| 61% |
With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; for 4h;Reflux; |
Methyl 4-bromo-3-methylbenzoate (11.4 g, 0.05 mol) was added to carbon tetrachloride (80 mL) in a 250 mL 3-three neck round-bottomed flask. To the resulting solution were added successively and in single portions, N-bromosuccinimide (9.3 g, 0.053 mol) and dibenzoylperoxide (0.6 g, 5 mol %). The resulting suspension was then heated to reflux for 4 h. Upon cooling to ambient temperature, the reaction mixture was filtered, and the filter cake washed with a few portions of carbon tetrachloride. The filtrate was then removed under reduced pressure, and the resulting semi-solid was partitioned between EtOAc and an aqueous ½ saturated sodium carbonate solution. The organic layer was washed with water and brine, and then dried over magnesium sulfate. The solution was filtered and solvent was removed under reduced pressure, providing 15.5 g of an off-white solid, which was purified by silica gel chromatography (0% to 6% EtOAc/hexanes) to afford the title compound (9.5 g, 61% yield). |
| 61.5% |
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; at 80℃; for 16h; |
To a solution of methyl 4-bromo-3-methylbenzoate (5.0 g, 21.83 mmol) in carbon tetrachloride (120 mL) was added NBS (4.67 g, 26.20 mmol), the suspension was heated at 80 C for 5 min. Then AIBN (1.79 g, 10.92 mmol) was added. The suspension was stirred at 80 C for 16 h. The reaction was cooled to RT and filtered. The filtrate was concentrated and purified by silica gel chromatography eluting with EA/petroleum ether from 0% to 3% to give methyl 4-bromo-3-(bromomethyl)benzoate (4.12 g, 61.5%) as a white solid. |
| 57% |
With N-Bromosuccinimide;dibenzoyl peroxide; In tetrachloromethane; for 18h;Reflux; |
Preparation 23: methyl 4-bromo-3-(bromomethyl)benzoateTo a CCl4 (30 mL) solution of 4-bromo-3-methyl benzoic acid methyl ester (10 g 43.6 mmol) was added NBS (4.8 g, 44 mmol) and a catalytic amount of benzolyl peroxide. The reaction was heated at reflux for eighteen hours. The mixture was cooled to room temperature and diluted with CH2Cl2 (50 mL). The organic phase was washed with water (3×20 mL) and concentrated using rotary evaporation at low pressure. The residual material was dissolved in hexanes and applied to a 120 g cartridge of silica gel. The product was eluted with an ethyl acetate gradient in hexanes to provide methyl 4-bromo-3-(bromomethyl)benzoate (7.73 g, 57%). 1H NMR (400 MHz, CDCl3) delta ppm 3.95 (s, 3H) 4.64 (s, 2H) 7.68 (d, J=8.34 Hz, 1H) 7.83 (dd, J=8.34, 2.02 Hz, 1H) 8.14 (d, J=2.02 Hz, 1H). |
| 47% |
With N-Bromosuccinimide; In tetrachloromethane;Reflux; |
Step 1 Methyl 4-bromo-3-(bromomethyl)benzoate Into a 500-mL round-bottom flask, was placed a solution of methyl 4-bromo-3-methylbenzoate (10 g, 43.65 mmol, 1.00 equiv) in CCl4 (150 ml), NBS (8.12 g, 45.62 mmol, 1.05 equiv). The resulting solution was heated to reflux overnight under 100 w incandescent bulb. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:30-1:10). This resulted in 6 g (47%) of methyl 4-bromo-3-(bromomethyl)benzoate as a off-white solid. |
| 33% |
With N-Bromosuccinimide; dibenzoyl peroxide; In dichloromethane; at 20℃;Inert atmosphere; |
Methyl 4-bromo-3-(bromomethyl)benzoate To a solution of methyl 4-bromo-3-methylbenzoate (5.00 g, 21.83 mmol) in dichloromethane (30 mL) was added NBS (4.66 g, 26.18 mmol) and benzoperoxide (110 mg, 0.43 mmol) at room temperature. The resulting solution was stirred overnight at room temperature and then diluted with water (50 mL). The mixture was extracted with ethyl acetate (100 mL*3). The organic phases were combined, washed with brine and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with ethyl acetate in hexane (0% to 10% gradient) to yield methyl 4-bromo-3-(bromomethyl)benzoate as brown solid (2.2 g, 33%). |
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A. Methyl 4-bromo-3-(bromomethyl)benzoate Methyl 4-bromo-3-methylbenzoate (20 g, 87 mmol) was brominated according to General Method 13. The crude orange solid was triturated with 4:1 hexanes/ethyl acetate to provide 232A (14.7 g) as a white solid. |
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With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; at 70℃; for 60h; |
N-Bromosuccinimide (1.0 mL, 12 mmol) and 2,2'-azobisisobutyronitrile (0.005 g, 0.03 mmol) was added to a stirred solution of methyl 4-bromo-3-methylbenzoate (2.190 g, 9.56 mmol) in carbon tetrachloride (50 mL) and the resulting mixture was stirred at 70 C. for 2.5 days. Water and chloroform was added. The aqueous phase was extracted with chloroform and the combined organic phases were washed with water and 5% aqueous sodium hydrogen carbonate, dried over magnesium sulfate and the solvent was evaporated to give 3.015 g of the title compound.GC MS (EI) m/z 308 [M]+. |
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With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In chloroform; at 70℃; for 48h; |
To a solution of methyl 4-bromo-3-methylbenzoate (Aldrich 532878, 50 g; 218 mmol; 1 eq.) in CHCI3 (I L) were added NBS (46.6 g; 262 mmol; 1.2 eq.) in one portion and alpha,alpha'- azoisobutyronitrile (0.72 g; 4.37 mmol; 0.02 eq.) and the reaction mixture was stirred at 700C for 2 days. The mixture was cooled down to room temperature and water (500 mL) was added. The organic layer was washed with aq. NaHCO3 (400 mL), then brine (500 mL), dried over MgSCU and concentrated in vacuo. The residue was washed with n-pentane (2 x 500 mL) to afford the title compound as a yellow solid.HPLC (Method A) : Rt 4.44 min (purity 97.9%). 1H NMR (DMSO-d6, 400 MHz) delta 8.24 (d, J = 1.9Hz, 1 H), 7.88-7.82 (m, 2H), 4.87 (s, 2H), 3.91 (s, 3H). |
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With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; at 70℃; for 2.5h; |
N-Bromosuccinimide (1.0 mL, 12 mmol) and 2,2'-azobisisobutyronitrile (0.005 g, 0.03 mmol) was added to a stirred solution of methyl 4-bromo-3-methylbenzoate (2.190 g, 9.56 mmol) in carbon tetrachloride (50 mL) and the resulting mixture was stirred at 70 0C for 2.5 days. Water and chloroform was added. The aqueous phase was extracted with chloroform and the combined organic phases were washed with water and 5% aqueous <n="107"/>sodium hydrogen carbonate, dried over magnesium sulfate and the solvent was evaporated to give 3.015 g of the title compound. GC MS (EI) m/z 308 [M]+. |
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With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In chloroform; at 70℃; for 48h; |
Under N2, to a solution of methyl 4-bromo-3-methylbenzoate (Aldrich 532878, 50 g; 218.27 mmol; 1 eq.) in CHCI3 (1 000 mL) were added NBS (46.62 g; 261.93 mmol; 1.20 eq.) in one portion and alpha, alpha'-azoisobutyronitrile (0.72 g; 4.37 mmol; 0.02 eq.). The mixture was stirred at 7O0C for 2 days. The reaction mixture was cooled to RT and water (500 mL) was added. The organic layer was washed with 50 mL NaHCO3 sat. solution, water (340 mL), then brine (500 mL), dried over MgSO4 and concentrated affording the title compound as a yellow solid. It was washed with pentane (2 x 500 mL) affording the title compound as a yellow solid. 1H NMR (DMSO-de, 300 MHz) delta 8.24 (d, J= 1 .91 Hz, 1 H), 7.88-7.82 (m, 2H), 4.87 (s, 2H), 3.91 (s, 3H). HPLC (Method A) Rt 4.44 min (Purity: 97.9%). |
