(4-BROMO-3-METHYLPHENYL)METHANOL

White low melting crystalline solid

4-Bromo-5-methylbenzylalcohol (2) Preparation of (4-bromo-3-methylphenyl)methanol [0163] To a solution of 4-bromo-3-methylbenzoic acid (30 g, 0.14 mol) in THF 300 mL) was added borane (10 M in THF, 70 mL, 0.7 mol) dropwise at 0 °C and the mixture was stirred at room temperature overnight. The reaction was quenched with methanol and water (10 mL). After removal of the solvent by rotary evaporation, the residue was extracted with dichloromethane. The organic layer was washed with brine, dried over NaGeneral procedure: 4-bromo-3-methylbenzoic acid (9.9 g, 46.04 mmol) was dissolved in THF (200 mL), to this was slowly added BH4-Bromo-3-methylbenzylalcohol (4) [00156] Step 1 : To a solution of methyl 4-bromo-3-methylbenzoate (50 g, 219 mmol) in THF (500 mL) at 0 °C was added lithium aluminum hydride (262 mL of 1 M solution in THF, 262 mmol) over 15 min. After stirring for 20 min, water (50 mL) was added dropwise, followed by 1 M NaOH (50 mL), and water (50 mL). The reaction mixture was filtered through Celite and concentrated in vacuo. The resulting residue was azeotroped once with toluene, then dissolved in DCM, dried over NaStep 2: 82A.Step a intermediate 44(4-Bromo-3 -methylphenyl)methanolMethyl 4-bromo-3-methylbenzoate (17.0 g, 74.2 mmol) is dissolved in anhydrous THF (100 mL). The solution is cooled to 0To a stirred solution of LiAlHNaBH4 (4.27 g, 2.50 mmol, 2.5 eq) was added to a solution of 4-bromo-3-methylbenzaldehyde (9.00 g, 45.21 mmol, 1.0 eq)in THF and EtOH (10:1, 150 mL) under nitrogen atmosphere and the solution was stirred at ambient temperature for 4 h. After complete consumption of starting material, the reaction mixture was diluted with EtOAc and washed with 0.5 N aq HC1 followed by water and brine. The organic extract was then dried over anhydrous sodium sulfate, filtered, and solvents evaporated from the filtrate under reduced pressure to afford (4-bromo-3-methylphenyl)methanol (9.0 g, 100percent) as yellow oil.Preparation of l-bromo-4-(bromomethyl)-2-methylbenzene [0164] To a solution of 82B.1-bromo-4-(bromomethyl)-2-methylbenzene To a stirred solution of 82A (775 mg, 3.85 mmol) and carbon tetrabromide (1.69 g, 5.05 mmol) in dichloromethane (19 mL) at rt was added triphenylphosphine (1.35 g, 5.10 mmol).The resulting solution was stirred at rt for 22 h and then mostly evaporated.The residue was taken up in ether (50 mL) and sonicated.The resulting suspension was filtered and the solid was rinsed with ether (2*5 mL).The filtrate and the rinses were combined and evaporated.Chromatography (SiO2 230-400 mesh, Hex to 95/5 Hex/EtOAc) of the crude afforded 82B (colorless liquid, 872.3 mg, 81percent yield).1H NMR (CDCl3, 400 MHz): delta 7.49 (d, J=8.2 Hz, 1H), 7.26 (s, 1H), 7.07 (dd, J=8.2, 2.2 Hz, 1H), 4.41 (s, 2H), 2.39 (s, 3H).To a stirred solution of PPh3 (2.1 g, 8.006 mmol, 2.0 eq.) in dry THF (10 mL, 12 vol.) were added bromo benzyl alcohol 1 (0.8 g, 3.980 mol, 1.0 equi) followed by BS (1.5 g, 8.427 mol, 2.1 eq.) portion wise on stirring for 10 min at 0°C under nitrogen atmosphere and then stirred for 16 h up to completion of the reaction. The reaction was diluted with water (100 mL) and extracted with EtOAc (3X250 mL). The combined organic layers were washed with saturated NaHC03 followed by brine solution. Then the organic portion was dried over anhydrous Na2S04, filtered and concentrated to obtain compound 2 as a brown oil, which was used directly in the next step without any further purification (0.8 g, 76percent).Step 16: 1-bromo-4-(bromomethyl)-2-methylbenzeneTo a solution of PBr3 (14.54 g, 53.71mmol, 1.2 eq) was added to a solution of (4-bromo-3-methylphenyl) methanol (9.0 g, 44.76mmol, 1.0 eq) in CHC13 (100 mL) at 0 °C under nitrogen atmosphere and the solution wasallowed to warm up to ambient temperature with constant stirring. The solution was then stirred at ambient temperature for a further 3 h. After complete consumption of starting material, the reaction mixture was diluted with chloroform and washed with saturated aq NaHCO3 and brine. The organic extract was then dried over anhydrous sodium sulfate, filtered, and solvents evaporated from the filtrate under reduced pressure to afford 1-bromo-4-(bromomethyl)-2-methylbenzene (7.0 g, 59percent) as yellow oil.Step b intermediate 45l-Bromo-4-(bromomethyl)-2-methylbenzene(4-Bromo-3-methylphenyl)methanol (14.4 g, 71.6 mmol) is dissolved in anhydrous CH2Cl2 (150 mL) and CBr4 (26.1 g, 79.0 mmol) is added. The reaction mixture is cooled to 00C and PPh3 (20.7 g, 79.0 mmol) is added in small portions. The reaction mixture is stirred 2 h and the triphenylphosphine oxide that forms is filtered off and the solvent removed in vacuo. The resulting semi solid is filtered on a silica gel pad and rinsed with hexane / EtOAc (9:1) to provide the expected product l-Bromo-4-(bromomethyl)-2-methylbenzene as a clear oil contaminated with bromoform which is used directly in the next step. IH NMR (400 MHz, CHLOROFORM- D) 5 ppm 4.39 - 4.44 (m, 3 H) 7.07 (dd, /=8.20, 2.34 Hz, 1 H) 7.26 (t, /=1.17 Hz, 1 H) 7.49 (d, /=8.20 Hz, 1 H)Step 3: Preparation of 4-bromo-3-methylbenzaldehyde To a solution of 3.7 g (43 mmol, 10 eq) of manganese dioxide are added to a solution of 900 mg (4.3 mmol, 1 eq) of

Molecular Weight:201.06
XLogP3:2.1
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:1
Rotatable Bond Count:1
Exact Mass:199.98368
Monoisotopic Mass:199.98368
Topological Polar Surface Area:20.2
Heavy Atom Count:10
Complexity:105
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes