68% |
With phosphorus tribromide In dichloromethane for 16h; |
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63% |
With phosphorus tribromide In diethyl ether at 0℃; for 2.5h; Inert atmosphere; Reflux; |
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61% |
With phosphorus tribromide In toluene at 0℃; for 2h; Heating / reflux; |
1
Example 1Synthesis of 3-(para-Methoxyphenyl)-1-propylmercaptyl(2S)-N-(benzenesulfonyl)pyrrolidine-2-carboxylate (4)3-(p-Methoxyphenyl)-1-propylbromideTo a solution of 3-(p-methoxyphenyl)-1-propanol (16.6 g; 0.1 mol) in 250 mL of toluene, cooled to 0° C., was added dropwise 26 mL of phosphorus tribromide (0.27 mol). Following completion of the addition, the reaction was stirred at room temperature for 1 hour, then refluxed for an additional hour. The reaction was cooled and poured onto ice, the layers were separated, and the organic phase washed with saturated sodium bicarbonate (3×) and brine (3×). The crude material obtained upon drying and evaporation of the solvent was chromatographed, eluting with 10% EtOAc/hexane, to obtain 14 g (61%) of 3-(p-methoxyphenyl)-1-propylbromide. |
55% |
With phosphorus tribromide In diethyl ether at 0 - 20℃; Inert atmosphere; |
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42% |
With sulfuric acid; hydrogen bromide In hexane for 6h; Reflux; |
A solution of 3-(4-methoxyphenyl)-1-propanol (2.72 g, 16.5 mmol), sulfuric acid (1 ml) and aqueous hydrobromic acid (48%, 15 ml) was stirred at reflux for 6 h, After cooling to rt, the reaction mixture was neutralised with saturated sodium hydrogencarbonate solution, and then washed with ethyl acetate (3×60 ml). The combined organic layers were washed with brine (100 ml), dried over magnesium sulfate, and then concentrated in vacuo. Purification by flash chromatography on silica (dichloromethane) afforded the titled compound as a colourless oil (1.58 g, 42%).1H NMR (300 MHz; CDCl3) 2.15 (3H, m), 2.71 (4H, t, J 7.5 Hz), 3.20 (2H, t, J 6.8 Hz), 3.80 (3H, s), 6.85 (2H, d, J 8.6 Hz, Ph-H), 7.02 (2H, d, J 8.6 Hz, Ph-H);13C NMR (75.5 MHz; CDCl3) 33.1, 34.4 and 35.2, 55.3, 114.0, 129.5, 132.6, 158.1;m/z (+ES) 230 (30, MH+), 135 (100, [M-CH2Br]+). |
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With tetrachloromethane; phosphorus tribromide at 60℃; |
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With phosphorus tribromide |
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With phosphorus tribromide In benzene |
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With carbon tetrabromide; triphenylphosphine In dichloromethane at 0℃; for 24h; |
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Multi-step reaction with 2 steps
1: 81 percent / pyridine / 4 h / 0 °C
2: LiBr / acetone / 24 h |
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14 g (61%) |
With phosphorus tribromide In toluene |
10 3-(p-Methoxyphenyl)-1-propylbromide
3-(p-Methoxyphenyl)-1-propylbromide To a solution of 3-(p-methoxyphenyl)-1-propanol (16.6 g; 0.1 mol) in 250 ml of toluene, cooled to 0° C., was added dropwise 26 ml of phosphorus tribromide (0.27 mol). Following completion of the addition, the reaction was stirred at room temperature for 1 hour, then refluxed for an additional hour. The reaction was cooled and poured onto ice, the layers were separated, and the organic phase washed with saturated sodium bicarbonate (3*) and brine (3*). The crude material obtained upon drying and evaporation of the solvent was chromatographed, eluding with 10% EtOAc/hexane, to obtain 14 g (61%) of 3-(p-methoxyphenyl)-1-propylbromide. |
14 g (61%) |
With phosphorus tribromide In toluene |
10 3-(p-Methoxyphenyl)-1-propylbromide
3-(p-Methoxyphenyl)-1-propylbromide To a solution of 3-(p-methoxyphenyl)-1-propanol (16.6 g; 0.1 mol) in 250 mL of toluene, cooled to 0° C., was added dropwise 26 mL of phosphorus tribromide (0.27 mol). Following completion of the addition, the reaction was stirred at room temperature for 1 hour, then refluxed for an additional hour. The reaction was cooled and poured onto ice, the layers were separated, and the organic phase washed with saturated sodium bicarbonate (3*) and brine (3*). The crude material obtained upon drying and evaporation of the solvent was chromatographed, eluding with 10% EtOAc/hexane, to obtain 14 g (61%) of 3-(p-methoxyphenyl)-1-propylbromide. |
14 g (61%) |
With phosphorus tribromide |
1 3-(p-Methoxyphenyl)-1-propylbromide
