5-bromo-2-iodo-4-methylaniline

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 5-bromo-2-iodo-4-methylaniline (5.25 g, 16.8 mmol) and zinc cyanide (0.988 g, 8.41 mmol) in DMF (80 mL) was subjected to three evacuate-fill cycles with nitrogen. The mixture was treated with tetrakis(triphenylphosphine)palladium (0.972 g, 0.841 mmol) and heated at 90° C. overnight. The cooled mixture was diluted with EtOAc and washed sequentially with 10% aqueous LiCl (twice) and brine. The aqueous layers were extracted with EtOAc, and the combined organic layers were dried and concentrated. The residue was purified by column chromatography on silica gel, eluting with EtOAc-hexanes (sequentially 1%, 2.5%, 5% and 50%), to give a brown solid. The residue was further purified by trituration with MeOH to give three crops of solid. The filtrate was again purified by column chromatography on silica gel, eluting with EtOAc-hexanes (5%, then 10%). The resulting solid was combined with the other crops to provide 2-amino-4-bromo-5-methylbenzonitrile as a tan solid (2.95 g, 83% yield). Mass spectrum m/z 211, 213 (M+H)+. evacuate-fill cycles with nitrogen washed sequentially with 10% aqueous LiCl (twice) and brine The aqueous layers were extracted with EtOAc the combined organic layers were dried concentrated The residue was purified by column chromatography on silica gel eluting with EtOAc-hexanes (sequentially 1%, 2.5%, 5% and 50%), to give a brown solid The residue was further purified by trituration with MeOH to give three crops of solid The filtrate was again purified by column chromatography on silica gel eluting with EtOAc-hexanes (5%

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 5-bromo-2-iodo-4-methylaniline (5.25 g, 16.8 mmol) and zinc cyanide (0.988 g, 8.41 mmol) in DMF (80 mL) was subjected to three evacuate-fill cycles with nitrogen. The mixture was treated with tetrakis(triphenylphosphine)palladium (0.972 g, 0.841 mmol) and heated at 90° C. overnight. The cooled mixture was diluted with EtOAc and washed sequentially with 10% aqueous LiCl (twice) and brine. The aqueous layers were extracted with EtOAc, and the combined organic layers were dried and concentrated. The residue was purified by column chromatography on silica gel, eluting with EtOAc-hexanes (sequentially 1%, 2.5%, 5% and 50%), to give a brown solid. The residue was further purified by trituration with MeOH to give three crops of solid. The filtrate was again purified by column chromatography on silica gel, eluting with EtOAc-hexanes (5%, then 10%). The resulting solid was combined with the other crops to provide 2-amino-4-bromo-5-methylbenzonitrile as a tan solid (2.95 g, 83% yield). Mass spectrum m/z 211, 213 (M+H)+. evacuate-fill cycles with nitrogen washed sequentially with 10% aqueous LiCl (twice) and brine The aqueous layers were extracted with EtOAc the combined organic layers were dried concentrated The residue was purified by column chromatography on silica gel eluting with EtOAc-hexanes (sequentially 1%, 2.5%, 5% and 50%), to give a brown solid The residue was further purified by trituration with MeOH to give three crops of solid The filtrate was again purified by column chromatography on silica gel eluting with EtOAc-hexanes (5%

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

Procedure: A solution of 3-bromo-4-methylaniline (5.00 g, 26.9 mmol), N-iodosuccinimide (4.53 g, 20.2 mmol) and bis(pyridine)iodonium tetrafluoroborate (2.70 g, 7.26 mmol) in DCM (100 mL) was stirred at room temperature overnight. The mixture was diluted with DCM, washed sequentially with saturated aqueous NaHSO3 and water, and dried and concentrated. The residue was purified by column chromatography on silica gel, eluting with EtOAc-hexanes (sequentially 1%, 2% and 3%), to provide 5-bromo-2-iodo-4-methylaniline as a yellow solid (5.27 g, 63% yield). Mass spectrum m/z 312, 314 (M+H)+. 1H NMR (500 MHz, CDCl3) δ 7.49 (d, J=0.6 Hz, 1H), 6.94 (s, 1H), 4.17-3.91 (br.s, 2H), and 2.25 (s, 3H). washed sequentially with saturated aqueous NaHSO3 and water dried concentrated The residue was purified by column chromatography on silica gel eluting with EtOAc-hexanes (sequentially 1%, 2% and 3%),

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 5-bromo-2-iodo-4-methylaniline (5.25 g, 16.8 mmol) and zinc cyanide (0.988 g, 8.41 mmol) in DMF (80 mL) was subjected to three evacuate-fill cycles with nitrogen. The mixture was treated with tetrakis(triphenylphosphine)palladium (0.972 g, 0.841 mmol) and heated at 90° C. overnight. The cooled mixture was diluted with EtOAc and washed sequentially with 10% aqueous LiCl (twice) and brine. The aqueous layers were extracted with EtOAc, and the combined organic layers were dried and concentrated. The residue was purified by column chromatography on silica gel, eluting with EtOAc-hexanes (sequentially 1%, 2.5%, 5% and 50%), to give a brown solid. The residue was further purified by trituration with MeOH to give three crops of solid. The filtrate was again purified by column chromatography on silica gel, eluting with EtOAc-hexanes (5%, then 10%). The resulting solid was combined with the other crops to provide 2-amino-4-bromo-5-methylbenzonitrile as a tan solid (2.95 g, 83% yield). Mass spectrum m/z 211, 213 (M+H)+. evacuate-fill cycles with nitrogen washed sequentially with 10% aqueous LiCl (twice) and brine The aqueous layers were extracted with EtOAc the combined organic layers were dried concentrated The residue was purified by column chromatography on silica gel eluting with EtOAc-hexanes (sequentially 1%, 2.5%, 5% and 50%), to give a brown solid The residue was further purified by trituration with MeOH to give three crops of solid The filtrate was again purified by column chromatography on silica gel eluting with EtOAc-hexanes (5%

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

Procedure: A solution of 3-bromo-4-methylaniline (5.00 g, 26.9 mmol), N-iodosuccinimide (4.53 g, 20.2 mmol) and bis(pyridine)iodonium tetrafluoroborate (2.70 g, 7.26 mmol) in DCM (100 mL) was stirred at room temperature overnight. The mixture was diluted with DCM, washed sequentially with saturated aqueous NaHSO3 and water, and dried and concentrated. The residue was purified by column chromatography on silica gel, eluting with EtOAc-hexanes (sequentially 1%, 2% and 3%), to provide 5-bromo-2-iodo-4-methylaniline as a yellow solid (5.27 g, 63% yield). Mass spectrum m/z 312, 314 (M+H)+. 1H NMR (500 MHz, CDCl3) δ 7.49 (d, J=0.6 Hz, 1H), 6.94 (s, 1H), 4.17-3.91 (br.s, 2H), and 2.25 (s, 3H). washed sequentially with saturated aqueous NaHSO3 and water dried concentrated The residue was purified by column chromatography on silica gel eluting with EtOAc-hexanes (sequentially 1%, 2% and 3%),