4-(bromomethyl)-1-chloro-2-methoxybenzene

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

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 4-bromomethyl-1-chloro-2-methoxy-benzene (68.5 g, 0.29 mol) in C2H5OH (90%, 500 mL) was added NaCN (28.5 g, 0.58 mol). The mixture was stirred at 60° C. overnight. Ethanol was evaporated and the residue was dissolved in H2O. The mixture was extracted with ethyl acetate (300 mL×3). The combined organic layers were washed with brine, dried over Na2SO4 and purified by column chromatography on silica gel (Petroleum Ether/EtOAc 30:1) to give 2-(4-chloro-3-methoxyphenyl)acetonitrile (25 g, 48%). 1H NMR (400 MHz, CDCl3) δ 7.36 (d, J=8 Hz, 1H), 6.88-6.84 (m, 2H), 3.92 (s, 3H), 3.74 (s, 2H). 13C NMR (100 MHz, CDCl3) δ 155.4, 130.8, 129.7, 122.4, 120.7, 117.5, 111.5, 56.2, 23.5. Ethanol was evaporated the residue was dissolved in H2O The mixture was extracted with ethyl acetate (300 mL×3) The combined organic layers were washed with brine dried over Na2SO4 purified by column chromatography on silica gel (Petroleum Ether/EtOAc 30:1)

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

Procedure: To a solution of 1-chloro-2-methoxy-4-methyl-benzene (50 g, 0.32 mol) in CCl4 (350 mL) was added NBS (57.2 g, 0.32 mol) and AIBN (10 g, 60 mmol). The mixture was heated at reflux for 3 hours. The solvent was evaporated under vacuum and the residue was purified by column chromatography on silica gel (Petroleum Ether/EtOAc=20:1) to give 4-bromomethyl-1-chloro-2-methoxy-benzene (69 g, 92%). 1H NMR (400 MHz, CDCl3) δ 7.33-7.31 (m, 1H), 6.95-6.91 (m, 2H), 4.46 (s, 2H), 3.92 (s, 3H). The mixture was heated at reflux for 3 hours The solvent was evaporated under vacuum the residue was purified by column chromatography on silica gel (Petroleum Ether/EtOAc=20:1)

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 4-bromomethyl-1-chloro-2-methoxy-benzene (68.5 g, 0.29 mol) in C2H5OH (90%, 500 mL) was added NaCN (28.5 g, 0.58 mol). The mixture was stirred at 60° C. overnight. Ethanol was evaporated and the residue was dissolved in H2O. The mixture was extracted with ethyl acetate (300 mL×3). The combined organic layers were washed with brine, dried over Na2SO4 and purified by column chromatography on silica gel (Petroleum Ether/EtOAc 30:1) to give 2-(4-chloro-3-methoxyphenyl)acetonitrile (25 g, 48%). 1H NMR (400 MHz, CDCl3) δ 7.36 (d, J=8 Hz, 1 H), 6.88-6.84 (m, 2 H), 3.92 (s, 3 H), 3.74 (s, 2 H). 13c NMR (100 MHz, CDCl3) δ 155.4, 130.8, 129.7, 122.4, 120.7, 117.5, 111.5, 56.2, 23.5. Ethanol was evaporated the residue was dissolved in H2O The mixture was extracted with ethyl acetate (300 mL×3) The combined organic layers were washed with brine dried over Na2SO4 purified by column chromatography on silica gel (Petroleum Ether/EtOAc 30:1)

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

Procedure: To a solution of 1-chloro-2-methoxy-4-methyl-benzene (50 g, 0.32 mol) in CCl4 (350 mL) was added NBS (57.2 g, 0.32 mol) and AIBN (10 g, 60 mmol). The mixture was heated at reflux for 3 hours. The solvent was evaporated under vacuum and the residue was purified by column chromatography on silica gel (Petroleum Ether/EtOAc=20:1) to give 4-bromomethyl-1-chloro-2-methoxy-benzene (69 g, 92%). 1H NMR (400 MHz, CDCl3) δ 7.33-7.31 (m, 1 H), 6.95-6.91 (m, 2 H), 4.46 (s, 2 H), 3.92 (s, 3 H). The mixture was heated at reflux for 3 hours The solvent was evaporated under vacuum the residue was purified by column chromatography on silica gel (Petroleum Ether/EtOAc=20:1)

