N-(2-chloro-4-hydroxyphenyl)acetamide

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

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

Procedure: Part H. A solution of the aniline from Part G (7.98 g, 50 mmol) in conc. HCl (25 mL) was cooled to −5° C., and treated dropwise with a concentrated aqueous solution of sodium nitrite (3.80 g, 55.1 mmol). After 30 minutes, the mixture was charged with 15 mL cyclohexane and 15 mL dichloromethane, then treated dropwise with a concentrated aqueous solution of potassium iodide (16.6 g, 100 mmol). This mixture was allowed to stir for 4 hours, then was extracted with dichloromethane (2×100 mL). The extracts were washed in sequence with 1 N aqueous sodium bisulfite (100 mL) and brine (60 mL), then combined, dried over magnesium sulfate, filtered and evaporated to afford sufficiently pure product, 3-chloro-4-iodoanisole (7.00 g, 26.1 mmol, 52%). TLC RF 0.39 (5:95 ethyl acetate-hexane). 1H NMR (300 MHz, CDCl3): d 7.69 (1H, d, J=8.8 Hz), 7.03 (1H, d, J=3.0 Hz), 6.57 (1H, dd, J=8.8, 3.0 Hz), 3.78 (3H, s). MS (H2O-GC/MS): m/e 269 (100). was extracted with dichloromethane (2×100 mL) The extracts were washed in sequence with 1 N aqueous sodium bisulfite (100 mL) and brine (60 mL) dried over magnesium sulfate filtered evaporated

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

Procedure: Part H. A solution of the aniline from Part G (7.98 g, 50 mmol) in conc. HCl (25 mL) was cooled to −5° C., and treated dropwise with a concentrated aqueous solution of sodium nitrite (3.80 g, 55.1 mmol). After 30 minutes, the mixture was charged with 15 mL cyclohexane and 15 mL dichloromethane, then treated dropwise with a concentrated aqueous solution of potassium iodide (16.6 g, 100 mmol). This mixture was allowed to stir for 4 hours, then was extracted with dichloromethane (2×100 mL). The extracts were washed in sequence with 1 N aqueous sodium bisulfite (100 mL) and brine (60 mL), then combined, dried over magnesium sulfate, filtered and evaporated to afford sufficiently pure product, 3-chloro-4-iodoanisole (7.00 g, 26.1 mmol, 52%). TLC RF 0.39 (5:95 ethyl acetate-hexane). 1H NMR (300 MHz, CDCl3): d 7.69 (1H, d, J=8.8 Hz), 7.03 (1H, d, J=3.0 Hz), 6.57 (1H, dd, J=8.8, 3.0 Hz), 3.78 (3H, s). MS (H2O-GC/MS): m/e 269 (100). was extracted with dichloromethane (2×100 mL) The extracts were washed in sequence with 1 N aqueous sodium bisulfite (100 mL) and brine (60 mL) dried over magnesium sulfate filtered evaporated

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

Procedure: Part E. A solution of 4-amino-3-chlorophenol hydrochloride (18.6 g, 103 mmol) and sodium acetate (18.6 g, 227 mmol) in glacial acetic acid (200 mL) was heated to gentle reflux for 12 hours, then cooled and poured into 4 volumes water. This was neutralized with portionwise addition of sodium bicarbonate, and the resulting mixture was extracted with ethyl acetate (2×500 mL). The extracts were washed with brine, combined, dried over magnesium sulfate, filtered and evaporated. The resulting solid was triturated with warm ether; filtration and vacuum drying gave 4-acetamido-3-chlorophenol (16.1 g, 86.7 mmol, 84%). m.p. 128-129° C. TLC RF 0.14 (50:50 ethyl acetate-hexane). 1H NMR (300 MHz, 4:1 CDCl3.CD3OD): d 7.66 (1H, d, J=8.8 Hz), 6.88 (1H, d, J=1.7 Hz), 6.74 (1H, dd, J=8.8, 1.7 Hz), 2.19 (3H, s). MS (H2O-GC/MS): m/e 186 (100). to gentle reflux for 12 hours cooled the resulting mixture was extracted with ethyl acetate (2×500 mL) The extracts were washed with brine dried over magnesium sulfate filtered evaporated The resulting solid was triturated with warm ether filtration and vacuum drying

