(5-chloro-2-iodophenyl)methanol

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a stirred solution of iPr2NH (0.31 mL, 2.24 mmol) in THF (10 mL) at −78° C. under nitrogen atmosphere was added 2.5M n-BuLi in THF solution (0.75 mL, 1.86 mmol). The solution was stirred for 15 min at −78° C. and added to it in one portion was 2-iodo-5-chlorobenzyl alcohol (0.5 g, 1.86 mmol). This solution was stirred for 30 min at −78° C. then was concentrated in vacuo and placed under high vacuum for 1 h. The residue, under nitrogen atmosphere, was dissolved in THF (20 mL), cooled to −78° C., and 2.5M n-BuLi in THF solution (0.75 mL, 1.86 mmol) was added. This solution was stirred for 15 min at −78° C. and added drop wise was N-ethylidene-2-methyl-2-propanesulfinamide from the previous step (0.274 g, 1.86 mmol) dissolved in THF (5 mL). This solution was stirred for 30 min at −78° C. then was allowed to equilibrate to ambient temperature over 1 h. Saturated NH4Cl was added (3 mL), and the mixture was partitioned between EtOAc and water. The EtOAc layer was separated, dried over anhydrous Na2SO4, and filtered. The filtrate solvent was removed under reduced pressure and the residue was purified by flash silica gel chromatography eluting with a methanol in dichloromethane gradient (1% to 3% MeOH in 0.5% increments). After concentration of desired fractions in vacuo, the separate isomers of 2-(1-tert-butylsulfinamidylethyl)-5-chlorobenzyl alcohol were obtained as a yellow oils (isomer 1(less polar) 120 mg; HPLC RT=2.93 min, method A; LC-MS m/z=290.1; 1H NMR, 400 MHz, CDCl3, 7.38 ppm (s, 1H), 7.36 ppm (d, 1H), 7.28 ppm (dd, 1H), 4.86 ppm (d, 1H), 4.82 ppm (m, 1H), 4.54 ppm (d, 1H), 4.3 ppm (br s, 1H), 3.94 ppm (d, 1H), 1.54 ppm (d, 3H), 1.2 ppm (s, 9H); isomer 2(more polar) 38 mg; HPLC RT=2.69 min; LC-MS m/z=290.1; 1H NMR, 400 MHz, CDCl3 7.4 ppm (d, 1H), 7.365 ppm (d, 1H), 7.28 ppm (dd, 1H), 4.86 ppm (m, 1H), 4.78 ppm (dd, 1H), 4.64 ppm (dd, 1H), 3.67 ppm (br s, 1H), 3.65 ppm (d, 1H), 1.52 ppm (d, 3H), 1.18 ppm (s, 9H)). added to it in one portion This solution was stirred for 30 min at −78° C. then was concentrated in vacuo placed under high vacuum for 1 h The residue, under nitrogen atmosphere, was dissolved in THF (20 mL) cooled to −78° C. This solution was stirred for 15 min at −78° C. This solution was stirred for 30 min at −78° C. to equilibrate to ambient temperature over 1 h the mixture was partitioned between EtOAc and water The EtOAc layer was separated dried over anhydrous Na2SO4 filtered The filtrate solvent was removed under reduced pressure the residue was purified by flash silica gel chromatography eluting with a methanol in dichloromethane gradient (1% to 3% MeOH in 0.5% increments)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Triisopropylsilylchloride (14.59 mL, 68.16 mmol) was added to a stiffed solution of 5-chloro-2-iodobenzyl alcohol (12.2 g, 45.44 mmol) and imidazole (4.64 g, 68.16 mmol) in DMF (45 mL). After 1 h the mixture was partitioned between hexanes and water. The organic layer was dried (Na2SO4) and evaporated in vacuo to an oil which was purified by flash column chromatography on silica (eluting with 5% methylene chloride/hexanes) to give [(5-chloro-2-iodobenzyl)oxy](triisopropyl)silane as an oil (1611 g): 1H NMR (CDCl3, 400 MHz) δ 1.11 (d, J=6.8 Hz, 18H), 1.20 (septet, J=6.8 Hz, 3H), 4.65 (s, 2H), 6.96 (dd, J=2.6, 8.4 Hz, 1H), 7.56 (d, J=2.8 Hz, 1H), 7.66 (d, J=8.2 Hz, 1H). After 1 h the mixture was partitioned between hexanes and water The organic layer was dried (Na2SO4) evaporated in vacuo to an oil which was purified by flash column chromatography on silica (eluting with 5% methylene chloride/hexanes)

