4-bromo-1-(chloromethyl)-2-methylbenzene

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Add sodium hydride (8.29 g, 0.21 mol, 60% dispersion in oil) to a solution of methyl 4-methyl-3-oxovalerate (27.1 mL, 0.19 mol) in tetrahydrofuran at 0° C. After 30 min at room temperature, add a solution of 4-bromo-1-chloromethyl-2-methyl-benzene (35.0 g, 0.16 mol) in tetrahydrofuran (50 mL). Heat the resulting mixture at 70° C. overnight (18 hours). Add 1.0 M HCl (20 mL) to quench the reaction. Extract with ethyl acetate (200 mL), wash extract with water (200 mL) and brine (200 mL), dry over Na2SO4, filter and concentrate under reduced pressure. Dissolve the resulting residue in toluene (200 mL) and add hydrazine monohydrate (23.3 mL, 0.48 mol). Heat the mixture at 120° C. for 2 hours with a Dean-Stark apparatus to remove water. Cool and remove the solvent under the reduced pressure, dissolve the residue with dichloromethane (50 mL) and methanol (50 mL). Pour this solution slowly to a beaker with water (250 mL). Collect the resulting precipitated product by vacuum filtration. Dry in vacuo in an oven overnight at 40° C. to yield the title compound as a solid (48.0 g, 0.16 mol). MS (m/z): 311.0 (M+1), 309.0 (M−1). to quench the reaction Extract with ethyl acetate (200 mL) wash extract with water (200 mL) and brine (200 mL) dry over Na2SO4 filter concentrate under reduced pressure Dissolve the resulting residue in toluene (200 mL) Heat the mixture at 120° C. for 2 hours with a Dean-Stark apparatus to remove water Cool remove the solvent under the reduced pressure dissolve the residue with dichloromethane (50 mL) and methanol (50 mL) Pour this solution slowly to a beaker with water (250 mL) Collect the resulting precipitated product by vacuum filtration Dry in vacuo in an oven overnight at 40° C.

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Add sodium hydride (8.29 g, 0.21 mol, 60% dispersion in oil) to a solution of methyl 4-methyl-3-oxovalerate (27.1 mL, 0.19 mol) in tetrahydrofuran at 0° C. After 30 min at room temperature, add a solution of 4-bromo-1-chloromethyl-2-methyl-benzene (35.0 g, 0.16 mol) in tetrahydrofuran (50 mL). Heat the resulting mixture at 70° C. overnight (18 hours). Add 1.0 M HCl (20 mL) to quench the reaction. Extract with ethyl acetate (200 mL), wash extract with water (200 mL) and brine (200 mL), dry over Na2SO4, filter and concentrate under reduced pressure. Dissolve the resulting residue in toluene (200 mL) and add hydrazine monohydrate (23.3 mL, 0.48 mol). Heat the mixture at 120° C. for 2 hours with a Dean-Stark apparatus to remove water. Cool and remove the solvent under the reduced pressure, dissolve the residue with dichloromethane (50 mL) and methanol (50 mL). Pour this solution slowly to a beaker with water (250 mL). Collect the resulting precipitated product by vacuum filtration. Dry in vacuo in an oven overnight at 40° C. to yield the title compound as a solid (48.0 g, 0.16 mol). MS (m/z): 311.0 (M+1), 309.0 (M−1). to quench the reaction Extract with ethyl acetate (200 mL) wash extract with water (200 mL) and brine (200 mL) dry over Na2SO4 filter concentrate under reduced pressure Dissolve the resulting residue in toluene (200 mL) Heat the mixture at 120° C. for 2 hours with a Dean-Stark apparatus to remove water Cool remove the solvent under the reduced pressure dissolve the residue with dichloromethane (50 mL) and methanol (50 mL) Pour this solution slowly to a beaker with water (250 mL) Collect the resulting precipitated product by vacuum filtration Dry in vacuo in an oven overnight at 40° C.

