ethyl 4-bromo-1-benzofuran-2-carboxylate

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

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

Conditions: temp:95.01; pressure:0.00; stir:

Procedure: ethyl 4-bromobenzofuran-2-carboxylate (2 g, 7.43 mmol), tert-butyl piperazine-1-carboxylate (1.384 g, 7.43 mmol), Tris(dibenzylideneacetone)dipalladium(0) (0.340 g, 0.37 mmol), 2-Dicyclohexylphosphino-2',4',6'-tri-iso-propyl-1,1'-biphenyl (0.354 g, 0.74 mmol) and CESIUM CARBONATE (3.15 g, 9.66 mmol) were heated under argon to 95 °C overnight. The mixture was allowed to cool. The mixture was diluted with EtOAc and the mixture was filtered through a pad of Celite. The filterate was collected and the solvent was removed by rotary evaporation. The crude product was added to a silica gel column and was eluted with 0-50% EtOAc in heptane. The collected fractions were combined and the solvent was removed to yield tert-butyl 4-(2-(ethoxycarbonyl)benzofuran-4-yl)piperazine-1-carboxylate (1.250 g, 44.9 %). MS (m+1) = 375.6. HPLC Peak RT = 3.29 minutes is product. Purity = 99%.

Conditions: temp:95.01; pressure:0.00; stir:

Procedure: ethyl 4-bromobenzofuran-2-carboxylate (7.7 g, 28.61 mmol), tert-butyl piperazine-1-carboxylate (5.33 g, 28.61 mmol), Tris(dibenzylideneacetone)dipalladium(0) (1.310 g, 1.43 mmol), 2-Dicyclohexylphosphino-2',4',6'-tri-iso-propyl-1,1'-biphenyl (1.364 g, 2.86 mmol) and CESIUM CARBONATE (12.12 g, 37.20 mmol) in dioxane (40 mL) was heated under argon to 95 °C overnight. The mixture was allowed to cool. The mixture was diluted with EtOAc and the mixture was filtered through a pad of Celite. The filterate was collected and the solvent was removed by rotary evaporation. The crude product was added to a silica gel column and was eluted with 0-50% EtOAc in heptane. The collected fractions were combined and the solvent was removed to yield tert-butyl 4-(2-(ethoxycarbonyl)benzofuran-4-yl)piperazine-1-carboxylate (4.92 g, 45.9 %). MS (m+1) = 375.8. HPLC Peak RT = 3.27 minutes is product. Purity = 96%.

Conditions: temp:95.01; pressure:0.00; stir:

Procedure: tert-butyl piperazine-1-carboxylate (0.692 g, 3.72 mmol), ethyl 4-bromobenzofuran-2-carboxylate (1 g, 3.72 mmol), 2-Dicyclohexylphosphino-2',4',6'-tri-iso-propyl-1,1'-biphenyl (0.177 g, 0.37 mmol), Tris(dibenzylideneacetone)dipalladium(0) (0.170 g, 0.19 mmol) and CESIUM CARBONATE (1.574 g, 4.83 mmol) were heated under argon to 95 °C overnight. The mixture was allowed to cool. The mixture was diluted with EtOAc and the mixture was filtered through a pad of Celite. The filterate was collected and the solvent was removed by rotary evaporation. The crude product was added to a silica gel column and was eluted with 0-50% EtOAc in heptane. The collected fractions were combined and the solvent was removed to yield tert-butyl 4-(2-(ethoxycarbonyl)benzofuran-4-yl)piperazine-1-carboxylate (0.990 g, 71.1 %). 1H NMR in CDCl3 is consistent with desired product MS (m+1) = 375.6. HPLC Peak RT = 3.27 minutes is product. Purity = 95%.

Conditions: temp:95.01; pressure:0.00; stir:

Procedure: ethyl 4-bromobenzofuran-2-carboxylate (5 g, 18.58 mmol), 1-benzylpiperazine (3.22 mL, 18.58 mmol), 2-Dicyclohexylphosphino-2',4',6'-tri-iso- propyl-1,1'-biphenyl (0.886 g, 1.86 mmol), Tris(dibenzylideneacetone)dipalladium(0) (0.851 g, 0.93 mmol) and CESIUM CARBONATE (7.87 g, 24.16 mmol) were heated under argon to 95 °C overnight. The mixture was allowed to cool. The mixture was diluted with EtOAc and the mixture was filtered through a pad of Celite. The filterate was collected and the solvent was removed by rotary evaporation. The crude product was added to a silica gel column and was eluted with 0-50% EtOAc in heptane. The collected fractions were combined and the solvent was removed to yield ethyl 4-(4-benzylpiperazin-1-yl)benzofuran-2-carboxylate (2.160 g, 31.9 %). MS (m+1) = 365.6. HPLC Peak RT = 3.30 minutes is product. Purity = 94%.

