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1 New address: S. T. Hilton, Chemistry Department, Christopher Ingold Laboratories, University College London, 20 Gordon Street, London, WC1H 0AJ, UK.
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Representative Procedure: (2-
t
-Butylcarbamoyl-1
H
-indol-3-yl)-acetic Acid Methyl Ester (9)
: Boron trifluoride diethyl etherate (7.2 mL, 8.1 g, 57.5 mmol) was added to a stirred solution of indole-3-acetic acid methyl ester (8, 5.4 g, 28.8 mmol) and freshly distilled t-butyl isocyanate (4.9 mL, 4.3 g, 43.1 mmol) in CH2Cl2 (40 mL) at 0 °C. The reaction was allowed to stir for 18 h whereupon organic solvent was removed under reduced pressure and the residue taken up in CH2Cl2 (100 mL) and washed with a solution of sat. NH4Cl (100 mL). The aqueous phase was extracted with CH2Cl2 (2 × 100 mL) and the combined organic extracts washed with brine (200 mL), dried (MgSO4), filtered and organic solvent removed under reduced pressure. The crude product was purified by flash column chromatography (3:1, hexane-EtOAc) to give amide 9 as colourless crystalline needles (8.00 g, 97%); mp 159.5-160.5 °C; R
f
= 0.31 (3:1, hexane-EtOAc); (m/z calcd for C16H20N2O3 [M+]: 288.1474. Found: 288.1473 [M+]). IR: νmax = 3273.1 (NH), 1720.1 (CO2CH3), 1638.0 (CONHt-Bu) cm-1. 1H NMR: (300 MHz, CDCl3): δ = 1.91 [9 H, s, C(CH
3)3], 3.75 (3 H, s, OCH
3), 3.98 (2 H, s, CH
2CO2CH3), 7.17 (1 H, td, J = 8.0 and 1.0 Hz, C-5H), 7.29 (1 H, td, J = 8.0 and 1.0 Hz, C-6H), 7.53 (1 H, d, J = 8.0 Hz, C-7H), 7.70 (1 H, d, J = 8.0 Hz, C-4H), 8.13 (1 H, br s, NH), 10.68 (1 H, br s, CONH). 13C NMR (75 MHz, CDCl3): δ = 29.04 [C(CH3)3], 31.05 (CH2CO2CH3), 52.17 [C(CH3)3], 52.68 (CO2
CH3), 106.86 (C-3), 112.27 (C-7), 119.53 (Ar-C-H), 120.13 (Ar-C-H), 124.15 (Ar-C-H), 127.76 (quaternary C), 131.32 (quaternary C), 135.36 (C-7a), 161.89 (CONH), 173.80 (CO2CH3). MS: m/z (%) = 288.15 (87.6) [M+], 215.04 (95.4), 200.05 (92.1), 188.07 (56.1), 183.03 (62.1), 156.04 (89.5), 128.05 (100.0), 58.16 (67.4).
19
Representative Procedure: (2-Cyano-1
H
-indol-3-yl)-acetic Acid Methyl Ester (
10): A solution of ester 9 (48.90 g, 0.20 mol) and phosphorus oxychloride (50.0 mL, 82.30 g, 0.54 mol) in benzene (300 mL) was heated under reflux for 7 h. Organic solvent was removed under reduced pressure and the residue partitioned between CH2Cl2 (200 mL) and a solution of sat. NaHCO3 (200 mL) and stirred for 1 h. The organic layer was separated and the aqueous phase extracted with CH2Cl2 (3 × 200 mL). The combined organic extracts were washed with brine (200 mL), dried (MgSO4), filtered and solvent removed under reduced pressure. The crude product was purified by flash column chromatography (5:1, hexane-EtOAc) to give nitrile 10 as a colourless crystalline solid (26.87 g, 77%); mp 88.0-89.5 °C.9
