1-Bromo-4-(bromomethyl)-2-methylbenzene

Preparation of l-bromo-4-(bromomethyl)-2-methylbenzene [0164] To a solution of (4-bromo-3-methylphenyl)methanol (27.5 g, 136.8 mmol) in dichloromethane (250 mL) was added PPh82B.To a stirred solution of PPhStep 16: 1-bromo-4-(bromomethyl)-2-methylbenzeneTo a solution of (4-bromo-3-methylphenyl)methanol (5.15 g, 25.6 mmol) and NBS (9.07 g, 51.2 mmol) in DCM (100mL) was added drop wise PPhPBr3 (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.Preparation of l-bromo-4-(bromomethyl)-2-methylbenzene [0164] To a solution of (4-bromo-3-methylphenyl)methanol (27.5 g, 136.8 mmol) in dichloromethane (250 mL) was added PPh3 (39.4 g, 150.5 mmol) and CBr4 (49.9 g, 150.5 mmol) and the mixture was stirred for 2 hrs at room temperature. Water was added. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated. The crude product was purified by chromatography to give l-bromo-4- (bromomethyl)-2-methylbenzene (34 g, 94percent). 1H NMR (400 MHz, CDC13) delta 7.94- 7.92 (d, 1H), 7.70 (s, 1H), 7.53-7.51 (d, 1H), 4.86 (s, 2H), 2.83 (s, 3H).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 (4-bromo-3-methylphenyl)methanol (5.15 g, 25.6 mmol) and NBS (9.07 g, 51.2 mmol) in DCM (100mL) was added drop wise PPh3 (13.36 g, 51.2 mmol) in DCM (50 mL) at rt and the reaction mixture was stirred for 15 mins at rt. Then, water (50 mL) was added and the organic layers were washed with water (100 mL x 2) and dried over anhydrous Na2S04. After the removal of solvent, the residue was purified with column chromatography to afford 1-bromo-4-(bromomethyl)-2-methylbenzene (4.15 g, 65 percent yield) as a colorless oil. 1H NMR (300MHz, CHLOROFORM-d) delta: 7.50 - 7.48 (d, 1 H), 7.26 (s, 1 H), 7.08 - 7.05 (m, 1 H), 4.41 (s, 2H), 2.39 (s, 3H), .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)The suspension of l-(lH-imidazol-2-yl)ethanol (0.10 g), potassium carbonate (0.49 g) and 1- bromo-4-(bromomethyl)-2-methyl'benzene (0.35 g) in acetonitrile (4.5 mL) was stirred for 4 hours at 80 C. The mixture was allowed to cool to room temperature and filtered. The filtrate was diluted with water and was extracted with EtOAc. The organic layer was dried over MgS04, filtered and evaporated. The residue was charged onto ISOLUTE HM-N, purified with OH-type silica gel column chromatography (0'10 % MeOH in CHC) twice and then re-purified with amino-type silica gel column chromatography (0-10 % MeOH in CHCl3) to give the title compound (46 mg, 17 % yield) as pale yellowish solid.1H-NMR, MS and LCMS retention time data of Compound-31 are shown in Table 3.Intermediate 12 (E)-Methyl 3-(3-(N-(4-bromobenzyl)cyclohexanecarboxamido)phenyl)acrylate [00408] Sodium hydride (5.43 g, 136 mmol) was added in portions to a solution of Intermediate 9 (30 g, 104 mmol) in THF (800 mL) at 0 C. The mixture was stirred for 30 min, and then l-bromo-4-(bromomethyl)benzene (31.3 g, 125 mmol) was added in portions at 0 C. The resulting mixture was slowly warmed to 15 C and stirred for 14 h. Water (400 mL) was added, and the mixture was extracted with ethyl acetate (3 x500 mL). The combined organic layers were washed with brine (2x500 mL), dried over anhydrous Na2S04, filtered and concentrated. The residue was purified by column chromatography (Si02, petroleum ether/ethyl acetate; 3/1) to give (£)-methyl 3-(3-(JV-(4- bromobenzyl)cyclohexanecarboxamido)phenyl)acrylate (35 g, 66%) as a white solid. 1H NMR (DMSO-i): delta 7.58-7.72 (m, 3H), 7.37-7.50 (m, 3H), 7.06-7.18 (m, 3H), 6.67 (d, 1H), 4.82 (br s, 2H), 3.73 (s, 3H), 2.16 (br s, 1H), 1.56-1.72 (m, 4H), 1.32-1.54 (m, 3H), 1.10 (q, 1H), 0.88 (d, 2H); MS: 456.2 [M+H]+. The Intermediates below were synthesized from the appropriate starting materials following the procedure described for Intermediate 12Notes: Reaction time: 2-16h; *DMF insteac of THF; Cs2C03, CH3CN also utilized.

Molecular Weight:263.96
XLogP3:3.5
Rotatable Bond Count:1
Exact Mass:263.89723
Monoisotopic Mass:261.89928
Heavy Atom Count:10
Complexity:103
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes