methyl 2,3-dihydro-1H-indole-2-carboxylate

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Racemic indoline-2-carboxylic acid, as a starting material of Reaction Scheme 1, is dissolved in methanol and then the reaction is conducted under the slow addition of thionyl chloride to obtain racemic indoline-2-carboxylic acid methyl ester.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To the mixture of 7.8 g of powdered potassium carbonate, 5.0 g of indoline-2-carboxylic acid methyl ester and 50 ml of methylene chloride, 4.7 g of 3-acetylthiopropanoyl chloride [Helv. Chim. Acta 40, 2148 (1957)] in 10 ml of methylene chloride are added at room temperature. After 1 hour the mixture is diluted with 100 ml of methylene chloride and washed with 50 ml of water, 50 ml of 1N hydrochloric acid and 50 ml of saturated aqueous sodium bicarbonate. The organic layer is dried and evaporated, to give the 1-(3-acetylthiopropanoyl)-indoline-2-carboxylic acid methyl ester as an oil, showing IR-bands at 1710, 1690 and 1640 cm-1. are added at room temperature washed with 50 ml of water, 50 ml of 1N hydrochloric acid and 50 ml of saturated aqueous sodium bicarbonate The organic layer is dried evaporated

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To the stirred mixture of 5.0 g of indoline-2-carboxylic acid methyl ester [J. Am. Chem. Soc. 92, 2476 (1970)], 7.8 g of powdered potassium carbonate and 50 ml of methylene chloride, 5.1 g of 3-acetylthio-2-methylpropanoyl chloride (Belgium Pat. No. 868,532) in 20 ml of methylene chloride are added during 3 minutes at room temperature. After 2 hours the mixture is diluted with 100 ml of methylene chloride and washed with 100 ml of water, 100 ml of 1N hydrochloric acid and 100 ml of saturated aqueous sodium bicarbonate. The organic layer is dried and evaporated, to give the 1-(3-acetylthio-2-methylpropanoyl)-indoline-2-carboxylic acid methyl ester as an oil, showing in the IR-spectrum bands at 1710, 1690 and 1675 cm-1. washed with 100 ml of water, 100 ml of 1N hydrochloric acid and 100 ml of saturated aqueous sodium bicarbonate The organic layer is dried evaporated

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To the stirred mixture of 5.0 g of indoline-2-carboxylic acid methyl ester [J. Am. Chem. Soc. 92, 2476 (1970)], 7.8 g of powdered potassium carbonate and 50 ml of methylene chloride, 5.1 g of 3-acetylthio-2-methylpropanoyl chloride (Belgium Pat. No. 868,532) in 20 ml of methylene chloride are added during 3 minutes at room temperature. After 2 hours the mixture is diluted with 100 ml of methylene chloride and washed with 100 ml of water, 100 ml of 1N hydrochloric acid and 100 ml of saturated aqueous sodium bicarbonate. The organic layer is dried and evaporated, to give the 1-(3-acetylthio-2-methylpropanoyl)-indoline-2-carboxylic acid methyl ester as an oil, showing in the IR-spectrum bands at 1710, 1690 and 1675 cm-1. washed with 100 ml of water, 100 ml of 1N hydrochloric acid and 100 ml of saturated aqueous sodium bicarbonate The organic layer is dried evaporated

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Following a procedure analogous to that for the synthesis of Intermediate 72A, methyl indoline-2-carboxylate (Lee, S. et al., Eur. J. Org. Chem., 38:459-471 (2003)) (3.23 g, 18.3 mmol) and 3,4-dichlorobenzoyl chloride (4.21 g, 20.1 mmol) were converted to the title compound (5.30 g, 83%) after purification using flash column chromatography (gradient from 0% to 5% EtOAc/CH2Cl2). 1H NMR (CDCl3, 1:1 mixture of amide rotamers) δ 7.67 (s, 1H), 7.55 (d, J=8.4 Hz, 1H), 7.41-7.37 (m, 1.5H), 7.23-7.20 (m, 1.5H), 7.04-7.01 (m, 2H), 5.31-5.08 (m, 1H), 3.77-3.75 (m, 3H), 3.62-3.55 (m, 1H), 3.24-3.19 (m, 1H); MS(ESI+) m/z 350.1 (M+H)+.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Magnesium turnings (6.449 g) are added to a suspension of ethyl indole-2-carboxylate (I, Aldrich, 25.083 g) in methanol (freshly opened, HPLC grade, 350 ml). The mixture is stirred at 24° for 10 minutes, then placed in an ice bath. After stirring for 15 minutes in the ice bath, there is much gas evolution and the temperature rises to 35° but then subsides to 0° within one hour. After stirring for another two hours at 0°, cold hydrochloric acid (3N, 250 ml) is added slowly. The mixture turns to a gel. The gel is then treated with ammonium hydroxide (3N, 250 ml). Upon adding methylene chloride to the gel, it forms an inseparable suspension. The crude mixture is made acidic (pH 1) with aqueous sodium bisulfate (10%) then made alkaline (pH 8-9) with ammonium hydroxide (3N). This mixture is then extracted with methylene chloride. The combined organic layers are dried over magnesium sulfate and concentrated to provide a mixture of an oil with some solid. From this mixture an off white solid is obtained by washing the mixture with ethyl acetate/hexane (25/75). A small sample (620 mg) of the recovered oil is purified by passing it over a silica column (20.5×2.5 cm, 40-63μ). The column is eluted with ethyl acetate/hexane (1/3, 11; 1/1, 0.5 l) collecting 25 ml fractions. The appropriate fractions are pooled and concentrated to give the title compound, NMR (CDCl3, 300 MHz) 7.04, 6.71, 4.46, 4.37, 3.74 and 3.35 δ; CMR (CDCl3, 75.47 MHz) 33.69, 52.42, 59.81, 110.05, 119.48, 124.45, 126.63, 127.67, 150.03 and 174.62 δ; IR (CHCl3) 3480, 3390, 2970, 1730, 1605, 1480, 1460, 1430 and 1200 cm-1 ; MS (m/e) 177, 147, 129, 119, 118, 117, 91, 86, 84 and 49, exact mass calcd for C10H11NO2 (177.0790), found 177.0789; TLC (ethyl acetate/hexane, 1/1) Rf 32 0.55 (UV). placed in an ice bath rises to 35° subsides to 0° within one hour After stirring for another two hours at 0° This mixture is then extracted with methylene chloride The combined organic layers are dried over magnesium sulfate concentrated to provide a mixture of an oil with some solid From this mixture an off white solid is obtained by washing the mixture with ethyl acetate/hexane (25/75) A small sample (620 mg) of the recovered oil is purified The column is eluted with ethyl acetate/hexane (1/3, 11; 1/1, 0.5 l) collecting 25 ml fractions concentrated