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

Procedure: Methanesulfonyl chloride (6.83 mL, 88.3 mmol) is added slowly to a solution of (4-bromo-2-methyl-phenyl)methanol (16.14 g, 80.27 mmol) and triethylamine (16.78 mL; 120.4 mmol) in dichloromethane (80.7 mL) cooled in ice/water. The mixture is allowed to slowly warm to ambient temperature and is stirred for 16 hours. Further methanesulfonyl chloride (1.24 mL; 16.1 mmol) is added and the mixture is stirred at ambient temperature for 2 hours. Water (80 mL) is added and the phases are separated. The organic layer is washed with hydrochloric acid (1N; 80 mL) then saturated aqueous sodium hydrogen carbonate solution (80 mL), then water (80 mL), and is dried over Na2SO4 Filtration and concentration under reduced pressure gives a residue which is purified by flash chromatography (eluting with hexane) to give the title compound (14.2 g; 80.5% yield). 1H NMR (300.11 MHz, CDCl3): δ 7.36-7.30 (m, 2H), 7.18 (d, J=8.1 Hz, 1H), 4.55 (s, 2H), 2.41 (s, 3H). the mixture is stirred at ambient temperature for 2 hours the phases are separated The organic layer is washed with hydrochloric acid (1N; 80 mL) saturated aqueous sodium hydrogen carbonate solution (80 mL), then water (80 mL), and is dried over Na2SO4 Filtration and concentration under reduced pressure gives a residue which is purified by flash chromatography (eluting with hexane)

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

Procedure: Add thionyl chloride (14.31 mL, 0.2 mol,) to a solution of (4-bromo-2-methyl-phenyl)methanol (32.9 g, 0.16 mol) in dichloromethane (200 mL) and dimethylformamide (0.025 mol, 2.0 mL) at 0° C. After 1 hour at room temperature pour the mixture into ice-water (100 g), extract with dichloromethane (300 mL), wash extract with 5% aq. sodium bicarbonate (30 mL) and brine (200 mL), dry over sodium sulfate, and concentrate under reduced pressure to give the crude title compound as a white solid (35.0 g, 0.16 mol). The material is used for the next step of reaction without further purification. 1H NMR (CDCl3): δ 2.38 (s, 3H), 4.52 (s, 2H), 7.13-7.35 (m, 3H). extract with dichloromethane (300 mL) wash extract with 5% aq. sodium bicarbonate (30 mL) and brine (200 mL) dry over sodium sulfate concentrate under reduced pressure

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

Procedure: 4-Bromo-1-chloromethyl-2-methyl-benzene (63 g, 287 mmol) was dissolved in DMF (180 mL). NaCN (15.5 g, 316 mmol, 1.1 eq.) was added in 1 portion, and the reaction was stirred at room temperature overnight under a N2 atmosphere. The mixture was concentrated under reduced pressure, and the residue was taken into a mixture of sat. aq. NH4Cl (300 mL) and EtOAc (300 mL). The bi-phase solution was diluted with H2O (200 mL). The EtOAc layer was separated, and the aqueous layer was re-extracted with EtOAc (2×200 mL). The combined organic layers were washed with brine (3×300 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure, yielding the title compound (58.8 g, 280 mmol, 98%) with acceptable purity as a brown oil, which solidified to a brown solid on standing. 1H-NMR (CDCl3, 300 MHz) δ ppm 2.34 (s, 3H); 3.63 (s, 2H); 7.26 (t, 1H); 7.38 (d, 2H). The mixture was concentrated under reduced pressure the residue was taken into a mixture of sat. aq. NH4Cl (300 mL) and EtOAc (300 mL) The bi-phase solution was diluted with H2O (200 mL) The EtOAc layer was separated the aqueous layer was re-extracted with EtOAc (2×200 mL) The combined organic layers were washed with brine (3×300 mL) dried (Na2SO4) filtered concentrated under reduced pressure

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

Procedure: 4-Bromo-1-chloromethyl-2-methyl-benzene (63 g, 287 mmol) was dissolved in DMF (180 mL). NaCN (15.5 g, 316 mmol, 1.1 eq.) was added in 1 portion, and the reaction was stirred at room temperature overnight under a N2 atmosphere. The mixture was concentrated under reduced pressure, and the residue was taken into a mixture of sat. aq. NH4Cl (300 mL) and EtOAc (300 mL). The bi-phase solution was diluted with H2O (200 mL). The EtOAc layer was separated, and the aqueous layer was re-extracted with EtOAc (2×200 mL). The combined organic layers were washed with brine (3×300 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure, yielding the title compound (58.8 g, 280 mmol, 98%) with acceptable purity as a brown oil, which solidified to a brown solid on standing. 1H-NMR (CDCl3, 300 MHz) δ ppm 2.34 (s, 3H); 3.63 (s, 2H); 7.26 (t, 1H); 7.38 (d, 2H). The mixture was concentrated under reduced pressure the residue was taken into a mixture of sat. aq. NH4Cl (300 mL) and EtOAc (300 mL) The bi-phase solution was diluted with H2O (200 mL) The EtOAc layer was separated the aqueous layer was re-extracted with EtOAc (2×200 mL) The combined organic layers were washed with brine (3×300 mL) dried (Na2SO4) filtered concentrated under reduced pressure