反応条件: temp:22.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Borane methylsulfide (7.3 mL, 73 mmol) was added to a stirred solution of 5-chloro-2-iodobenzoic acid (17.17 g, 60.79 mmol) in THF (40 mL) and trimethylborate (20 mL), maintaining the internal temperature at 20-25° C. After 16 h methanol (8.87 mL, 0.219 mol) was added cautiously and the solution was evaporated in vacuo, azeotroping with methanol (3×50 mL). The resulting solid was recrystallized (hexanes/ethyl acetate, 5:1, 120 mL) to give 5-chloro-2-iodobenzyl alcohol (12.2 g): 1H NMR (CDCl3, 400 MHz) δ 2.00 (br s, 1H), 4.64 (s, 2H), 7.00 (dd, J=2.6, 8.4 Hz, 1H), 7.49 (d, J=2.4, 1H), 7.72 (d, J=8.2 Hz, 1H). the solution was evaporated in vacuo azeotroping with methanol (3×50 mL) The resulting solid was recrystallized (hexanes/ethyl acetate, 5:1, 120 mL)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: DPPA (0.442 mL, 2.05 mmol) followed by DBU (0.306 mL, 2.05 mmol) were added to a stirred solution of 5-chloro-2-iodobenzyl alcohol (500 mg, 1.86 mmol) in DMF (10 mL) at 0° C. and the reaction mixture was warmed to room temperature. After 16 h the mixture was warmed to 70° C. for 2 hr. The reaction was then concentrated and the residue was partitioned between EtOAc and 10% NaHCO3. The organic layer was washed with water and brine, dried (Na2SO4) and evaporated to give 5-chloro-2-iodobenzylazide (588 mg): 1H NMR (CDCl3, 400 MHz) δ 4.43 (s, 2H), 7.03 (dd, J=2.6, 8.4 Hz, 1H), 7.39 (d, J=2.6, 1H), 7.78 (d, J=8.4 Hz, 1H). After 16 h the mixture was warmed to 70° C. for 2 hr The reaction was then concentrated the residue was partitioned between EtOAc and 10% NaHCO3 The organic layer was washed with water and brine dried (Na2SO4) evaporated

反応条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of 5-chloro-2-iodobenzylalcohol (0.948 g, 3.53 mmol) in dry THF (27 mL) was added, rinsing with dry THF, to a stirred suspension of NaH (0.155 g, 3.89 mmol) in dry THF (9 mL) at 0° C. After 5 min the mixture was cooled to −78° C. and n-butyl-lithium (2.5 M in hexanes, 2.97 mL, 7 mmol) was added dropwise over 5 minutes. After a further 10 min, a solution of N-(2,2-difluoroethylidene)-N-(4-methoxyphenyl)amine (0.654 g, 3.53 mmol) in dry THF (9 mL) was added. After 1 h the mixture was quenched with excess saturated aqueous NH4Cl at −78° C. then was stirred at ambient temperature for 15 min. The solution was partitioned between EtOAc and brine. The EtOAc layer was dried (Na2SO4) and evaporated in vacuo and the residue was purified by flash column chromatography on silica (eluting with 5% methylene chloride, 5-30% ethyl acetate/hexanes gradient) to give (5-chloro-2-{2,2-difluoro-1-[(4-methoxyphenyl)amino]ethyl}phenyl)methanol (0.439 g) as an oil: MS 328.4 (M+1); 1H NMR (CDCl3, 400 MHz) δ 2.00 (br s, 1H), 3.70 (s, 3H), 4.14 (br s, 1H), 4.82 (m, 2H), 5.02 (m, 1H), 6.08 (dt, J=3.0 Hz, 56.0 Hz, 1H), 6.57 (d, J=9.0 Hz, 2H), 6.71 (d, J=9.0 Hz), 2H), 7.29 (dd, J=2.2 and 8.4 Hz, 1H), 7.40 (d, J=2.2 Hz, 1H), 7.47 (d, J=8.4 Hz, 1H). After 1 h the mixture was quenched with excess saturated aqueous NH4Cl at −78° C. The solution was partitioned between EtOAc and brine The EtOAc layer was dried (Na2SO4) evaporated in vacuo the residue was purified by flash column chromatography on silica (eluting with 5% methylene chloride, 5-30% ethyl acetate/hexanes gradient)

