(2-chloro-5-iodophenyl)methanol

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

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 2-chloro-5-iodobenzyl alcohol (0.537 g, 2.0 mmol) in THF (10 mL) was added to sodium hydride (88 mg of a 60% dispersion in mineral oil, 2.2 mmol) at 0° C. with stirring under nitrogen. After 5 min the mixture was cooled to −78° C. and n-butyl-lithium (2.5 M in hexanes, 1.66 mL, 4.15 mmol) was added over 6 min. After a further 5 min a solution of N-(4-methoxyphenyl)-N-(-2,2,2-trifluoroethylidene)amine (0.406 g, 2.0 mmol) in THF (2 mL) was added over 5 min. After a further 5 min the reaction was quenched with saturated ammonium chloride solution and the mixture was warmed to ambient temperature and partitioned between ethyl acetate and brine. The organic layer was dried (Na2SO4) and evaporated to a gum which was purified by chromatography on silica (eluting with 2% methanol/chloroform) to give N-{1-[4-chloro-2-(hydroxymethyl)phenyl]-2,2,2-trifluoroethyl}-N-(4-methoxyphenyl)amine as a 1:1.7 mixture with 3-chlorobenzyl alcohol (0.38 g) as a gum: MS 346.4 (M+1). After a further 5 min the reaction was quenched with saturated ammonium chloride solution the mixture was warmed to ambient temperature partitioned between ethyl acetate and brine The organic layer was dried (Na2SO4) evaporated to a gum which was purified by chromatography on silica (eluting with 2% methanol/chloroform)

Conditions: temp:22.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 100 mL of 4-necked flask equipped with thermometer and mechanical stirrer was charged with (2-chloro-5-iodophenyl)methanol (268.5 mg, 1 mmol), anhydrous ZnCl2 (136.3 mg, 1 mmol), dichloromethane (5.0 mL) and n-hexane (29 mL) under argon. After stirring for 10 min at 20 to 25° C., HBr (gas) was bubbled into the mixture for 10 min and a solution of phenol (197.6 mg, 2.1 mmol) in dry dichloromethane (3.0 mL) was added dropwise over 30 min. After bubbling HBr for additional 2 h, the mixture was refluxed for 3 days. The conversion was about 65%. The mixture was quenched with ice water (50 mL), extracted with ethyl acetate (2×30 mL), washed with water (2×30 mL), brine (30 mL), concentrated and the residue was purified by flash chromatography (PE:EA=25:1 as eluant, 200 mL) to give an off-white solid. Yield: 180 mg (52%). 1H NMR (CDCl3, 400 MHz): δ 7.44 (d, J=8.4 Hz, 2H), 7.03˜7.09 (m, 3H), 6.77 (d, J=8.4 Hz, 2H), 4.76 (s, 1H), 3.95 (s, 2H), 3.82 (s, 2H). MS ESI (m/z): 345 [M+1]+. 13C NMR (CDCl3, 100 MHz): δ 154.1, 141.4, 139.5, 136.6, 134.2, 131.2, 130.9, 130.1, 115.5, 91.67, 38.07. A 100 mL of 4-necked flask equipped with thermometer and mechanical stirrer HBr (gas) was bubbled into the mixture for 10 min After bubbling HBr for additional 2 h the mixture was refluxed for 3 days The mixture was quenched with ice water (50 mL) extracted with ethyl acetate (2×30 mL) washed with water (2×30 mL), brine (30 mL) concentrated the residue was purified by flash chromatography (PE:EA=25:1 as eluant, 200 mL) to give an off-white solid

