(4-bromo-3-methylphenyl)methanol

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (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 0° C. 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 1-Bromo-4-(bromomethyl)-2-methylbenzene as a clear oil contaminated with bromoform which is used directly in the next step. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 4.39-4.44 (m, 3H) 7.07 (dd, J=8.20, 2.34 Hz, 1H) 7.26 (t, J=1.17 Hz, 1H) 7.49 (d, J=8.20 Hz, 1H) the triphenylphosphine oxide that forms is filtered off the solvent removed in vacuo The resulting semi solid is filtered on a silica gel pad rinsed with hexane/EtOAc (9:1)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Methyl 4-bromo-3-methylbenzoate (17.0 g, 74.2 mmol) is dissolved in anhydrous THF (100 mL). The solution is cooled to 0° C. and a 2 M solution of lithium aluminum hydride in THF (40 mL) is added to the mixture. The solution is left stirring 30 min. at this temperature. A cold HCl solution is then added drop wise to the reaction mixture until dissolution of the aluminum complex. The desired product is extracted with ethyl acetate, the organic phase is washed with brine (200 mL), dried with MgSO4 and concentrated in vacuo. to provide the expected product (4-Bromo-3-methylphenyl)methanol (14.4 g, 97%) as a clear yellow oil, pure by proton NMR, and is used as such in the next step. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 2.40 (s, 3 H) 4.61 (s, 2H) 6.89-7.10 (m, J=8.20, 1.56, 0.59 Hz, 1H) 7.23 (d, J=2.34 Hz, 1H) 7.50 (d, J=8.20 Hz, 1H) The solution is left until dissolution of the aluminum complex The desired product is extracted with ethyl acetate the organic phase is washed with brine (200 mL) dried with MgSO4 concentrated in vacuo

Conditions: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 93 ml of a 1M solution of borane-tetrahydrofuran complex in tetrahydrofuran are added dropwise to a solution of 10 g (46.5 mmol) of 4-bromo-3-methyl-benzoic acid in 100 ml of tetrahydrofuran at 0° C. under argon. After the reaction mixture has been heated to 20° C., it is stirred at this temperature for 16 hours. The excess borane complex is then destroyed by careful addition of water (end of the evolution of hydrogen), the mixture is extracted twice with in each case 250 ml of ethyl acetate and the combined organic phases are washed twice with in each case 100 ml of saturated sodium bicarbonate solution, water and saturated sodium chloride solution, dried over sodium sulphate and concentrated. The compound is reacted further without purification. The excess borane complex is then destroyed by careful addition of water (end of the evolution of hydrogen), the mixture is extracted twice with in each case 250 ml of ethyl acetate the combined organic phases are washed twice with in each case 100 ml of saturated sodium bicarbonate solution, water and saturated sodium chloride solution dried over sodium sulphate concentrated The compound is reacted further without purification

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3.7 g (43 mmol, 10 eq) of manganese dioxide are added to a solution of 900 mg (4.3 mmol, 1 eq) of (4-bromo-3-methylphenyl)methanol in 8 mL of dichloromethane. The reaction mixture is stirred for 12 hours at room temperature. The solid is filtered off and the solvent is evaporated off. 900 mg of 4-bromo-3-methylbenzaldehyde are obtained in oil form and used in the following reaction without further purification. The solid is filtered off the solvent is evaporated off