Indole-5-carboxylic acid synthesis
- Product Name:Indole-5-carboxylic acid
- CAS Number:1670-81-1
- Molecular formula:C9H7NO2
- Molecular Weight:161.16
10075-50-0
124-38-9
1670-81-1
To a solution of 5-bromo-1H-indole (0.86 g, 4.4 mmol, 1.0 eq.) in anhydrous THF (20 mL) was slowly added 2 M isopropylmagnesium chloride (i-PrMgCl) in a solution of THF (2.2 mL, 4.4 mmol, 1.0 eq.) at 0 °C, keeping the reaction temperature at 0 °C. After addition, the clarified solution was continued to be stirred at the same temperature for 5 minutes. Subsequently, a hexane solution (3.5 mL, 8.8 mmol, 2.0 eq.) of 2.5 M n-butyllithium (n-BuLi) was added dropwise over 5 min, controlling the reaction temperature to not exceed 20 °C. After addition, the reaction mixture was stirred at 0 °C for 30 min. Then, dry carbon dioxide gas (0.2 g, 4.4 mmol, 1.0 eq.) was passed into the reaction system and the reaction mixture was slowly warmed up to 20°C over 0.5 hr. Upon completion of the reaction, the reaction was quenched with deionized water (6 mL) and stirring was continued for 10 min. The organic and aqueous phases were separated and the aqueous phase was extracted once with ethyl acetate (10 mL). The organic phases were combined, and after the suspension was returned to room temperature, it was filtered through a silica gel pad (0.51 cm, eluting with 10 mL of ethyl acetate). The filtrate was concentrated and the residue was purified by rapid column chromatography on silica gel (eluent: petroleum ether/ethyl acetate = 3:1) to afford indole-5-carboxylic acid (3das) as an off-white solid (0.46 g, yield: 65%), melting point: 210 °C. 1H NMR (600 MHz, DMSO) δ 12.39 (s, 1H), 11.46 (s, 1H), 8.25 (s, 1H), 7.72 (dd, J = 8.5, 1.5 Hz, 1H), 7.45 (dd, J = 8.4, 5.7 Hz, 2H), 6.57 (s, 1H). 13C NMR (151 MHz, DMSO) δ 168.90, 138.80, 127.64, 127.35, 123.28, 122.67, 121.87, 111.57, 102.93.
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1670-81-1
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Yield:1670-81-1 65%
Reaction Conditions:
Stage #1: 5-bromo-1H-indolewith isopropylmagnesium chloride in tetrahydrofuran at 0; for 0.166667 h;
Stage #2: with n-butyllithium in tetrahydrofuran;hexane at -20; for 0.5 h;
Stage #3: carbon dioxide in tetrahydrofuran;hexane at -20; for 0.5 h;
Steps:
1H-Indole-5-carboxylic acid (3d)
To a solution of 5-Bromo-1H-indole (0.86 g, 4.4 mmol, 1.0 equiv.) in dryTHF (20 mL) at 0 C was added a 2 M solution of i-PrMgCl in THF (2.2 mL, 4.4 mmol, 1 equiv.) during5 min. The clear solution was stirred at that temperature for an additional 5 min, and a 2.5Msolution ofn-BuLi in hexanes (3.5 mL, 8.8 mmol, 2.0 equiv.) was added dropwise during 5 min, while maintainingthe temperature below 20 C. The resulting mixture was stirred at that temperature for 0.5 h, dry CO2(0.2 g, 4.4 mmol, 1.0 equiv.) was added to 20 C. The resulting mixture was warmed to 20 C in0.5 h and quenched with water (6 mL). After stirring the mixture below for 10 min, the phases wereseparated and the water phase was extracted one additional time with ethyl acetate. The resultingsuspension was allowed to reach room temperature and fitered through a 0.5 1 cm pad of silicagel eluted with 10 mL of ethyl acetate. The ltrate was concentrated and the residue was puried byflash chromatography on silica gel (eluent: petroleum ether/ethyl acetate = 3:1) to afford product 3das off-white solid, 0.46 g (yield: 65%), m.p.: 210-214 C. 1H-NMR (600 MHz, DMSO) 12.39 (s, 1H),11.46 (s, 1H), 8.25 (s, 1H), 7.72 (dd, J = 8.5, 1.5 Hz, 1H), 7.45 (dd, J = 8.4, 5.7 Hz, 2H), 6.57 (s, 1H).13C-NMR (151 MHz, DMSO) 168.90, 138.80, 127.64, 127.35, 123.28, 122.67, 121.87, 111.57, 102.93.
References:
Tian, Qingqiang;Shang, Suqin;Wang, Huajun;Shi, Guoqiang;Li, Zhiyao;Yuan, Jianyong [Molecules,2017,vol. 22,# 11,art. no. 1952] Location in patent:supporting information
1011-65-0
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1670-81-1
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1670-81-1
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16066-91-4
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124-38-9
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1670-81-1
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$6.00/250mg
124-38-9
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1670-81-1
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