5-AMINO-4-IODO-2-FLUOROTOLUENE

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

Procedure: Into a mixture of 4-fluoro-2-iodo-5-methylaniline (12.0 g, 47.8 mmol, plus ca. 10% of the undesired isomer), PdCl2(PPh3)2 (1.68 g, 2.39 mmol) and copper(I) iodide (0.455 g, 2.39 mmol) in triethylamine (125 mL) at 0° C. was added trimethylsilylacetylene (5.15 g, 52.6 mmol) dropwise. The mixture was warmed to room temperature and stirred overnight. The solvent was evaporated and the residue was dissolved in ethyl ether and filtered. The filtrate was evaporated and purified via flash chromatography with 5-35% ethyl acetate in hexane to give 4-fluoro-5-methyl-2-((trimethylsilyl)ethynyl)aniline (10.3 g, 97%), which contained ˜10% of the undesired isomer (4-fluoro-3-methyl-2-((trimethylsilyl)ethynyl)aniline). The solvent was evaporated the residue was dissolved in ethyl ether filtered The filtrate was evaporated purified via flash chromatography with 5-35% ethyl acetate in hexane

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

Procedure: Into a solution of 4-fluoro-3-methylaniline (8.75 g, 70 mmol) in methanol (65 mL) and water (65 mL) was added sodium bicarbonate (5.88 g, 70 mmol) followed by portionwise addition of powdered I2 (17.78 g, 70 mmol). The mixture was stirred at room temperature overnight then treated with water (300 mL). The aqueous mixture was extracted with CH2Cl2 (3×200 mL). The organics were combined and washed with sat. aq. sodium thiosulfate, water, and brine. The mixture was dried over Na2SO4 and concentrated. The residue was purified by flash chromatography with 30-100% CH2Cl2/hexane to give 4-fluoro-2-iodo-5-methylaniline (12.1 g, 69%), which contained ˜10% of the undesired isomer (4-fluoro-2-iodo-3-methylaniline). The aqueous mixture was extracted with CH2Cl2 (3×200 mL) washed with sat. aq. sodium thiosulfate, water, and brine The mixture was dried over Na2SO4 concentrated The residue was purified by flash chromatography with 30-100% CH2Cl2/hexane

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

Procedure: Into a solution of 4-fluoro-3-methylaniline (8.75 g, 70 mmol) in methanol (65 mL) and water (65 mL) was added sodium bicarbonate (5.88 g, 70 mmol) followed by portionwise addition of powdered I2 (17.78 g, 70 mmol). The mixture was stirred at room temperature overnight then treated with water (300 mL). The aqueous mixture was extracted with CH2Cl2 (3×200 mL). The organics were combined and washed with sat. aq. sodium thiosulfate, water, and brine. The mixture was dried over Na2SO4 and concentrated. The residue was purified by flash chromatography with 30-100% CH2Cl2/hexane to give 4-fluoro-2-iodo-5-methylaniline (12.1 g, 69%), which contained ˜10% of the undesired isomer (4-fluoro-2-iodo-3-methylaniline). The aqueous mixture was extracted with CH2Cl2 (3×200 mL) washed with sat. aq. sodium thiosulfate, water, and brine The mixture was dried over Na2SO4 concentrated The residue was purified by flash chromatography with 30-100% CH2Cl2/hexane

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

Procedure: Into a mixture of 4-fluoro-2-iodo-5-methylaniline (12.0 g, 47.8 mmol, plus ca. 10% of the undesired isomer), PdCl2(PPh3)2 (1.68 g, 2.39 mmol) and copper(I) iodide (0.455 g, 2.39 mmol) in triethylamine (125 mL) at 0° C. was added trimethylsilylacetylene (5.15 g, 52.6 mmol) dropwise. The mixture was warmed to room temperature and stirred overnight. The solvent was evaporated and the residue was dissolved in ethyl ether and filtered. The filtrate was evaporated and purified via flash chromatography with 5-35% ethyl acetate in hexane to give 4-fluoro-5-methyl-2-((trimethylsilyl)ethynyl)aniline (10.3 g, 97%), which contained ˜10% of the undesired isomer (4-fluoro-3-methyl-2-((trimethylsilyl)ethynyl)aniline). The solvent was evaporated the residue was dissolved in ethyl ether filtered The filtrate was evaporated purified via flash chromatography with 5-35% ethyl acetate in hexane

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

Procedure: Into a solution of 4-fluoro-3-methylaniline (8.75 g, 70 mmol) in methanol (65 mL) and water (65 mL) was added sodium bicarbonate (5.88 g, 70 mmol) followed by portionwise addition of powdered I2 (17.78 g, 70 mmol). The mixture was stirred at room temperature overnight then treated with water (300 mL). The aqueous mixture was extracted with CH2Cl2 (3×200 mL). The organics were combined and washed with sat. aq. sodium thiosulfate, water, and brine. The mixture was dried over Na2SO4 and concentrated. The residue was purified by flash chromatography with 30-100% CH2Cl2/hexane to give 4-fluoro-2-iodo-5-methylaniline (12.1 g, 69%), which contained ˜10% of the undesired isomer (4-fluoro-2-iodo-3-methylaniline). The aqueous mixture was extracted with CH2Cl2 (3×200 mL) washed with sat. aq. sodium thiosulfate, water, and brine The mixture was dried over Na2SO4 concentrated The residue was purified by flash chromatography with 30-100% CH2Cl2/hexane