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

Procedure: (4-Bromo-2-methyl-phenyl)-methanol (40.0 g, 199 mmol) was added to thionyl chloride (106.6 g, 0.896 mole, 65.3 mL). The mixture was heated to reflux, for 1.5 hours. After cooling to room temperature the mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc (300 mL) and added carefully to saturated aqueous NaHCO3 (500 mL). The EtOAc layer was separated, and the aqueous layer was extracted with EtOAc (250 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo yielding the title compound (34.19 g, 157 mmol, 79%) as a slightly colored oil that solidified to a white solid upon standing. 1H NMR (CDCl3, 300 MHz) δ ppm 2.38 (s, 3H); 4.57 (s, 2H); 7.12 (d, 1H); 7.28 (s, 1H); 7.55 (d, 1H) The mixture was heated to reflux, for 1.5 hours was concentrated under reduced pressure The residue was dissolved in EtOAc (300 mL) added carefully to saturated aqueous NaHCO3 (500 mL) The EtOAc layer was separated the aqueous layer was extracted with EtOAc (250 mL) The combined organic layers were dried (Na2SO4) filtered concentrated in vacuo

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Add sodium hydride (8.29 g, 0.21 mol, 60% dispersion in oil) to a solution of methyl 4-methyl-3-oxovalerate (27.1 mL, 0.19 mol) in tetrahydrofuran at 0° C. After 30 min at room temperature, add a solution of 4-bromo-1-chloromethyl-2-methyl-benzene (35.0 g, 0.16 mol) in tetrahydrofuran (50 mL). Heat the resulting mixture at 70° C. overnight (18 hours). Add 1.0 M HCl (20 mL) to quench the reaction. Extract with ethyl acetate (200 mL), wash extract with water (200 mL) and brine (200 mL), dry over Na2SO4, filter and concentrate under reduced pressure. Dissolve the resulting residue in toluene (200 mL) and add hydrazine monohydrate (23.3 mL, 0.48 mol). Heat the mixture at 120° C. for 2 hours with a Dean-Stark apparatus to remove water. Cool and remove the solvent under the reduced pressure, dissolve the residue with dichloromethane (50 mL) and methanol (50 mL). Pour this solution slowly to a beaker with water (250 mL). Collect the resulting precipitated product by vacuum filtration. Dry in vacuo in an oven overnight at 40° C. to yield the title compound as a solid (48.0 g, 0.16 mol). MS (m/z): 311.0 (M+1), 309.0 (M−1). to quench the reaction Extract with ethyl acetate (200 mL) wash extract with water (200 mL) and brine (200 mL) dry over Na2SO4 filter concentrate under reduced pressure Dissolve the resulting residue in toluene (200 mL) Heat the mixture at 120° C. for 2 hours with a Dean-Stark apparatus to remove water Cool remove the solvent under the reduced pressure dissolve the residue with dichloromethane (50 mL) and methanol (50 mL) Pour this solution slowly to a beaker with water (250 mL) Collect the resulting precipitated product by vacuum filtration Dry in vacuo in an oven overnight at 40° C.