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

Procedure: A 250 mL of 4-necked flask equipped with thermometer and mechanical stirring was charged with NaBH4 (4.16 g, 0.11 mol) and THF (60 mL) under argon. After cooling to 0˜5° C. with stirring, a solution of iodine in THF (12.7 g I2 in 25 mL THF) was added slowly dropwise over 30 min and the reaction temperature was maintained below 10° C. After the addition was completed, a solution of 2-chloro-5-iodobenzoic acid (15.0 g, 50 mmol) in THF (20 mL) was added dropwise over 30 min and kept the reaction temperature below 10° C. After stirring for another 3 h at 20˜25° C., the reaction mixture was heated to reflux for additional 16 h and monitored by TLC (PE/EA=1:1, Rf=0.2). The mixture was cooled to 20˜25° C. and poured into ice water (100 mL), extracted with ethyl acetate (2×100 mL), washed with water (2×100 mL), brine (100 mL), concentrated and the residue was purified by flash chromatography (PE:EA=20:1 as eluant, 200 mL) to give an off-white solid. Yield: 10.0 g (70%) MS ESI (m/z): 269 [M+1]+. A 250 mL of 4-necked flask equipped with thermometer After cooling to 0˜5° C. with stirring the reaction temperature was maintained below 10° C After the addition the reaction temperature below 10° C After stirring for another 3 h at 20˜25° C. the reaction mixture was heated to reflux for additional 16 h The mixture was cooled to 20˜25° C. extracted with ethyl acetate (2×100 mL) washed with water (2×100 mL), brine (100 mL) concentrated the residue was purified by flash chromatography (PE:EA=20:1 as eluant, 200 mL) to give an off-white solid

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

Procedure: A methylene chloride solution (99 mL) of (2-chloro-5-iodophenyl)methanol (9.01 g, 33.5 mmol) and PCC (8.67 g, 40.2 mmol) were combined and stirred at rt. After 16 h, Et2O was added and the solution stirred for 30 minutes. The solution was then filtered and the organic layer was washed with H2O (2×), NaHCO3 (3×), and brine. The organic layer was dried (Na2SO4), concentrated, and purified by Biotage chromatography (0%-20% EtOAc/hexanes) to afford 5.94 g of product (67%). 1H NMR (400 MHz, chloroform-d) δ ppm 10.38 (s, 1 H) 8.22 (d, J=2.02 Hz, 1 H) 7.83 (dd, J=8.46, 2.15 Hz, 1 H) 7.21 (d, J=8.59 Hz, 1 H). the solution stirred for 30 minutes The solution was then filtered the organic layer was washed with H2O (2×), NaHCO3 (3×), and brine The organic layer was dried (Na2SO4) concentrated purified by Biotage chromatography (0%-20% EtOAc/hexanes)

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

Procedure: A solution of 2-chloro-5-iodobenzoic acid (28 g, 99 mmoles) and toluene (198 mL) was cooled to 0° C. A 1M diisobutyl aluminium hydride (DIBAL) solution in toluene 208 mL, 208 mmol) solution was added drop wise over 20 minutes. The solution was allowed to slowly warm to rt. After 16 h the solution was cooled to 0° C., MeOH and 1M HCl was slowly added (exothermic reaction). The solution became clumpy and was filtered and the clumps washed with EtOAc. The organic phase was then isolated and the aqueous layer washed with EtOAc. The combined organic extracts were then washed with brine, dried (Na2SO4), and concentrated. The product was purified by Biotage chromatography (0%-100% EtOAc/Hexanes) to afford 9.01 g of product as a solid (34%). 1H NMR (400 MHz, chloroform-d) δ ppm 7.85 (d, J=2.02 Hz, 1 H) 7.55 (dd, J=8.34, 2.27 Hz, 1 H) 7.09 (d, J=8.34 Hz, 1 H) 4.74 (s, 2 H) 2.25 (s, 1 H). After 16 h the solution was cooled to 0° C. (exothermic reaction) was filtered the clumps washed with EtOAc The organic phase was then isolated the aqueous layer washed with EtOAc The combined organic extracts were then washed with brine dried (Na2SO4) concentrated The product was purified by Biotage chromatography (0%-100% EtOAc/Hexanes)

