4-bromo-3-chloro-2-methylaniline

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

Procedure: To a solution of 4-bromo-3-chloro-2-methylaniline (11 g, 49.9 mmol) in acetic acid (450 mL) was added NaNO2 (5.4 g, 78.3 mmol) in H2O (15 mL) at 10° C. The resulting mixture was stirred at room temperature for 30 minutes. Upon completion, the reaction mixture was diluted with H2O (500 mL) and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was triturated with petroleum ether affording the title compound (4.5 g) as yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 13.60 (s, 1H), 8.15 (s, 1H), 7.62 (d, 1H), 7.52 (d, 1H). extracted with EtOAc The organic layer was dried over Na2SO4 concentrated in vacuo The residue was triturated with petroleum ether affording the title compound (4.5 g) as yellow solid

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

Procedure: To a solution of 3-chloro-2-methylaniline (30 g, 0.212 mol) in CH3CN (300 mL) was added NBS (45.2 g, 0.254 mol) in portions at 10° C. The resulting mixture was stirred at room temperature for 30 minutes. Upon completion, saturated Na2S2O3 (500 mL) was added slowly into the reaction mixture at 10° C. The organic layer was separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The residue was washed with petroleum ether to afford the title compound (30 g), which was used in the next step without further purification. 1H NMR (300 MHz, CDCl3): δ 7.24 (d, 1H), 6.48 (d, 1H), 3.70 (br, 2H), 2.28 (s, 3H). The organic layer was separated the aqueous layer was extracted with EtOAc The combined organic layers were dried over Na2SO4 concentrated in vacuo The residue was washed with petroleum ether

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

Procedure: To a solution of 3-chloro-2-methylaniline (30 g, 0.212 mol) in CH3CN (300 mL) was added NBS (45.2 g, 0.254 mol) in portions at 10° C. The resulting mixture was stirred at room temperature for 30 minutes. Upon completion, saturated Na2S2O3 (500 mL) was added slowly into the reaction mixture at 10° C. The organic layer was separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The residue was washed with petroleum ether to afford the title compound (30 g), which was used in the next step without further purification. 1H NMR (300 MHz, CDCl3): δ 7.24 (d, 1H), 6.48 (d, 1H), 3.70 (br, 2H), 2.28 (s, 3H). The organic layer was separated the aqueous layer was extracted with EtOAc The combined organic layers were dried over Na2SO4 concentrated in vacuo The residue was washed with petroleum ether

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

Procedure: Concentrated HCl was added to a solution of 4-bromo-3-chloro-2-methyl-phenylamine (4.98 g, 22.60 mmol) in EtOH. NaNO2 (3.00 g, 43.50 mmol) was added and the resulting mixture was heated to 70° C. for 2 hours. Ethanol was distilled off and the residue was purified by column chromatography using hexanes as the eluant to afford the title compound. Spectroscopic data: 1H NMR (300 MHz, CDCl3) δ 2.43 (s, 3H), 7.01 (t, J=7.91 Hz, 1H), 7.18 (d, J=7.62 Hz, 1H), 7.47 (d, J=7.91 Hz, 1H). Ethanol was distilled off the residue was purified by column chromatography

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

Procedure: A solution of N-(4-bromo-3-chloro-2-methyl-phenyl)-acetamide (3.37 g, 12.80 mmol) in H2SO4: H2O (1:1) was refluxed for 3 hours. The reaction mixture was cooled to room temperature and neutralized with NaOH and extracted with Et2O (3×150 mL). The combined organic phases were washed with H2O (3×100 mL) and brine (1×100 mL), then dried over MgSO4 and concentrated. Purification by column chromatography using hex:EtOAc (4:1) as the eluant afforded the title aniline. Spectroscopic data: 1H NMR (300 MHz, CDCl3) δ 2.31 (s, 3H), 3.93 (br s, 2H), 6.47 (d, J=8.79 Hz, 1H), 7.24 (d, J=7.91 Hz, 1H). extracted with Et2O (3×150 mL) The combined organic phases were washed with H2O (3×100 mL) and brine (1×100 mL) dried over MgSO4 concentrated Purification by column chromatography

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

Procedure: The title compound was prepared (0.70 g, 83% yield) from 22A in a manner similar to that described in Experiment 2D.

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

Procedure: The title compound was prepared (0.70 g, 83% yield) from 22A in a manner similar to that described in Experiment 2D.

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

Procedure: The title compound was prepared (0.70 g, 83% yield) from 22A in a manner similar to that described in Experiment 2D.

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

Procedure: To a solution of 4-bromo-3-chloro-2-methylaniline (11 g, 49.9 mmol) in CH3CO2H (450 mL) was added NaNO2 (5.4 g, 78.3 mmol) in H2O (15 mL) at 10° C. The resulting mixture was stirred at room temperature for 30 minutes. Upon completion, the reaction mixture was diluted with H2O (500 mL) and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was triturated with petroleum ether affording the title compound (4.5 g) as yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 13.60 (s, 1H), 8.15 (s, 1H), 7.62 (d, 1H), 7.52 (d, 1H). extracted with EtOAc The organic layer was dried over Na2SO4 concentrated in vacuo The residue was triturated with petroleum ether affording the title compound (4.5 g) as yellow solid

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

Procedure: To a solution of 3-chloro-2-methylaniline (30 g, 0.212 mol) in CH3CN (300 mL) was added NBS (45.2 g, 0.254 mol) in portions at 10° C. The resulting mixture was stirred at room temperature for 30 minutes. Upon completion, saturated Na2S2O3 (500 mL) was added slowly into the reaction mixture at 10° C. The organic layer was separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The residue was washed with petroleum ether to afford the title compound (30 g), which was used in the next step without further purification. 1H NMR (300 MHz, CDCl3): δ 7.24 (d, 1H), 6.48 (d, 1H), 3.70 (br, 2H), 2.28 (s, 3H). The organic layer was separated the aqueous layer was extracted with EtOAc The combined organic layers were dried over Na2SO4 concentrated in vacuo The residue was washed with petroleum ether

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

Procedure: To a solution of 4-bromo-3-chloro-2-methylaniline (11 g, 49.9 mmol) in CH3CO2H (450 mL) was added NaNO2 (5.4 g, 78.3 mmol) in H2O (15 mL) at 10° C. The resulting mixture was stirred at room temperature for 30 minutes. Upon completion, the reaction mixture was diluted with H2O (500 mL) and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was triturated with petroleum ether affording the title compound (4.5 g) as yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 13.60 (s, 1H), 8.15 (s, 1H), 7.62 (d, 1H), 7.52 (d, 1H). extracted with EtOAc The organic layer was dried over Na2SO4 concentrated in vacuo The residue was triturated with petroleum ether affording the title compound (4.5 g) as yellow solid

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

Procedure: To a solution of 3-chloro-2-methylaniline (30 g, 0.212 mol) in CH3CN (300 mL) was added NBS (45.2 g, 0.254 mol) in portions at 10° C. The resulting mixture was stirred at room temperature for 30 minutes. Upon completion, saturated Na2S2O3 (500 mL) was added slowly into the reaction mixture at 10° C. The organic layer was separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The residue was washed with petroleum ether to afford the title compound (30 g), which was used in the next step without further purification. 1H NMR (300 MHz, CDCl3): δ 7.24 (d, 1H), 6.48 (d, 1H), 3.70 (br, 2H), 2.28 (s, 3H). The organic layer was separated the aqueous layer was extracted with EtOAc The combined organic layers were dried over Na2SO4 concentrated in vacuo The residue was washed with petroleum ether