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Magnesium turnings (6.449 g) are added to a suspension of ethyl indole-2-carboxylate (I, Aldrich, 25.083 g) in methanol (freshly opened, HPLC grade, 350 ml). The mixture is stirred at 24° for 10 minutes, then placed in an ice bath. After stirring for 15 minutes in the ice bath, there is much gas evolution and the temperature rises to 35° but then subsides to 0° within one hour. After stirring for another two hours at 0°, cold hydrochloric acid (3N, 250 ml) is added slowly. The mixture turns to a gel. The gel is then treated with ammonium hydroxide (3N, 250 ml). Upon adding methylene chloride to the gel, it forms an inseparable suspension. The crude mixture is made acidic (pH 1) with aqueous sodium bisulfate (10%) then made alkaline (pH 8-9) with ammonium hydroxide (3N). This mixture is then extracted with methylene chloride. The combined organic layers are dried over magnesium sulfate and concentrated to provide a mixture of an oil with some solid. From this mixture an off white solid is obtained by washing the mixture with ethyl acetate/hexane (25/75). A small sample (620 mg) of the recovered oil is purified by passing it over a silica column (20.5×2.5 cm, 40-63μ). The column is eluted with ethyl acetate/hexane (1/3, 11; 1/1, 0.5 l) collecting 25 ml fractions. The appropriate fractions are pooled and concentrated to give the title compound, NMR (CDCl3, 300 MHz) 7.04, 6.71, 4.46, 4.37, 3.74 and 3.35 δ; CMR (CDCl3, 75.47 MHz) 33.69, 52.42, 59.81, 110.05, 119.48, 124.45, 126.63, 127.67, 150.03 and 174.62 δ; IR (CHCl3) 3480, 3390, 2970, 1730, 1605, 1480, 1460, 1430 and 1200 cm-1 ; MS (m/e) 177, 147, 129, 119, 118, 117, 91, 86, 84 and 49, exact mass calcd for C10H11NO2 (177.0790), found 177.0789; TLC (ethyl acetate/hexane, 1/1) Rf 32 0.55 (UV). placed in an ice bath rises to 35° subsides to 0° within one hour After stirring for another two hours at 0° This mixture is then extracted with methylene chloride The combined organic layers are dried over magnesium sulfate concentrated to provide a mixture of an oil with some solid From this mixture an off white solid is obtained by washing the mixture with ethyl acetate/hexane (25/75) A small sample (620 mg) of the recovered oil is purified The column is eluted with ethyl acetate/hexane (1/3, 11; 1/1, 0.5 l) collecting 25 ml fractions concentrated

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Magnesium turnings (3.60 g) are added to a mixture of ethyl indole-2-carboxylate (I, Aldrich Chemical, 13.963 g) in methanol (200 ml). After evolution of gas has started, the mixture is placed in an ice bath and the temperature kept below 45°. After 4.5 hours all of the magnesium is used up and the temperature is 7°. At this time the mixture is added to ice cold hydrochloric acid (3N, 120 ml). The acidic mixture is then made alkaline (pH 10) with ammonium hydroxide (3N). The mixture is then extracted with methylene chloride (3×). The combined organic layers are dried over magnesium sulfate and concentrated to give the title compound. the mixture is placed in an ice bath kept below 45° is 7° The mixture is then extracted with methylene chloride (3×) The combined organic layers are dried over magnesium sulfate concentrated