2-(4-amino-3-iodophenyl)ethanol

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

Procedure: To a solution of 4-amino-3-iodophenethyl alcohol from Step A (10 g, 38 mmol) and benzyl acetoacetate (7.3 g, 38 mmol) in benzene (150 mL) was added p-toluenesulfonic acid (361 mg, 1.9 mmol). The mixture was heated at reflux overnight using a Dean Stark condenser. The mixture was washed with water and brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo to give 16.6 g (99%) of the crude desired product as a light brown oil: MS(APCI+): m/z 438.1 (MH+). The compound was taken to Step C without further purification. The mixture was heated at reflux overnight The mixture was washed with water and brine dried over Na2SO4 filtered The filtrate was concentrated in vacuo

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

Procedure: To a mixture of 4-aminophenethyl alcohol (20 g, 145.8 mmol) and calcium carbonate (18.2 g, 145.8 mmol) in methanol (200 mL) was added iodine (37 g, 182.3 mmol) in portions. The mixture was heated at reflux overnight and then concentrated in vacuo to give a dark brown residue, which was partitioned between ethyl acetate and saturated sodium bisulfite solution. The organic phase was washed with water and brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo to give 14.1 g (37%) of desired product as a light brown syrup. MS(APCI+): m/z 264.1 (MH+). The compound was taken to Step B without further purification. The mixture was heated at reflux overnight concentrated in vacuo to give a dark brown residue, which was partitioned between ethyl acetate and saturated sodium bisulfite solution The organic phase was washed with water and brine dried over Na2SO4 filtered The filtrate was concentrated in vacuo

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

Procedure: To a mixture of 4-aminophenethyl alcohol (20 g, 145.8 mmol) and calcium carbonate (18.2 g, 145.8 mmol) in methanol (200 mL) was added iodine (37 g, 182.3 mmol) in portions. The mixture was heated at reflux overnight and then concentrated in vacuo to give a dark brown residue, which was partitioned between ethyl acetate and saturated sodium bisulfite solution. The organic phase was washed with water and brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo to give 14.1 g (37%) of desired product as a light brown syrup. MS(APCI+): m/z 264.1 (MH+). The compound was taken to Step B without further purification. The mixture was heated at reflux overnight concentrated in vacuo to give a dark brown residue, which was partitioned between ethyl acetate and saturated sodium bisulfite solution The organic phase was washed with water and brine dried over Na2SO4 filtered The filtrate was concentrated in vacuo

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

Procedure: 2-(4-Amino-3-iodo-phenyl)-ethanol (6.0 g, 23 mmol, 1.0 eq) was added to the solution of the 4,4,4-trifluoro-but-2-ynoic acid benzyl ester (5.7 g, 25 mmol, 1.1 eq) obtained from previous step in methanol (20 mL) at room temperature. The reaction mixture was stirred for 1 hour. After the solvent was removed, the residue was purified by flash chromatography (SiO2, hexanes-ethyl acetate) to yield 9.5 g of the desired enamine as pale yellow liquid (84.0% yield). After the solvent was removed the residue was purified by flash chromatography (SiO2, hexanes-ethyl acetate)

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

Procedure: 2-(4-Amino-3-iodo-phenyl)-ethanol (6.0 g, 23 mmol, 1.0 eq) was added to the solution of the 4,4,4-trifluoro-but-2-ynoic acid benzyl ester (5.7 g, 25 mmol, 1.1 eq) obtained from previous step in methanol (20 mL) at room temperature. The reaction mixture was stirred for 1 hour. After the solvent was removed, the residue was purified by flash chromatography (SiO2, hexanes-ethyl acetate) to yield 9.5 g of the desired enamine as pale yellow liquid (84.0% yield). After the solvent was removed the residue was purified by flash chromatography (SiO2, hexanes-ethyl acetate)

