Ethanone, 1-(7-broMo-1H-indol-3-yl)- synthesis

Yield:944086-09-3 93%

Reaction Conditions:

Stage #1: 7-bromo-1H-indolewith diethylaluminium chloride in dichloromethane at 0; for 0.416667 h;
Stage #2: acetyl chloride in dichloromethane at 0; for 1 - 3 h;

Steps:

3

Typical procedure 3 (See Scheme 2) (TP3):1 -(7-bromo-l -(3-chloroproρyO-l H-indol-3-yDethanone[0216] To a solution of 7-bromo-l //-indole (442 mg, 2.25 mmol) in dry CH₂Cl₂ (10 mL) at 0 ⁰C was added Et₂AlCl (3.4 mL, 1.0 M, 3.4 mmol) dropwise. The mixture was stirred at 0 ⁰C for 25 min. A solution of AcCl (0.24 mL, 3.36 mmol) in CH₂Cl₂ (5 mL) was added dropwise and the mixture was stirred at 0 ⁰C until TLC showed complete conversion of the indole (1-3 h). Saturated aqueous NaHCO₃ (10 mL) was added slowly and the mixture was allowed to reach room temperature. The mixture was diluted with CH₂Cb (60 mL) and the mixture was cautiously acidified to pH 4-5 with 2 M HCl (approx. 10 mL) to facilitate phase separation. The aqueous layer was extracted with CH₂Cl₂ (2x 10 mL) and the combined organic layers where washed with saturated aqueous NaHCθ₃ and evaporated to dryness to give the acetylated compound (496 mg, 93%). This acetyl ated crude product was dissolved in CH₃CN (10 mL). To this solution was added Cs₂CO₃ (1.55 g, 4.76 mmol) and 1 - chloro-3-iodopropane (0.70 mL, 6.52 mmol) and the mixture was stirred at 50 ⁰C overnight. The suspension was diluted with CH₂Cl₂ (70 mL), filtered and adsorbed onto celite. After purification by flash chromatography (heptanes - > heptanes: EtOAc 3:2) the title product was obtained (61 1 mg, 86% over two steps. [0217] ¹H NMR (400 MHz, CDCl₃) δ 8.41 (dd, J= 8.0, 1.1 Hz₉ IH), 7.75 (s, IH), 7.44 (dd, J= 7.7, 1.1 Hz, IH), 7.12-7.08 (m, IH), 4.73 (t, J= 6.7 Hz, 2H), 3.50-3.47 (m, 2H), 2.50 (s, 3H), 2.39-2.33 (m, 2H).[0218] ¹³C NMR (100 MHz, CDCl₃) δ 192.5, 137.7, 132.8, 129.7, 128.7, 123.7, 122.1, 1 16.5, 103.5, 45.8, 41.3, 34.1 , 27.5.

References:

WO2007/79239,2007,A2 Location in patent:Page/Page column 75-76