g, 1.38 mmol, 69%) : R_f 0.10 (ethyl acetate /hexanes = 1:3), m.p. 182－183 ^oC.

1

H NMR (400 MHz, CDCl

₃): δ 7.72 (d, J = 8.3 Hz, 2H), 7.65 – 7.59 (m, 2H), 7.59 – 7.53 (m, 2H), 7.22 (d, J = 8.1 Hz, 2H), 6.62 (d, J = 3.4 Hz, 1H), 6.26 (d,

J = 3.3 Hz, 1H), 5.03 – 4.96 (m, 1H), 4.27 (d, J = 6.2 Hz, 2H), 2.32 (s, 3H)

ppm.

13

C NMR (100 MHz, CDCl

₃): δ 151.9, 151.0, 143.6, 136.4, 134.0, 132.5, 129.6, 127.0, 123.8, 118.8, 110.9, 110.5, 108.7, 40.2, 21.4 ppm.

IR (CH

₂Cl₂): ν 3301, 2363, 1620, 1436, 1316, 1159, 1064, 795, 658, 560 cm^-1.

MS (ESI) m/e (%) 351.3 ([M－H]

^－, 100).

HRMS (ESI) m/e calcd for C

₁₉H₁₅N₂O₃S [M－H]^－ 351.0803, found 351.0805.

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3.4 Synthesis of tert-Butyl ((5-(arylethynyl)furan-2-yl)methyl)(tosyl)

在文檔中 三氯化金輔佐C-2炔醯胺呋喃化合物的分子內環化反應：吡咯衍生物的合成 (頁 53-65)