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

Procedure: 4-Aminophenethyl alcohol (9.60 g, 70 mmol, 1.0 eq) was added to a mixture of iodine (17.78 g, 70 mmol, 1.0 eq) and silver sulfate (21.83 g, 70 mmol, 1.0 eq) in anhydrous ethanol (200 mL) at room temperature. The reaction mixture was stirred under nitrogen for 1.5 hours. After stirring was stopped, the solid was removed by filtration. The filtrate was concentrated, and the residue was dissolved in dichloromethane (200 mL), and then washed with aqueous 5% NaOH solution (2×150 mL) and water (150 mL). The organic layer was dried over MgSO4, filtered and concentrated in vacuo to give a crude oil which was purified by flash chromatography (SiO2, hexanes-ethyl acetate) to yield 6.0 g of the desired ortho-iodo aniline as orange gel-like solid (32.4% yield). After stirring the solid was removed by filtration The filtrate was concentrated the residue was dissolved in dichloromethane (200 mL) washed with aqueous 5% NaOH solution (2×150 mL) and water (150 mL) The organic layer was dried over MgSO4 filtered concentrated in vacuo to give a crude oil which was purified by flash chromatography (SiO2, hexanes-ethyl acetate)

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

Procedure: To a solution of 4-amino-3-iodophenethyl alcohol from Step A (10 g, 38 mmol) and benzyl acetoacetate (7.3 g, 38 mmol) in benzene (150 mL) was added p-toluenesulfonic acid (361 mg, 1.9 mmol). The mixture was heated at reflux overnight using a Dean Stark condenser. The mixture was washed with water and brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo to give 16.6 g (99%) of the crude desired product as a light brown oil: MS(APCI+): m/z 438.1 (MH+). The compound was taken to Step C without further purification. The mixture was heated at reflux overnight The mixture was washed with water and brine dried over Na2SO4 filtered The filtrate was concentrated in vacuo

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

Procedure: To a mixture of 4-aminophenethyl alcohol (20 g, 145.8 mmol) and calcium carbonate (18.2 g, 145.8 mmol) in methanol (200 mL) was added iodine (37 g, 182.3 mmol) in portions. The mixture was heated at reflux overnight and then concentrated in vacuo to give a dark brown residue, which was partitioned between ethyl acetate and saturated sodium bisulfite solution. The organic phase was washed with water and brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo to give 14.1 g (37%) of desired product as a light brown syrup. MS(APCI+): m/z 264.1 (MH+). The compound was taken to Step B without further purification. The mixture was heated at reflux overnight concentrated in vacuo to give a dark brown residue, which was partitioned between ethyl acetate and saturated sodium bisulfite solution The organic phase was washed with water and brine dried over Na2SO4 filtered The filtrate was concentrated in vacuo

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

Procedure: 2-(4-Amino-3-iodo-phenyl)-ethanol (6.0 g, 23 mmol, 1.0 eq) was added to the solution of the 4,4,4-trifluoro-but-2-ynoic acid benzyl ester (5.7 g, 25 mmol, 1.1 eq) obtained from previous step in methanol (20 mL) at room temperature. The reaction mixture was stirred for 1 hour. After the solvent was removed, the residue was purified by flash chromatography (SiO2, hexanes-ethyl acetate) to yield 9.5 g of the desired enamine as pale yellow liquid (84.0% yield). After the solvent was removed the residue was purified by flash chromatography (SiO2, hexanes-ethyl acetate)

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

Procedure: 4-Aminophenethyl alcohol (9.60 g, 70 mmol, 1.0 eq) was added to a mixture of iodine (17.78 g, 70 mmol, 1.0 eq) and silver sulfate (21.83 g, 70 mmol, 1.0 eq) in anhydrous ethanol (200 mL) at room temperature. The reaction mixture was stirred under nitrogen for 1.5 hours. After stirring was stopped, the solid was removed by filtration. The filtrate was concentrated, and the residue was dissolved in dichloromethane (200 mL), and then washed with aqueous 5% NaOH solution (2×150 mL) and water (150 mL). The organic layer was dried over MgSO4, filtered and concentrated in vacuo to give a crude oil which was purified by flash chromatography (SiO2, hexanes-ethyl acetate) to yield 6.0 g of the desired ortho-iodo aniline as orange gel-like solid (32.4% yield). After stirring the solid was removed by filtration The filtrate was concentrated the residue was dissolved in dichloromethane (200 mL) washed with aqueous 5% NaOH solution (2×150 mL) and water (150 mL) The organic layer was dried over MgSO4 filtered concentrated in vacuo to give a crude oil which was purified by flash chromatography (SiO2, hexanes-ethyl acetate)