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With copper(l) iodide; triethylamine;bis-triphenylphosphine-palladium(II) chloride; In tetrahydrofuran; at 50℃; for 4h;
Methyl 3-hydroxy-4-iodobenzoate (5.22 g, 18.8 mmol) is combined with trimethylsilylacetylene (3.71 mL, 26.3 mmol), bis(triphenylphosphine)palladium dichloride (386 mg, 0.55 mmol) and cuprous iodide (54 mg, 0.28 mmol) in THF (20 mL)/CHCl3 (40 mL) in a dry flask, under nitrogen. Triethylamine (8.14 mL, 58.4 mmol) is added and the mixture is heated to 50° C. for 4 h. The mixture is diluted with CHCl3 (60 mL), washed with 5percent HCl (2.x.40 mL), dried (MgSO4) and concentrated to a brown oily-solid (8.31 g). The crude material is chromatographed over a standard 90 g Biotage column, eluting with 10percent EtOAc/hexane (1 L) followed by 15percent EtOAc/hexane (1 L). The appropriate fractions are combined and concentrated to afford 4.22 g (91percent) of methyl 3-hydroxy-4-[(trimethylsilyl)ethynyl]benzoate as a yellow solid. HRMS (FAB) calcd for C13H16O3SI+H: 249.0947, found 249.0947 (M+H)+.
4.22 g (91%)
With triethanolamine; copper(I) iodide;bis(triphenylphosphine)palladium(II) dichloride; In tetrahydrofuran; hexane; chloroform; ethyl acetate;
Methyl 3-hydroxy-4-iodobenzoate (5.22 g, 18.8 mmol) is combined with trimethylsilylacetylene (3.71 mL, 26.3 mmol), bis(triphenylphosphine)palladium dichloride (386 mg, 0.55 mmol) and cuprous iodide (54 mg, 0.28 mmol) in THF (20 mL) CHCl3 (40 mL) in a dry flask, under nitrogen. TEA (8.14 mL<58.4 mmol) is added and the mixture is heated to 50° C. for 4 h. The mixture is diluted with CHCl3 (60 mL), washed with 5percent HCl (2*40 mL), dried over anhydrous MgSO4 and concentrated to a brown paste (8.31 g). The crude material is chromatographed over a standard 90 g Biotage column, eluding with 10percent EtOAc/hexane (1 L) followed by 15percent EtOAc/hexane (1 L). The appropriate fractions are combined and concentrated to afford 4.22 g (91percent) of methyl 3-hydroxy-4-[(trimethylsilyl)ethynyl]benzoate as a yellow solid. HRMS (FAB) calcd for C13H16O3SI+H1: 249.0947, found 249.0947.
4.22 g (91%)
With triethanolamine; copper(I) iodide;bis(triphenylphosphine)palladium(II) dichloride; In tetrahydrofuran; hexane; chloroform; ethyl acetate;
Methyl-3-hydroxy-4-iodobenzoate (5.22 g, 18.8 mmol) is combined with trimethylsilylacetylene (3.71 mL, 26.3 mmol), bis(triphenylphosphine)palladium dichloride (386 mg, 0.55 mmol) and cuprous iodide (54 mg, 0.28 mmol) in THF (20 mL)/CHCl3 (40 mL) in a dry flask under nitrogen. TEA (8.14 mL<58.4 mmol) is added and the mixture is heated to 50° C. for 4 h. The mixture is diluted with CHCl3 (60 mL), washed with 5percent HCl (2*40 mL), dried over MgSO4 and concentrated to a brown oily-solid (8.31 g). The crude material is chromatographed over a standard 90 g Biotage column, eluding with 10percent EtOAc/hexane (1 L) followed by 15percent EtOAc/hexane (1 L). The appropriate fractions are combined and concentrated to afford 4.22 g (91percent) of methyl 3-hydroxy-4-[(trimethylsilyl)ethynyl]benzoate as a yellow solid. HRMS (FAB) calcd for C13H16O3Si+H: 249.0947, found 249.0947 (M+H)+.
With sodium hydroxide; copper(I) iodide; In methanol; ethanol; water; triethylamine;
Methyl-3-hydroxy-4-[(trimethylsilyl)ethynyl]benzoate (3.0 g, 12.1 mmol) is dissolved in 30 ml 1:1 EtOH/Et3N, is treated with cuprous iodide (114 mg, 0.6 mmol), and the reaction is warmed to 75° C. for 3 h. The mixture is treated with DARCO and 15 ml MeOH and is heated to reflux for 1 h. The reaction is filtered through a fine fritted glass funnel, the filtrate is treated with 3N NaOH (24.2 ml, 72.5 mmol), and the mixture is stirred overnight at RT. The mixture is concentrated to dryness, the residue is dissolved in 20 ml water, and the pH of the mixture is adjusted to 2 with 12N HCl. The resulting yellow precipitate is collected, washed with water, and is dried to give 1.83 g (93percent) of benzofuran-6-carboxylic acid as a tan solid. HRMS (FAB) calcd for C9H6O3+H: 163.0395, found 163.0389 (M+H)+.
Methyl 3-hydroxy-4-[(trimethylsilyl)ethynyl]benzoate (540 mg, 2.17 mmole) is combined with 4 ml formic acid under nitrogen. The reaction is warmed to 80° C. for 12 h, is cooled to rt, and the volatiles are removed in vacuo. The black residue is chromatographed over 25 g silica gel (230-400 mesh) eluding with 15percent EtOAc/hexane. The appropriate fractions are combined and concentrated to provide 350 mg (83percent) of methyl 4-acetyl-3-hydroxybenzoate as a pale yellow solid. 1H NMR (CDCl3) delta 2.70, 3.95, 7.54, 7.64, 7.82, 12.10 ppm.
Methyl 3-hydroxy-4-[(trimethylsilyl)ethynyl]benzoate (3.0 g, 12.1 mmol) is dissolved in 1:1 EtOH/Et3N (30mL), is treated with CuI (114 mg, 0.6 mmol), and the reaction is warmed to 75° C. for 3 h. The mixture is treated with DARCO and MeOH (15 mL) and heated to reflux for 1 h. The reaction is filtered through a fine fritted-glass funnel, the filtrate is treated with 3N NaOH (24.2 ml, 72.5 mmol), and the mixture is stirred overnight at RT. The mixture is concentrated to dryness, the residue is dissolved in H2O (20 mL), and the pH of the mixture is adjusted to 2 with 12N HCl. The resulting yellow precipitate is collected, washed with water, and is dried to give 1.83 g (93percent) of benzofuran-6-carboxylic acid as a tan solid. HRMS (FAB) calcd for C9H6O3+H: 163.0395, found 163.0389 (M+H)+.
Methyl 3-hydroxy-4-[(trimethylsilyl)ethynyl]benzoate (4.15 g, 16.7 mmol) is dissolved in MeOH (45 ml) and treated with DIA (2.34 ml, 16.7 mmol). Copper iodide (159 mg, 0.84 mmol) is added portion-wise and the reaction is heated at 75° C. for 3 h. DARCO (2 g) is added and the reaction is stirred at 95° C. for an additional 2 h, then overnight at RT. The reaction is filtered, concentrated to a brown oil and the crude material is chromatographed over 300 g slurry-packed silica gel, eluting with 10percent EtOAc/hexane. The appropriate fractions are collected and concentrated to afford 2.05 g (70percent) of methyl 1-benzofuran-6-carboxylate as an orange crystalline solid. 1H NMR (400 MHz, CDCl3) delta3.97, 6.84, 7.65, 7.78, 7.98, 8.22 ppm.
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