5-chloro-6-fluoro-1H-indole

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:-75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1.56 ml (2.49 mmol) of a 1.6 M butyl lithium solution in hexane were diluted with 3.2 ml THF at −78° C. under nitrogen. 211 mg (1.24 mmol) of 5-chloro-6-fluoro-1H-indole as a 3:1 mixture of regioisomers dissolved in 0.8 ml THF were added within 15 min keeping the temperature below −70° C. After 5 min 279 mg (2.49 mmol) of potassium-tert-butylate dissolved in 1 ml THF were added within 15 min. The reaction mixture was stirred for 2 h at −75° C. to give a clear orange solution. Solid carbon dioxide was added at that temperature and the reaction mixture was allowed to warm to rt within 30 min. Water was added and the reaction mixture was extracted twice with diethyl ether. The aqueous layer was acidified with 1N aqueous HCl solution and extracted twice with diethyl ether. The combined organic layers were washed with saturated aqueous NaCl solution, dried over sodium sulfate, filtered and the solvent was evaporated. The residue was stirred with n-hexane and a trace of diethyl ether for 2 h and filtered to yield 121 mg (46 of 5-chloro-6-fluoro-1H-indole-7-carboxylic acid as a light brown solid. 1H NMR (DMSO-d6, 300 MHz): δ 13.6 (br, 1H), 11.3 (br, 1H), 8.00 (d, 1H), 7.42 (s, 1H), 6.52 (s, 1H). were added within 15 min the temperature below −70° C were added within 15 min to give a clear orange solution to warm to rt within 30 min the reaction mixture was extracted twice with diethyl ether extracted twice with diethyl ether The combined organic layers were washed with saturated aqueous NaCl solution dried over sodium sulfate filtered the solvent was evaporated The residue was stirred with n-hexane a trace of diethyl ether for 2 h filtered

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

Procedure: 382 mg (1.72 mmol) of 1-(2-amino-5-chloro-4-fluoro-phenyl)-2-chloro-ethanone as a 3:1 mixture of regioisomers were dissolved in 9.5 ml 90% aqueous dioxane and 72 mg (1.89 mmol) of sodium borohydride were added in portions. The reaction mixture was heated to reflux for 1 h, additional 72 mg (1.89 mmol) of sodium borohydride were added and the reaction mixture was heated to reflux over night. The solvent was evaporated, the residue dissolved in DCM. The organic layer was washed once with 1N aqueous HCl solution, once with saturated aqueous NaHCO3 solution and once with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and the solvent was evaporated. The residue was purified by column chromatography (25 g silica gel; heptane/DCM 4:1) to yield 153 mg (52%) 5-chloro-6-fluoro-1H-indole as light yellow crystals as a 3:1 mixture of regioisomers (predominantly the wanted one). 1H NMR (CDCl3, 300 MHz): δ 8.16 (br, 1H), 7.62 (d, 1H), 7.20 (s, 1H), 7.13 (d, 1H), 6.50 (s, 1H). The reaction mixture was heated to reflux for 1 h the reaction mixture was heated to reflux over night The solvent was evaporated the residue dissolved in DCM The organic layer was washed once with 1N aqueous HCl solution, once with saturated aqueous NaHCO3 solution and once with saturated aqueous sodium chloride solution dried over sodium sulfate filtered the solvent was evaporated The residue was purified by column chromatography (25 g silica gel; heptane/DCM 4:1)

Conditions: temp:10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 35 ml THF was cooled down to −75° C. under argon and 19.05 ml of a 1.6M solution of n-BuLi in hexane (30.5 mmol) were added. Then a solution of 2.35 g of 5-chloro-6-fluoro-1H-indole (13.7 mmol) in 9 ml THF was added dropwise (temperature kept between −70 and −75° C.) over 15 min. After 5 additional min stirring at this temperature a solution of 3.7 g potassium tert-butylate in 15 ml THF was added over 10 min (temperature kept between −70 and −75° C.). The brown solution was stirred 2 h at the same temperature and then treated with a large excess of solid CO2. The temperature was then raised to 10° C. over a period of 75 min, and treated with 30 ml water. After separation of the organic phase, the aqueous phase was extracted with 2×20 ml diethylether, treated with concentrated HCl until pH 1. The suspension was then filtered, the solid washed with water and dried in high vacuo. The residue was stirred with 10 ml hexane/diethylether 9:1 for 15 min and filtered, washed with 5 ml of the same mixture and the collected solid dried in high vacuo, leading to 2.2 g of 5-chloro-6-fluoro-1H-indole-7-carboxylic acid as a light brown solid (75%). MS: 212.2 (M−H)−. was added over 10 min (temperature kept between −70 and −75° C.) After separation of the organic phase the aqueous phase was extracted with 2×20 ml diethylether treated with concentrated HCl until pH 1 The suspension was then filtered the solid washed with water dried in high vacuo The residue was stirred with 10 ml hexane/diethylether 9:1 for 15 min filtered washed with 5 ml of the same mixture the collected solid dried in high vacuo

Conditions: temp:10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 35 ml THF was cooled down to −75° C. under argon and 19.05 ml of a 1.6M solution of n-BuLi in hexane (30.5 mmol) were added. Then a solution of 2.35 g of 5-chloro-6-fluoro-1H-indole (13.7 mmol) in 9 ml THF was added dropwise (temperature kept between −70 and −75° C.) over 15 min. After 5 additional min stirring at this temperature a solution of 3.7 g potassium tert-butylate in 15 ml THF was added over 10 min (temperature kept between −70 and −75° C.). The brown solution was stirred 2 h at the same temperature and then treated with a large excess of solid CO2. The temperature was then raised to 10° C. over a period of 75 min, and treated with 30 ml water. After separation of the organic phase, the aqueous phase was extracted with 2×20 ml diethylether, treated with concentrated HCl until pH 1. The suspension was then filtered, the solid washed with water and dried in high vacuo. The residue was stirred with 10 ml hexane/diethylether 9:1 for 15 min and filtered, washed with 5 ml of the same mixture and the collected solid dried in high vacuo, leading to 2.2 g of 5-chloro-6-fluoro-1H-indole-7-carboxylic acid as a light brown solid (75%). MS: 212.2 (M−H)−. was added over 10 min (temperature kept between −70 and −75° C.) After separation of the organic phase the aqueous phase was extracted with 2×20 ml diethylether treated with concentrated HCl until pH 1 The suspension was then filtered the solid washed with water dried in high vacuo The residue was stirred with 10 ml hexane/diethylether 9:1 for 15 min filtered washed with 5 ml of the same mixture the collected solid dried in high vacuo

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: