1-BROMO-3-METHOXY-2-METHYLBENZENE

1-bromo-3-methoxy-2-methylbenzeneTo a solution of 3-bromo-2-methyl-phenol (11.4 g, 60.95 mmol) in DMF (150 mL) was added KAfter stirring a mixture of cesium hydroxide hydrate (6.57 g, 39.1 mmol) and molecular sieves (4 Å, 15.06 g) in N, N-dimethylformamide (75 mL) at room temperature for 15 minutes, 10-1 (5.63 g, 30.1 mmol) was added. The mixture was stirred for 30 minutes and iodomethane (2.44 mL, 39.1 mmol) was added. 2-Methoxy-4-bromotoluene; Crude 2-methoxy-6-amino-toluene (max. 120 mmol) was suspended in HBr (48percent, 48 ml) and water (120 ml) and cooled to 0°C in an ice bath. Sodium nitrite (9.2 g) in water (24 ml) was added dropwise to the cold mixture, which turned yellow then brown. After 10 min, excess nitrite was destroyed by addition of urea (0.08 g) and the mixture was rapidly filtered into cold (0°C) acetone (480 ml) to give a bright yellow solution. CuBr (99.999percent, 18.89, 131 mmol) was then added portionwise and the resulting mixture stirred at 0°C for 3h. Gas evolution was observed. The mixture was allowed to warm to ambient temperature, and then concentrated in vacuo. Dichloromethane was then added and the mixture washed with sat. aq. sodium bicarbonate solution. The organic layer was separated, dried over magnesium sulphate and concentrated in vacuo to give the product (23.1 g, 96percent) as a red oil. No.H (CDCl3; 250MHz) 7.18-6.77 (3H, m, aromatics), 3.83 (3H, s, OCH3), 2.32 (3H, s, CH3).To 3-methoxy-2-methyl aniline(2.74 g, 20 mmol), water (6 mL) and 48percent aqueous solution of hydrobromic acid (2.4 mL) were added. To this sodium nitrite (2.76 g, 40 mmol) in water (1.20 mL) was added dropwise at 0°C for 10 minutes. After adding acetone (24 mL) to the reaction mixture, copper bromide (5.64 g, 40 mmol) was added at 0°C and stirred for 3hours. The reaction mixture was warmed to room temperature and concentrated. The residue was diluted with dichloromethane and washed with a mixture of saturated aqueous sodium hydrogen carbonate and aqueous ammonia. The organic layer was dried over anhydrous sodium sulfate and the filtrate was concentrated to obtain the title compound (2.5 g, yield : 62percent); m/z (ES+) : 201 [M+H]1-bromo-3-methoxy-2-methylbenzeneTo 3-bromo-2-methylphenol (500 mg, 2.67 mmol) in DMF (10 mL) was added potassium carbonate (1 108 mg, 8.02 mmol) and the mixture was stirred for 5 min before was added Mel (0.836 mL, 13.37 mmol) and let the reaction was stirred at 50 C for 2 h. The reaction was washed with waster (30 mL), extracted with EtOAc (20 mL + 3x 20 mL) and concentrated to give 450 mg (80 %) of the title compound. LC-MS m/z 305.9 (M+H)+, 1.09 (ret. time).A mixture of 7g2 (9.2 g, 50 mmol) and K2C03 (20 g, 150 mmol) in DMF (100 mL) is treated with iodomethane (9.2 mL, 150 mmol) and stirred at RT for 3 h. The mixture is diluted with EtOAc, washed with water followed by saturated aqueous NaCI. The organic layer is dried over MgS04 and the solvent is evaporated to give compound 7g3.To a solution of 3-bromo-2-methyl-phenol (11.4 g, 60.95 mmol) in DMF (150 mL) was added K2C03 (25.3 g, 183 mmol) and iodomethane (26.0 g, 183 mmol). The mixture was stirred at 25 C for 12 hrs, and then concentrated under reduced pressure. The residue was diluted with EtOAc (200 mL). The organic mixture was washed with water and brine, dried over anhydrous Na2S04 and concentrated under reduced pressure. The residue was purified by column chromatography to give 4-bromo-l-methoxy-2-(3-methoxypropoxy)benzene (11.0 g) as a colorless oilAfter stirring a mixture of cesium hydroxide hydrate (6.57 g, 39.1 mmol) and molecular sieves (4 A, 15.06 g) in N, N-dimethylformamide (75 mL) at room temperature for 15 minutes, 10-1 (5.63 g, 30.1 mmol) was added. The mixture was stirred for 30 minutes and iodomethane (2.44 mL, 39.1 mmol) was added. The reaction was stirred 4 hours then diluted with ethyl acetate and filtered through Celite. The filtrate was diluted with water and the aqueous layer was adjusted to pH 9 with aqueous sodium hydroxide (1N). The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated. The residue was taken up in 5% ethyl acetate in hexanes (250 mL) and filtered through a short plug of silica gel. The filtrate was concentrated to give 1-bromo-3-methoxy-2-methylbenzene (10-2, 4.57 g) as a yellow liquid. This procedure was also used to prepare 2-bromo-4-methoxy-1-methylbenzene.

Molecular Weight:201.06
XLogP3:3.6
Hydrogen Bond Acceptor Count:1
Rotatable Bond Count:1
Exact Mass:199.98368
Monoisotopic Mass:199.98368
Topological Polar Surface Area:9.2
Heavy Atom Count:10
Complexity:105
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes