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Typical Procedure for Iodolactonisation.
Under a N2 atmosphere, to a solution of 1-allyl-1H-indole-2-carboxylic acid (3a, 1.49 g, 7.4 mmol) in anhyd CH2Cl2 (90 mL), was added at -20 °C, 2,6-lutidine (1.30 mL, 11.1 mmol, 1.5 equiv) and NIS (3.83 g, 17.0 mmol, 2.3 equiv). The solution was stirred at -20 °C for 3.5 h. The reaction mixture was extracted with CH2Cl2 (2 × 20 mL). The organic phase was washed with 1 M HCl solution (10 mL), sat. aq solution of Na2S2O3 (2 × 30 mL), brine solution (2 × 30 mL), and sat. aq solution of NaHCO3. The organic phases were combined, dried over Na2SO4 and evaporated in vacuo. The crude solid was purified by recrystallisation from CH2Cl2 to afford 4a (2.73 g, 81%) as a white solid; mp 169 °C (dec., CH2Cl2). IR (KBr): 3020, 2950, 1710, 1100, 750 cm-1. 1H NMR (300 MHz, CDCl3): δ = 3.42 (dd, 1 H, J = 8.7, 10.6 Hz, CH2I), 3.59 (dd, 1 H, J = 4.4, 10.6 Hz, CH2I), 4.27 (dd, 1 H, J = 9.0, 12.8 Hz, NCH2), 4.74 (dd, 1 H, J = 3.3, 12.8 Hz, NCH2), 4.80-4.89 (m, 1 H, CH), 7.31 (t, 1 H, J = 8.0 Hz, Har), 7.36 (d, 1 H, J = 8.0 Hz, Har), 7.50 (t, 1 H, J = 8.0 Hz, Har), 7.62 (d, 1 H, J = 8.0 Hz, Har). 13C NMR (75 MHz, CDCl3): δ = 1.1 (CH2I), 44.9 (NCH2), 68.9 (C), 76.2 (CH), 110.4 (CH), 121.9 (C), 122.7 (CH), 124.2 (CH), 127.8 (CH), 131.1 (C), 136.8 (C), 157.4 (CO). ESI-MS:
m/z = 454 [M + H]+. Anal. Calcd for C12H9I2NO2: C, 31.82; H, 2.00; N, 3.09. Found: C, 32.11; H, 2.13; N, 2.95.
9
Typical Procedure for Lactam Formation.
A solution of iodolactone 4a (3.60 g, 7.95 mmol) in anhyd MeOH (60 mL) and anhyd THF (30 mL) was added dropwise over a period of 20 min to an ice-cold sat. NH3 in MeOH solution (30 mL). The reaction mixture was allowed to warm up to r.t. for 48 h. The solvents were then removed by evaporation and the crude residue was purified by recrystallisation from EtOAc-EtOH to afford 5a (1.75 g, 64%) as a white solid. The filtrate was then purified by flash chromatography on silica gel (CH2Cl2-MeOH, 94:6) to give 0.11 g of 5a (overall yield 68%) as a white solid; mp 199 °C (dec., EtOAc-EtOH). IR (KBr): 3410, 3320-3200, 3060, 2920, 1635, 1515, 1090, 745 cm-1. 1H NMR (300 MHz, DMSO-d
6): δ = 2.73-2.80 (m, 1 H, CH2NH), 3.15-3.21 (m, 1 H, CH2NH), 4.18-4.29 (m, 2 H, NCH2 and CH), 4.43-4.49 (m, 1 H, NCH2), 5.38 (d, 1 H, J = 3.4 Hz, OH), 7.19 (t, 1 H, J = 7.9 Hz, Har), 7.35 (t, 1 H, J = 7.9 Hz, Har), 7.39 (d, 1 H, J = 7.9 Hz, Har), 7.58 (d, 1 H, J = 7.9 Hz, Har), 8.30 (t, 1 H, J = 5.5 Hz, NH). 13C NMR (75 MHz, DMSO-d
6): δ = 45.3 (CH2), 48.7 (CH2), 61.3 (CI), 69.5 (CH), 111.0 (CH), 120.8 (CH), 121.7 (CH), 124.6 (CH), 129.2 (C), 133.4 (C), 137.2 (C), 164.0 (CO). ESI-MS: m/z = 343 [M + H]+. Anal. Calcd for C12H11IN2O2: C, 42.13; H, 3.24; N, 8.19. Found: C, 41.87; H, 3.12; N, 8.05.
10a
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Physical Data of Compound 6.
Mp >210 °C (washing EtOAc). IR (KBr): 3420, 3310-3250, 3070, 2980, 1640, 1550, 1490, 1085, 750, 700 cm-1. 1H NMR (300 MHz, DMSO-d
6): δ = 2.82-2.91 (m, 1 H, CH2NH), 3.20-3.30 (m, 1 H, CH2NH), 4.25-4.30 (m, 2 H, NCH2 and CH), 4.42-4.48 (m, 1 H, NCH2), 5.38 (d, 1 H, J = 3.4 Hz, OH), 7.12 (t, 1 H, J = 7.5 Hz, Har), 7.29-7.64 (m, 8 H, Har), 8.25 (t, 1 H, J = 5.9 Hz, NH). 13C NMR (75 MHz, DMSO-d
6): δ = 45.3 (CH2), 47.9 (CH2), 69.6 (CH), 110.5 (CH), 118.4 (C), 119.9 (CH), 120.3 (CH), 123.8 (CH), 125.4 (C), 126.4 (CH), 128.1 (2 CH), 129.7 (2 CH), 129.9 (C), 133.7 (C), 136.3 (C), 164.8 (CO). ESI-MS: m/z = 293 [M + H]+. Anal. Calcd for C18H16N2O2: C, 73.96; H, 5.52; N, 9.58. Found: C, 74.33; H, 5.67; N, 9.63.
12
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