反応条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of 5-chloro-2-iodobenzylalcohol (0.948 g, 3.53 mmol) in dry THF (27 mL) was added, rinsing with dry THF, to a stirred suspension of NaH (0.155 g, 3.89 mmol) in dry THF (9 mL) at 0° C. After 5 min the mixture was cooled to −78° C. and n-butyl-lithium (2.5 M in hexanes, 2.97 mL, 7 mmol) was added dropwise over 5 minutes. After a further 10 min, a solution of N-(2,2-difluoroethylidene)-N-(4-methoxyphenyl)amine (0.654 g, 3.53 mmol) in dry THF (9 mL) was added. After 1 h the mixture was quenched with excess saturated aqueous NH4Cl at −78° C. then was stirred at ambient temperature for 15 min. The solution was partitioned between EtOAc and brine. The EtOAc layer was dried (Na2SO4) and evaporated in vacuo and the residue was purified by flash column chromatography on silica (eluting with 5% methylene chloride, 5-30% ethyl acetate/hexanes gradient) to give (5-chloro-2-{2,2-difluoro-1-[(4-methoxyphenyl)amino]ethyl}phenyl)methanol (0.439 g) as an oil: MS 328.4 (M+1); 1H NMR (CDCl3, 400 MHz) δ 2.00 (br s, 1H), 3.70 (s, 3H), 4.14 (br s, 1H), 4.82 (m, 2H), 5.02 (m, 1H), 6.08 (dt, J=3.0 Hz, 56.0 Hz, 1H), 6.57 (d, J=9.0 Hz, 2H), 6.71 (d, J=9.0 Hz), 2H), 7.29 (dd, J=2.2 and 8.4 Hz, 1H), 7.40 (d, J=2.2 Hz, 1H), 7.47 (d, J=8.4 Hz, 1H). After 1 h the mixture was quenched with excess saturated aqueous NH4Cl at −78° C. The solution was partitioned between EtOAc and brine The EtOAc layer was dried (Na2SO4) evaporated in vacuo the residue was purified by flash column chromatography on silica (eluting with 5% methylene chloride, 5-30% ethyl acetate/hexanes gradient)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Borane-dimethylsulfide complex (3.7 mL, 38.9 mmol) was added slowly to a cold (0° C.) solution of 5-chloro-2-iodo-benzoic acid (10 g, 35.4 mmol) in THF (20 mL). The reaction mixture was allowed to warm to rt, stirred for 8 h, quenched by addition of a saturated aqueous solution of ammonium chloride, and extracted with EtOAc. The organic layer was dried (Na2SO4), filtered, and concentrated to provide 9.5 g of the title compound. tR: 4.72 min (HPLC 2); Rf=0.66 (hexane/EtOAc, 7:3). quenched by addition of a saturated aqueous solution of ammonium chloride extracted with EtOAc The organic layer was dried (Na2SO4) filtered concentrated

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 41.6 g of phosphorus tribromide, 25 ml of benzene and 8.2 ml of pyridine is prepared while cooling and while stirring it is treated dropwise at a maximum temperature of 10° C. with 108.3 g of 5-chloro-2-iodobenzyl alcohol. Then, it is stirred for 4 hours at room temperature and for 1 hour at 50° C. After cooling, it is diluted with 120 ml of chloroform, the mixture washed with 25 ml of 5% hydrochloric acid, a 5% sodium hydroxide solution and with water, dried with magnesium sulfate and evaporated. There are obtained 126 g (95%) of crude 5-chloro-2-iodobenzyl bromide melting at 75°-79° C. The pure product is obtained by crystallization from a mixture of benzene and petroleum ether, m.p. 77°-79° C. is prepared while cooling Then, it is stirred for 4 hours at room temperature and for 1 hour at 50° C After cooling the mixture washed with 25 ml of 5% hydrochloric acid a 5% sodium hydroxide solution and with water, dried with magnesium sulfate evaporated