3-(p-Methoxyphenyl)-1-propylbromide To a solution of 3-(p-methoxyphenyl)-1-propanol (16.6 g; 0.1 mol) in 250 mL of tolune, cooled to 0° C., was added dropwise 26 mL of phosphorus tribromide (0.27 mol). Following completion of the addition the reaction was stirred at room temperature for 1 hour, then refluxed for an additional hour. The reaction was cooled and poured onto ice, the layers were separated, and the organic phase washed with saturated sodium bicarbonate (3*) and brine (3*). The crude material obtained upon drying and evaporation of the solvent was chromatographed, eluding with 10%, EtOAc/hexane, to obtain 14 g (61%) of 3-(p-methoxyphenyl)-1-propylbromide. |
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With phosphorus tribromide In toluene |
1 3-(p-Methoxyphenyl)-1-propylbromide
3-(p-Methoxyphenyl)-1-propylbromide To a solution of 3-(p-methoxyphenyl)-1-propanol (16.6 g; 0.1 mol) in 250 mL of toluene, cooled to 0° C., was added dropwise 26 mL of phosphorus tribromide (0.27 mol). Following completion of the addition, the reaction was stirred at room temperature for 1 hour, then refluxed for an additional hour. The reaction was cooled and poured onto ice, the layers were separated, and the organic phase washed with saturated sodium bicarbonate (3*) and brine (3*). The crude material obtained upon drying and evaporation of the solvent was chromatographed, eluding with 10% EtOAc/hexane, to obtain 14 g (61) of 3-(p-methoxyphenyl)-1-propylbromide. |
14 g (61%) |
With phosphorus tribromide In toluene |
1 3-(4-Methoxyphenyl)-1-propylbromide
3-(4-Methoxyphenyl)-1-propylbromide To a solution of 3-(4-methoxyphenyl)-1-propanol (16.6 g; 0.1 mol) in 250 mL of toluene, cooled to 0° C., was added dropwise 26 mL of phosphorus tribromide (0.27 mol). Following completion of the addition the reaction was stirred at room temperature for 1 hour, then refluxed for an additional hour. The reaction was cooled and poured onto ice, the layers were separated, and the organic phase washed with saturated sodium bicarbonate (3*) and brine (3*). The crude material obtained upon drying and evaporation of the solvent was chromatographed, eluding with 10% EtOAc/hexane, to obtain 14 g (61%) of 3-(4-methoxyphenyl)-1-propylbromide. |
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With N-Bromosuccinimide; triphenylphosphine In dichloromethane at 20℃; for 6h; Ice-cooling; |
10-1
(10-1) Synthesis of 1-(3-bromopropyl)-4-methoxybenzene (compound 10-1) [Show Image] 3-(4-Methoxyphenyl)-1-propanol (5.00 g) was dissolved in methylene chloride (50 ml), triphenylphosphine (8.86 g) and N-bromosuccinimide (5.94 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 1 hr, and further at room temperature for 5 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (100 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane:ethyl acetate=100:1 - 3:1) to give the object product (990 mg) as a colorless oil. 1H-NMR(CDCl3) δ (ppm): 2.14(2H, quint, J=6.5Hz), 2.72(2H, t, J=7.2Hz), 3.38(2H, t, J=6.5Hz), 3.78(3H, s), 6.84(2H, d, J=8.6Hz), 7.11(2H, d, J=8.6Hz). |
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With N-Bromosuccinimide; triphenylphosphine In dichloromethane at 20℃; |
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With carbon tetrabromide; triphenylphosphine In dichloromethane at 0 - 20℃; for 18h; |
General procedure for obtaining derivatives of (3-Bromopropyl)benzene
General procedure: To a stirred solution of 3- or 4-substituted phenylpropanoic acid 51-63 (7.0 mmol) in dry THF (35 ml), borane dimethyl sulfide (21.0 mmol) was added dropwise at 0 oC. The reaction mixture was stirred for 18h at room temperature, quenched with H2O and concentrated in vacuo. The resulting residue was re-dissolved in diethyl ether (25 ml), and washed with 10%NaOH (30ml) and brine. The organic fraction was dried over Na2SO4, filtered, and concentrated in vacuo to give 3-phenylpropan-1-ol derivatives that were used in the next step without further purification. Triphenylphosphine (7.5 mmol) and carbon tetrabromide (7.1 mmol) were added to a stirred solution of the 3-phenylpropan-1-ol derivatives in dry CH2Cl2 at 0 oC. The reaction mixture was stirred for 18h at room temperature and quenched with brine. The organic fraction was dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (10:1 n-hexane/EtOAc) to give the corresponding title compound (38-50) in a 64-73% yield (two steps). These are also all known, but commercially unavailable compounds for which the chemical structure of each could be identified from the 1H- and 13C-NMR spectra. |