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 4-bromomethyl-1-chloro-2-methoxy-benzene (68.5 g, 0.29 mol) in C2H5OH (90%, 500 mL) was added NaCN (28.5 g, 0.58 mol). The mixture was stirred at 60° C. overnight. Ethanol was evaporated and the residue was dissolved in H2O. The mixture was extracted with ethyl acetate (300 mL×3). The combined organic layers were washed with brine, dried over Na2SO4 and purified by column chromatography on silica gel (Petroleum Ether/EtOAc 30:1) to give 2-(4-chloro-3-methoxyphenyl)acetonitrile (25 g, 48%). 1H NMR (400 MHz, CDCl3) δ 7.36 (d, J=8 Hz, 1 H), 6.88-6.84 (m, 2 H), 3.92 (s, 3 H), 3.74 (s, 2 H). 13C NMR (100 MHz, CDCl3) δ 155.4, 130.8, 129.7, 122.4, 120.7, 117.5, 111.5, 56.2, 23.5. Ethanol was evaporated the residue was dissolved in H2O The mixture was extracted with ethyl acetate (300 mL×3) The combined organic layers were washed with brine dried over Na2SO4 purified by column chromatography on silica gel (Petroleum Ether/EtOAc 30:1)

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 4-bromomethyl-1-chloro-2-methoxy-benzene (68.5 g, 0.29 mol) in C2H5OH (90%, 500 mL) was added NaCN (28.5 g, 0.58 mol). The mixture was stirred at 60° C. overnight. Ethanol was evaporated and the residue was dissolved in H2O. The mixture was extracted with ethyl acetate (300 mL×3). The combined organic layers were washed with brine, dried over Na2SO4 and purified by column chromatography on silica gel (Petroleum Ether/EtOAc 30:1) to give 2-(4-chloro-3-methoxyphenyl)acetonitrile (25 g, 48%). 1H NMR (400 MHz, CDCl3) δ 7.36 (d, J=8 Hz, 1 H), 6.88-6.84 (m, 2 H), 3.92 (s, 3 H), 3.74 (s, 2 H). 13C NMR (100 MHz, CDCl3) δ 155.4, 130.8, 129.7, 122.4, 120.7, 117.5, 111.5, 56.2, 23.5. Ethanol was evaporated the residue was dissolved in H2O The mixture was extracted with ethyl acetate (300 mL×3) The combined organic layers were washed with brine dried over Na2SO4 purified by column chromatography on silica gel (Petroleum Ether/EtOAc 30:1)

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

Procedure: To a solution of 1-chloro-2-methoxy-4-methyl-benzene (50 g, 0.32 mol) in CCl4 (350 mL) was added NBS (57.2 g, 0.32 mol) and AIBN (10 g, 60 mmol). The mixture was heated at reflux for 3 hours. The solvent was evaporated under vacuum and the residue was purified by column chromatography on silica gel (Petroleum Ether/EtOAc=20:1) to give 4-bromomethyl-1-chloro-2-methoxy-benzene (69 g, 92%). 1H NMR (400 MHz, CDCl3) δ 7.33-7.31 (m, 1 H), 6.95-6.91 (m, 2 H), 4.46 (s, 2 H), 3.92 (s, 3 H). The mixture was heated at reflux for 3 hours The solvent was evaporated under vacuum the residue was purified by column chromatography on silica gel (Petroleum Ether/EtOAc=20:1)