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

Procedure: Part E. A solution of 4-amino-3-chlorophenol hydrochloride (18.6 g, 103 mmol) and sodium acetate (18.6 g, 227 mmol) in glacial acetic acid (200 mL) was heated to gentle reflux for 12 hours, then cooled and poured into 4 volumes water. This was neutralized with portionwise addition of sodium bicarbonate, and the resulting mixture was extracted with ethyl acetate (2×500 mL). The extracts were washed with brine, combined, dried over magnesium sulfate, filtered and evaporated. The resulting solid was triturated with warm ether; filtration and vacuum drying gave 4-acetamido-3-chlorophenol (16.1 g, 86.7 mmol, 84%). m.p. 128-129° C. TLC RF 0.14 (50:50 ethyl acetate-hexane). 1H NMR (300 MHz, 4:1 CDCl3.CD3OD): d 7.66 (1H, d, J=8.8 Hz), 6.88 (1H, d, J=1.7 Hz), 6.74 (1H, dd, J=8.8, 1.7 Hz), 2.19 (3H, s). MS (H2O-GC/MS): m/e 186 (100). to gentle reflux for 12 hours cooled the resulting mixture was extracted with ethyl acetate (2×500 mL) The extracts were washed with brine dried over magnesium sulfate filtered evaporated The resulting solid was triturated with warm ether filtration and vacuum drying

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

Procedure: Part H. A solution of the aniline from Part G (7.98 g, 50 mmol) in conc. HCl (25 mL) was cooled to −5° C., and treated dropwise with a concentrated aqueous solution of sodium nitrite (3.80 g, 55.1 mmol). After 30 minutes, the mixture was charged with 15 mL cyclohexane and 15 mL dichloromethane, then treated dropwise with a concentrated aqueous solution of potassium iodide (16.6 g, 100 mmol). This mixture was allowed to stir for 4 hours, then was extracted with dichloromethane (2×100 mL). The extracts were washed in sequence with 1 N aqueous sodium bisulfite (100 mL) and brine (60 mL), then combined, dried over magnesium sulfate, filtered and evaporated to afford sufficiently pure product, 3-chloro-4-iodoanisole (7.00 g, 26.1 mmol, 52%). TLC RF 0.39 (5:95 ethyl acetate-hexane). 1H NMR (300 MHz, CDCl3): d 7.69 (1H, d, J=8.8 Hz), 7.03 (1H, d, J=3.0 Hz), 6.57 (1H, dd, J=8.8, 3.0 Hz), 3.78 (3H, s). MS (H2O-GC/MS): m/e 269 (100). was extracted with dichloromethane (2×100 mL) The extracts were washed in sequence with 1 N aqueous sodium bisulfite (100 mL) and brine (60 mL) dried over magnesium sulfate filtered evaporated

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

Procedure: Part E. A solution of 4-amino-3-chlorophenol hydrochloride (18.6 g, 103 mmol) and sodium acetate (18.6 g, 227 mmol) in glacial acetic acid (200 mL) was heated to gentle reflux for 12 hours, then cooled and poured into 4 volumes water. This was neutralized with portion wise addition of sodium bicarbonate, and the resulting mixture was extracted with ethyl acetate (2×500 mL). The extracts were washed with brine, combined, dried over magnesium sulfate, filtered and evaporated. The resulting solid was triturated with warm ether; filtration and vacuum drying gave 4-acetamido-3-chlorophenol (16.1 g, 86.7 mmol, 84%). m.p. 128-129° C. TLC RF 0.14 (50:50 ethyl acetate-hexane). 1H NMR (300 MHz, 4:1 CDCl3.CD3OD): d 7.66 (1H, d, J=8.8 Hz), 6.88 (1H, d, J=1.7 Hz), 6.74 (1H, dd, J=8.8, 1.7 Hz), 2.19 (3H, s). MS (H2O-GC/MS): m/e 186 (100). to gentle reflux for 12 hours cooled the resulting mixture was extracted with ethyl acetate (2×500 mL) The extracts were washed with brine dried over magnesium sulfate filtered evaporated The resulting solid was triturated with warm ether filtration and vacuum drying

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

Procedure: Part E. A solution of 4-amino-3-chlorophenol hydrochloride (18.6 g, 103 mmol) and sodium acetate (18.6 g, 227 mmol) in glacial acetic acid (200 mL) was heated to gentle reflux for 12 hours, then cooled and poured into 4 volumes water. This was neutralized with portion wise addition of sodium bicarbonate, and the resulting mixture was extracted with ethyl acetate (2×500 mL). The extracts were washed with brine, combined, dried over magnesium sulfate, filtered and evaporated. The resulting solid was triturated with warm ether; filtration and vacuum drying gave 4-acetamido-3-chlorophenol (16.1 g, 86.7 mmol, 84%). m.p. 128-129° C. TLC RF 0.14 (50:50 ethyl acetate-hexane). 1H NMR (300 MHz, 4:1 CDCl3.CD3OD): d 7.66 (1H, d, J=8.8 Hz), 6.88 (1H, d, J=1.7 Hz), 6.74 (1H, dd, J=8.8, 1.7 Hz), 2.19 (3H, s). MS (H2O-GC/MS): m/e 186 (100). to gentle reflux for 12 hours cooled the resulting mixture was extracted with ethyl acetate (2×500 mL) The extracts were washed with brine dried over magnesium sulfate filtered evaporated The resulting solid was triturated with warm ether filtration and vacuum drying