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With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In chloroform; at 70℃; for 48h;Inert atmosphere;Product distribution / selectivity; |
Methyl 4-bromo-3-(bromomethyl)benzoate:Under N2, to a solution of methyl 4-bromo-3-methylbenzoate (50 g; 218.27 mmol) in CHCI3 (1 000 mL) were added NBS (Merck, 46.62 g; 261.93 mmol) in one portion and alpha, alpha'- azoisobutyronitrile (0.72 g; 4.37 mmol). The mixture was stirred at 7O0C for 2 days. The reaction mixture was cooled to RT and water (500 mL) was added. The organic layer was washed with of a saturated aqueous solution of NaHCC>3, water (340 mL), then brine (500 mL), dried over MgSO4 and concentrated affording the title compound as a yellow solid. It was washed with pentane (2 x 500 mL) affording the title compound as a yellow solid. 1H NMR (DMSO-de) delta 8.24 (d, J= 1.91 Hz, 1 H), 7.88-7.82 (m, 2H), 4.87 (s, 2H), 3.91 (s, 3H). HPLC (Method A) Rt 4.44 min (Purity: 97.9%). |
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With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; water; for 2 - 3h;Heating / reflux; |
STEP06: Synthesis of 4-Bromo-3-bromomethyl-benzoic acid methyl ester.; <n="259"/>28 gm (O.llmol) 4-Bromo-3-methyl-benzoic acid ethyl ester was dissolved in 120ml of carbon tetrachloride, to it was added 22.65gm (0.12mol) N-Bromosuccinimide followed by addition of 1.4gm(0.005mol) Benzoyl peroxide (75% in water). This reaction mixture was stirred and reflux for 2 to 3hrs. Reaction mixture was cooled to O0C to get the crystalline solid, which was filtered under vacuum and was washed with 30ml of carbon tetrachloride. Thus filtrate obtained was evaporated under vacuum. Residue was diluted with 300ml hexane and cooled to O0C to get the crystalline solid, which was filtered under vacuum washed with hexane to give 17.5gm 4-Bromo-3-bromomethyl-benzoic acid ethyl ester. |
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With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; at 70 - 80℃; for 54h; |
d) Methyl 4-bromo-3-(bromomethyl)benzoateN-Bromosuccinimide (1.947 niL, 22.95 mmol) and 2,2'-azobisisobutyronitrile (0.0225 g, 0.14 mmol) was added to a stirred solution of methyl 4-bromo-3-methylbenzoate (5.0519 g, 22.05 mmol) in carbon tetrachloride (70 mL) and the resulting mixture was stirred at 70 0C for 2 days and at 80 0C for 6 h. Water and chloroform was added. The aqueous phase was extracted with chloroform and the combined organic phases were washed with water and saturated aqueous sodium hydrogen carbonate, dried over magnesium sulfate and the solvent was evaporated to give 6.63 g of the title compound used in the next step without further purification. 1H NMR (500 MHz, CDCl3) delta ppm 8.13 (d, 1 H) 7.83 (dd, 1 H) 7.68 (d, 1 H) 4.63 (s, 2 H) 3.94 (s, 3 H); GC, ms detection: GC MS (EI) m/z 308 [M]+*. |
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With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In chloroform; at 70℃; for 48h;Inert atmosphere of N2; |
NBS (46.6 g, 262 mmol) and AIBN (0.72 g, 4.4 mmol) were added in one portion into a solution of methyl 4-bromo-3-methylbenzoate (50.0 g, 218 mmol) in CHCI3 (1 L) under N2. The mixture was stirred at 700C for 2 days. The reaction mixture was cooled to RT and water (500 ml.) was added. The organic layer was washed with a saturated solution of NaHCC>;3 (50 ml_), water (350 ml.) and brine (500 ml_). The organic layer was dried (MgSO4) and concentrated under reduced pressure. The residue was washed with pentane (2 x 500 ml.) affording the title compound as a yellow solid. HPLC (Method A), Rt 4.9 min (Purity: 98.2%). 1H NMR (DMSOd6, 300 MHz) delta 8.24 (d, J= 1.9 Hz, 1 H), 7.85 (m, 2H), 4.87 (s, 2H), 3.91 (s, 3H). |
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