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

Procedure: A solution of 2-chloro-5-iodobenzoic acid (28 g, 99 mmoles) and toluene (198 mL) was cooled to 0° C. A 1M diisobutyl aluminium hydride (DIBAL) solution in toluene 208 mL, 208 mmol) solution was added drop wise over 20 minutes. The solution was allowed to slowly warm to rt. After 16 h the solution was cooled to 0° C., MeOH and 1M HCl was slowly added (exothermic reaction). The solution became clumpy and was filtered and the clumps washed with EtOAc. The organic phase was then isolated and the aqueous layer washed with EtOAc. The combined organic extracts were then washed with brine, dried (Na2SO4), and concentrated. The product was purified by Biotage chromatography (0%-100% EtOAc/Hexanes) to afford 9.01 g of product as a solid (34%). 1H NMR (400 MHz, chloroform-d) δ ppm 7.85 (d, J=2.02 Hz, 1 H) 7.55 (dd, J=8.34, 2.27 Hz, 1 H) 7.09 (d, J=8.34 Hz, 1 H) 4.74 (s, 2 H) 2.25 (s, 1 H). After 16 h the solution was cooled to 0° C. (exothermic reaction) was filtered the clumps washed with EtOAc The organic phase was then isolated the aqueous layer washed with EtOAc The combined organic extracts were then washed with brine dried (Na2SO4) concentrated The product was purified by Biotage chromatography (0%-100% EtOAc/Hexanes)

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

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 2-chloro-5-iodobenzyl alcohol (0.537 g, 2.0 mmol) in THF (10 mL) was added to sodium hydride (88 mg of a 60% dispersion in mineral oil, 2.2 mmol) at 0° C. with stirring under nitrogen. After 5 min the mixture was cooled to −78° C. and n-butyl-lithium (2.5 M in hexanes, 1.66 mL, 4.15 mmol) was added over 6 min. After a further 5 min a solution of N-(4-methoxyphenyl)-N-(-2,2,2-trifluoroethylidene)amine (0.406 g, 2.0 mmol) in THF (2 mL) was added over 5 min. After a further 5 min the reaction was quenched with saturated ammonium chloride solution and the mixture was warmed to ambient temperature and partitioned between ethyl acetate and brine. The organic layer was dried (Na2SO4) and evaporated to a gum which was purified by chromatography on silica (eluting with 2% methanol/chloroform) to give N-{1-[4-chloro-2-(hydroxymethyl)phenyl]-2,2,2-trifluoroethyl}-N-(4-methoxyphenyl)amine as a 1:1.7 mixture with 3-chlorobenzyl alcohol (0.38 g) as a gum: MS 346.4 (M+1). After a further 5 min the reaction was quenched with saturated ammonium chloride solution the mixture was warmed to ambient temperature partitioned between ethyl acetate and brine The organic layer was dried (Na2SO4) evaporated to a gum which was purified by chromatography on silica (eluting with 2% methanol/chloroform)