Conditions: temp:50.01; pressure:0.00; stir:

Procedure: **Purpose:** Buchwald-Hartwig coupling using unpurified ethyl 4-bromobenzofuran-2-carboxylate. The analysis on crude 4-bromobenzofuran-2-carboxylate shows traces of non cyclized and non aromoatized by-products. 2010-03-02 15:25:22: To a 25 mL roundbottomed flask was added ethyl 4-bromobenzofuran-2-carboxylate (LR; 1 g; 3.72 mmol) and toluene (7 mL/g-bulk- LR; 7 mL). The mixture was concentrated under reduced pressure. To the mixture was added toluene (7 mL/g-bulk-LR; 7 mL) and the mixture was concentrated a second time under reduced pressure. To the mixture was added toluene (7 mL/g-bulk-LR; 7 mL) followed by 1-benzylpiperazine (1.3 eq; 0.852 g; 0.84 mL), BINAP (0.04 eq; 93 mg) and TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (0.02 eq; 68 mg). The mixture was stirred for 5 minutes followed by addition of POTASSIUM TERT-BUTOXIDE (1.4 eq; 0.58 g). The mixture is stirred at Tm=50 °C. 15:45:57: IPC1 (15 min) sample was gathered. The sample was quenched with a mixture consisting of 700 mM acetic acid buffer pH=2 and methanol. The sample was filtered and analyzed by means of HPLC-UV (EN03690-30-001-F) which indicated 44 % conversion 17:09:21: IPC2 (100 min) sample was gathered. The sample was quenched with a mixture consisting of 700 mM acetic acid buffer pH=2 and methanol. The sample was filtered and analyzed by means of HPLC-UV (EN03690-30-001-H) which indicated 95 % conversion. 17:20:00: The temperature was allowed to reach rt and the mixture was stirred over night. 2010-03-03 09:51:29: IPC3 (18 h) sample was gathered. The sample was quenched with a mixture consisting of 700 mM acetic acid buffer pH=2 and methanol. The sample was filtered and analyzed by means of HPLC-UV (EN03690-30-001-J) which indicated +99 % conversion. 10:10:32: The mixture was transfered to a mixture consisting of 700 mM acetate buffer pH=2 (12.5 mL/g-bulk-LR; 12.5 mL) and isopropyl acetate (6.2 mL/g-bulk- LR; 6.2 mL) to give pH=5.65. To the mixture was added 4 M aqueous sulfuric acid (1.77 mL/g-bulk-LR; 1.77 mL) to give pH=2. The mixture was stirred for 15 minutes. The phases were separated and analyzed by means of HPLC-UV 12:32:57: To the water phase was added dichloromethane (10 mL/g-bulk-LR; 10 mL). The mixture was stirred and 50 % aqueous sodium hydroxide (1 mL) was added to give pH=12. The phases were separated and analyzed by means of HPLC- UV. The organic phase was concentrated under reduced pressure to give yellow oil. The crude product was purified by means of column chromatography (40 g SiO2; 4 % MeOH, 1 NH3 in MeOH in DCM; Rf=0.2). Yellow solid was obtained (250 mg). 1H NMR showed not correct product. **Result:** Correct product was not isolated.

Conditions: temp:95.01; pressure:0.00; stir:

Procedure: ethyl 4-bromobenzofuran-2-carboxylate (1 g, 3.72 mmol), 1-Benzylpiperazine (0.580 mL, 3.34 mmol), Tris(dibenzylideneacetone)dipalladium(0) (0.170 g, 0.19 mmol), 2-Dicyclohexylphosphino-2',4',6'-tri-iso-propyl-1,1'-biphenyl (0.177 g, 0.37 mmol) and CESIUM CARBONATE (1.574 g, 4.83 mmol) in dioxane (5 mL) were heated under argon to 95 °C overnight. The mixture was allowed to cool. The mixture was diluted with EtOAc and the mixture was filtered through a pad of Celite. The filterate was collected and the solvent was removed by rotary evaporation. The crude product was added to a silica gel column and was eluted with 0-50% EtOAc in heptane. The collected fractions were combined and the solvent was removed to yield ethyl 4-(4-benzylpiperazin-1-yl)benzofuran-2-carboxylate (0.360 g, 26.6 %). MS (m+1) = 365.6. HPLC Peak RT = 3.33 minutes is product. Purity = 96%.