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

Procedure: To a solution of 4-chloro-3-methoxytoluene (200 mg, 1.28 mmol) in carbon tetrachloride (12 mL) was added N-bromosuccinimide (228 mg, 1.28 mmol) and benzoyl peroxide (31 mg, 0.128 mmol). The mixture was heated at reflux for 2 hours. The reaction mixture was allowed to cool to room temperature and the solvent removed in vacuo. The resulting residue was partitioned between DCM and water. The organic layer was separated, dried over sodium sulphate and evaporated to yield an orange oil. The oil was purified by silica gel chromatography eluting with 30% heptanes in DCM to afford the title compound (45 mg) as a 3.5:1:1 mixture with 4-chloro-3-methoxytoluene and 1-chloro-4-(dibromomethyl)-2-methoxybenzene respectively, which was used in the next step without further purification. The mixture was heated at reflux for 2 hours the solvent removed in vacuo The resulting residue was partitioned between DCM and water The organic layer was separated dried over sodium sulphate evaporated to yield an orange oil The oil was purified by silica gel chromatography eluting with 30% heptanes in DCM

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

Procedure: To a solution of 4-chloro-3-methoxytoluene (200 mg, 1.28 mmol) in carbon tetrachloride (12 mL) was added N-bromosuccinimide (228 mg, 1.28 mmol) and benzoyl peroxide (31 mg, 0.128 mmol). The mixture was heated at reflux for 2 hours. The reaction mixture was allowed to cool to room temperature and the solvent removed in vacuo. The resulting residue was partitioned between DCM and water. The organic layer was separated, dried over sodium sulphate and evaporated to yield an orange oil. The oil was purified by silica gel chromatography eluting with 30% heptanes in DCM to afford the title compound (45 mg) as a 3.5:1:1 mixture with 4-chloro-3-methoxytoluene and 1-chloro-4-(dibromomethyl)-2-methoxybenzene respectively, which was used in the next step without further purification. The mixture was heated at reflux for 2 hours the solvent removed in vacuo The resulting residue was partitioned between DCM and water The organic layer was separated dried over sodium sulphate evaporated to yield an orange oil The oil was purified by silica gel chromatography eluting with 30% heptanes in DCM

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 4-bromomethyl-1-chloro-2-methoxy-benzene (68.5 g, 0.290 mol) in C2H5OH (90%, 500 mL) was added NaCN (28.5 g, 0.580 mol). The mixture was stirred at 60° C. overnight. Ethanol was evaporated and the residue was dissolved in H2O. The mixture was extracted with ethyl acetate (300 mL×3). The combined organic layers were washed with brine, dried over Na2SO4 and purified by column chromatography on silica gel (petroleum ether/ethyl acetate 30:1) to give 2-(4-chloro-3-methoxyphenyl)acetonitrile (25 g, 48%). 1H NMR (400 MHz, CDCl3) δ 7.36 (d, J=8 Hz, 1H), 6.88-6.84 (m, 2H), 3.92 (s, 3H), 3.74 (s, 2H). 13C NMR (100 MHz, CDCl3) δ 155.4, 130.8, 129.7, 122.4, 120.7, 117.5, 111.5, 56.2, 23.5. Ethanol was evaporated the residue was dissolved in H2O The mixture was extracted with ethyl acetate (300 mL×3) The combined organic layers were washed with brine dried over Na2SO4 purified by column chromatography on silica gel (petroleum ether/ethyl acetate 30:1)

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

Procedure: To a solution of 1-chloro-2-methoxy-4-methyl-benzene (50 g, 0.32 mol) in CCl4 (350 mL) was added NBS (57 g, 0.32 mol) and AIBN (10 g, 60 mmol). The mixture was heated at reflux for 3 hours. The solvent was evaporated under vacuum and the residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=20:1) to give 4-bromomethyl-1-chloro-2-methoxy-benzene (69 g, 92%). 1H NMR (400 MHz, CDCl3) δ 7.33-7.31 (m, 1H), 6.95-6.91 (m, 2H), 4.46 (s, 2H), 3.92 (s, 3H). The mixture was heated at reflux for 3 hours The solvent was evaporated under vacuum the residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=20:1)