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

Procedure: Methanesulfonyl chloride (6.83 mL, 88.3 mmol) is added slowly to a solution of (4-bromo-2-methyl-phenyl)methanol (16.14 g, 80.27 mmol) and triethylamine (16.78 mL; 120.4 mmol) in dichloromethane (80.7 mL) cooled in ice/water. The mixture is allowed to slowly warm to ambient temperature and is stirred for 16 hours. Further methanesulfonyl chloride (1.24 mL; 16.1 mmol) is added and the mixture is stirred at ambient temperature for 2 hours. Water (80 mL) is added and the phases are separated. The organic layer is washed with hydrochloric acid (1N; 80 mL) then saturated aqueous sodium hydrogen carbonate solution (80 mL), then water (80 mL), and is dried over Na2SO4. Filtration and concentration under reduced pressure gives a residue which is purified by flash chromatography (eluting with hexane) to give the title compound (14.2 g; 80.5% yield). 1H NMR (300.11 MHz, CDCl3): δ 7.36-7.30 (m, 2H), 7.18 (d, J=8.1 Hz, 1H), 4.55 (s, 2H), 2.41 (s, 3H). the mixture is stirred at ambient temperature for 2 hours the phases are separated The organic layer is washed with hydrochloric acid (1N; 80 mL) saturated aqueous sodium hydrogen carbonate solution (80 mL), then water (80 mL), and is dried over Na2SO4 Filtration and concentration under reduced pressure gives a residue which is purified by flash chromatography (eluting with hexane)

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

Procedure: Methanesulfonyl chloride (6.83 mL, 88.3 mmol) is added slowly to a solution of (4-bromo-2-methyl-phenyl)methanol (16.14 g, 80.27 mmol) and triethylamine (16.78 mL; 120.4 mmol) in dichloromethane (80.7 mL) cooled in ice/water. The mixture is allowed to slowly warm to ambient temperature and is stirred for 16 hours. Further methanesulfonyl chloride (1.24 mL; 16.1 mmol) is added and the mixture is stirred at ambient temperature for 2 hours. Water (80 mL) is added and the phases are separated. The organic layer is washed with hydrochloric acid (1N; 80 mL) then saturated aqueous sodium hydrogen carbonate solution (80 mL), then water (80 mL), and is dried over Na2SO4. Filtration and concentration under reduced pressure gives a residue which is purified by flash chromatography (eluting with hexane) to give the title compound (14.2 g; 80.5% yield). 1H NMR (300.11 MHz, CDCl3): δ 7.36-7.30 (m, 2H), 7.18 (d, J=8.1 Hz, 1H), 4.55 (s, 2H), 2.41 (s, 3H). the mixture is stirred at ambient temperature for 2 hours the phases are separated The organic layer is washed with hydrochloric acid (1N; 80 mL) saturated aqueous sodium hydrogen carbonate solution (80 mL), then water (80 mL), and is dried over Na2SO4 Filtration and concentration under reduced pressure gives a residue which is purified by flash chromatography (eluting with hexane)

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

Procedure: Add thionyl chloride (14.31 mL, 0.2 mol,) to a solution of (4-bromo-2-methyl-phenyl)methanol (32.9 g, 0.16 mol) in dichloromethane (200 mL) and dimethylformamide (0.025 mol, 2.0 mL) at 0° C. After 1 hour at room temperature pour the mixture into ice-water (100 g), extract with dichloromethane (300 mL), wash extract with 5% aq. sodium bicarbonate (30 mL) and brine (200 mL), dry over sodium sulfate, and concentrate under reduced pressure to give the crude title compound as a white solid (35.0 g, 0.16 mol). The material is used for the next step of reaction without further purification. 1H NMR (CDCl3): δ 2.38 (s, 3H), 4.52 (s, 2H), 7.13-7.35 (m, 3H). extract with dichloromethane (300 mL) wash extract with 5% aq. sodium bicarbonate (30 mL) and brine (200 mL) dry over sodium sulfate concentrate under reduced pressure

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

Procedure: Add thionyl chloride (14.31 mL, 0.2 mol,) to a solution of (4-bromo-2-methyl-phenyl)methanol (32.9 g, 0.16 mol) in dichloromethane (200 mL) and dimethylformamide (0.025 mol, 2.0 mL) at 0° C. After 1 hour at room temperature pour the mixture into ice-water (100 g), extract with dichloromethane (300 mL), wash extract with 5% aq. sodium bicarbonate (30 mL) and brine (200 mL), dry over sodium sulfate, and concentrate under reduced pressure to give the crude title compound as a white solid (35.0 g, 0.16 mol). The material is used for the next step of reaction without further purification. 1H NMR (CDCl3): δ 2.38 (s, 3H), 4.52 (s, 2H), 7.13-7.35 (m, 3H). extract with dichloromethane (300 mL) wash extract with 5% aq. sodium bicarbonate (30 mL) and brine (200 mL) dry over sodium sulfate concentrate under reduced pressure