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

Procedure: Part H. A solution of the aniline from Part G (7.98 g, 50 mmol) in conc. HCl (25 mL) was cooled to −5° C., and treated dropwise with a concentrated aqueous solution of sodium nitrite (3.80 g, 55.1 mmol). After 30 minutes, the mixture was charged with 15 mL cyclohexane and 15 mL dichloromethane, then treated dropwise with a concentrated aqueous solution of potassium iodide (16.6 g, 100 mmol). This mixture was allowed to stir for 4 hours, then was extracted with dichloromethane (2×100 mL). The extracts were washed in sequence with 1 N aqueous sodium bisulfite (100 mL) and brine (60 mL), then combined, dried over magnesium sulfate, filtered and evaporated to afford sufficiently pure product, 3-chloro-4-iodoanisole (7.00 g, 26.1 mmol, 52%). TLC RF 0.39 (5:95 ethyl acetate-hexane). 1H NMR (300 MHz, CDCl3): d 7.69 (1H, d, J=8.8 Hz), 7.03 (1H, d, J=3.0 Hz), 6.57 (1H, dd, J=8.8, 3.0 Hz), 3.78 (3H, s). MS (H2O-GC/MS): m/e 269 (100). was extracted with dichloromethane (2×100 mL) The extracts were washed in sequence with 1 N aqueous sodium bisulfite (100 mL) and brine (60 mL) dried over magnesium sulfate filtered evaporated

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

Procedure: Part E. A solution of 4-amino-3-chlorophenol hydrochloride (18.6 g, 103 mmol) and sodium acetate (18.6 g, 227 mmol) in glacial acetic acid (200 mL) was heated to gentle reflux for 12 hours, then cooled and poured into 4 volumes water. This was neutralized with portionwise addition of sodium bicarbonate, and the resulting mixture was extracted with ethyl acetate (2×500 mL). The extracts were washed with brine, combined, dried over magnesium sulfate, filtered and evaporated. The resulting solid was triturated with warm ether; filtration and vacuum drying gave 4-acetamido-3-chlorophenol (16.1 g, 86.7 mmol, 84%). m.p. 128-129° C. TLC RF 0.14 (50:50 ethyl acetate-hexane). 1H NMR (300 MHz, 4:1 CDCl3.CD3OD): d 7.66 (1H, d, J=8.8 Hz), 6.88 (1H, d, J=1.7 Hz), 6.74 (1H, dd, J=8.8, 1.7 Hz), 2.19 (3H, s). MS (H2O-GC/MS): m/e 186 (100). to gentle reflux for 12 hours cooled the resulting mixture was extracted with ethyl acetate (2×500 mL) The extracts were washed with brine dried over magnesium sulfate filtered evaporated The resulting solid was triturated with warm ether filtration and vacuum drying

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

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

Procedure: Part H. A solution of the aniline from Part G (7.98 g, 50 mmol) in conc. HCl (25 mL) was cooled to -5° C., and treated dropwise with a concentrated aqueous solution of sodium nitrite (3.80 g, 55.1 mmol). After 30 minutes, the mixture was charged with 15 mL cyclohexane and 15 mL dichloromethane, then treated dropwise with a concentrated aqueous solution of potassium iodide (16.6 g, 100 mmol). This mixture was allowed to stir for 4 hours, then was extracted with dichloromethane (2×100 mL). The extracts were washed in sequence with 1 N aqueous sodium bisulfite (100 mL) and brine (60 mL), then combined, dried over magnesium sulfate, filtered and evaporated to afford sufficiently pure product, 3-chloro-4-iodoanisole (7.00 g, 26.1 mmol, 52%). TLC RF 0.39 (5:95 ethyl acetate-hexane). 1H NMR (300 MHz, CDCl3): d 7.69 (1H, d, J=8.8 Hz), 7.03 (1H, d, J=3.0 Hz), 6.57 (1H, dd, J=8.8, 3.0 Hz), 3.78 (3H, s). MS(H2O-GC/MS): m/e 269 (100). was extracted with dichloromethane (2×100 mL) The extracts were washed in sequence with 1 N aqueous sodium bisulfite (100 mL) and brine (60 mL) dried over magnesium sulfate filtered evaporated