Conditions: temp:22.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 100 mL of 4-necked flask equipped with thermometer and mechanical stirrer was charged with (2-chloro-5-iodophenyl)methanol (268.5 mg, 1 mmol), anhydrous ZnCl2 (136.3 mg, 1 mmol), dichloromethane (5.0 mL) and n-hexane (29 mL) under argon. After stirring for 10 min at 20 to 25° C., HBr (gas) was bubbled into the mixture for 10 min and a solution of phenol (197.6 mg, 2.1 mmol) in dry dichloromethane (3.0 mL) was added dropwise over 30 min. After bubbling HBr for additional 2 h, the mixture was refluxed for 3 days. The conversion was about 65%. The mixture was quenched with ice water (50 mL), extracted with ethyl acetate (2×30 mL), washed with water (2×30 mL), brine (30 mL), concentrated and the residue was purified by flash chromatography (PE:EA=25:1 as eluant, 200 mL) to give an off-white solid. Yield: 180 mg (52%). 1H NMR (CDCl3, 400 MHz): δ 7.44 (d, J=8.4 Hz, 2H), 7.03˜7.09 (m, 3H), 6.77 (d, J=8.4 Hz, 2H), 4.76 (s, 1H), 3.95 (s, 2H), 3.82 (s, 2H). MS ESI (m/z): 345 [M+1]+. 13C NMR (CDCl3, 100 MHz): δ 154.1, 141.4, 139.5, 136.6, 134.2, 131.2, 130.9, 130.1, 115.5, 91.67, 38.07. A 100 mL of 4-necked flask equipped with thermometer and mechanical stirrer HBr (gas) was bubbled into the mixture for 10 min After bubbling HBr for additional 2 h the mixture was refluxed for 3 days The mixture was quenched with ice water (50 mL) extracted with ethyl acetate (2×30 mL) washed with water (2×30 mL), brine (30 mL) concentrated the residue was purified by flash chromatography (PE:EA=25:1 as eluant, 200 mL) to give an off-white solid

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

Procedure: A 250 mL of 4-necked flask equipped with thermometer and mechanical stirring was charged with NaBH4 (4.16 g, 0.11 mol) and THF (60 mL) under argon. After cooling to 0˜5° C. with stirring, a solution of iodine in THF (12.7 g I2 in 25 mL THF) was added slowly dropwise over 30 min and the reaction temperature was maintained below 10° C. After the addition was completed, a solution of 2-chloro-5-iodobenzoic acid (15.0 g, 50 mmol) in THF (20 mL) was added dropwise over 30 min and kept the reaction temperature below 10° C. After stirring for another 3 h at 20˜25° C., the reaction mixture was heated to reflux for additional 16 h and monitored by TLC (PE/EA=1:1, Rf=0.2). The mixture was cooled to 20˜25° C. and poured into ice water (100 mL), extracted with ethyl acetate (2×100 mL), washed with water (2×100 mL), brine (100 mL), concentrated and the residue was purified by flash chromatography (PE:EA=20:1 as eluant, 200 mL) to give an off-white solid. Yield: 10.0 g (70%) MS ESI (m/z): 269 [M+1]+. A 250 mL of 4-necked flask equipped with thermometer After cooling to 0˜5° C. with stirring the reaction temperature was maintained below 10° C After the addition the reaction temperature below 10° C After stirring for another 3 h at 20˜25° C. the reaction mixture was heated to reflux for additional 16 h The mixture was cooled to 20˜25° C. extracted with ethyl acetate (2×100 mL) washed with water (2×100 mL), brine (100 mL) concentrated the residue was purified by flash chromatography (PE:EA=20:1 as eluant, 200 mL) to give an off-white solid

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

Procedure: A methylene chloride solution (99 mL) of (2-chloro-5-iodophenyl)methanol (9.01 g, 33.5 mmol) and PCC (8.67 g, 40.2 mmol) were combined and stirred at rt. After 16 h, Et2O was added and the solution stirred for 30 minutes. The solution was then filtered and the organic layer was washed with H2O (2×), NaHCO3 (3×), and brine. The organic layer was dried (Na2SO4), concentrated, and purified by Biotage chromatography (0%-20% EtOAc/hexanes) to afford 5.94 g of product (67%). 1H NMR (400 MHz, chloroform-d) δ ppm 10.38 (s, 1 H) 8.22 (d, J=2.02 Hz, 1 H) 7.83 (dd, J=8.46, 2.15 Hz, 1 H) 7.21 (d, J=8.59 Hz, 1 H). the solution stirred for 30 minutes The solution was then filtered the organic layer was washed with H2O (2×), NaHCO3 (3×), and brine The organic layer was dried (Na2SO4) concentrated purified by Biotage chromatography (0%-20% EtOAc/hexanes)