Conditions: temp:100.01; pressure:0.00; stir:

Procedure: **Purpose:** Buchwald-Hartwig coupling using unpurified ethyl 4-bromobenzofuran-2-carboxylate. The analysis on crude 4-bromobenzofuran-2-carboxylate shows traces of non cyclized and non aromoatized by-products. 2010-03-10 16:38:11: To a 25 mL rounbottomed flask was added ethyl 4-bromobenzofuran-2-carboxylate (1 g; 3.72 mmol) and toluene (10 mL/g-bulk-LR; 10 mL). The mixture was concentrated under reduced pressure to remove traces of water. The procedure was repeated once more. and finally toluene (10 mL/g-bulk-LR; 10 mL). The system was inerted three times and stirred under nitrogen gas. 17:03:56: To the homogenous mixture was added 1-benzylpiperazine (1.3 eq; 0.852 g; 0.84 mL; 4.83 mmol), TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (0.02 eq; 68 mg; 0.07 mmol), 2-(DI-T-BUTYLPHOSPHINO)BIPHENYL (0.06 eq; 67 mg; 0.22 mmol) and CESIUM CARBONATE (1.2 eq; 1.453 g; 4.46 mmol). The system was inerted three times and stirred under nitrogen gas. 17:07:37: The Tj was set to Tj=100 °C. The mixture was stirred under nitrogen gas over night. 2010-03-11 08:42:44: IPC1 (15 h) sample was gathered and diluted with methanol. The analysis (EN03690-35-001-A) showed only 16 % conversion. **Results and conclusion:** The experiment was discarded due to poor conversion.

Conditions: temp:95.01; pressure:0.00; stir:

Procedure: 20/10 2009 10:10:14 +0200 To ethyl 4-bromobenzofuran-2-carboxylate (2.50 g, 9.29 mmol) and 1-benzylpiperazine (1.776 mL, 10.22 mmol) in dry degassed dioxane (30 mL) were added Cesium carbonate (3.94 g, 12.08 mmol), 2-Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (0.443 g, 0.93 mmol) and Tris(dibenzylideneacetone)dipalladium(0) (0.425 g, 0.46 mmol) under argon and the reaction heated at 95°C o/n. All starting material consumed. The crude solution was pooled with the corresponding solution in EN03307-46 Water and DCM were added and the layers separated. The aq phase was extracted with DCM (3x). The combined org phases were washed with water, dried (MgSO4), filtered and evaporated. The crude was purified by flash chrom. (SiO2; Heptane/EtOAc 70/30) to give 3.05 g (50%) of the product as a yellow solid.

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

Procedure: To a solution of 4-bromo-2-ethoxycarbonylbenzo[b]furan (0.5 g) in tetrahydrofuran (5 ml) was slowly added sodium borohydride (0.21 g) at room temperature. After 5 minutes, methanol (0.5 ml) was added thereto dropwise. The reaction mixture was stirred at room temperature for one hour and then ethyl acetate and water were added thereto. The mixture was adjusted to pH 5, and the layers were separated. The organic layer was washed with water and brine, dried over magnesium sulfate and evaporated to afford 4-bromo-2-hydroxymethylbenzofuran (0.36 g). at room temperature the layers were separated The organic layer was washed with water and brine dried over magnesium sulfate evaporated

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 6-bromo-2-hydroxybenzaldehyde (4.48 g), ethyl chloroacetate (3.55 g) and powdered potassium carbonate (6.16 g) in N,N-dimethylformamide (56 ml) was stirred at 120° C. for one hour. Insoluble materials were filtered off and the solvent was removed under reduced pressure. Ethyl acetate and water were added to the residue, and the mixture was acidified by hydrochloric acid solution. The layers were separated and the organic layer was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with a mixture of hexane and toluene (1:1) to afford 4-bromo-2-ethoxycarbonylbenzofuran (4.20 g). Insoluble materials were filtered off the solvent was removed under reduced pressure Ethyl acetate and water were added to the residue The layers were separated the organic layer was washed with water and brine dried over magnesium sulfate evaporated in vacuo The residue was purified by column chromatography on silica gel eluting with a mixture of hexane and toluene (1:1)