2-(2,6-dichlorophenyl)acetaldehyde

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

Conditions: temp:-70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of butyl lithium in hexane (5.1 mL; 2.5 M) is treated with a solution of 3-cyclopentyloxy-4-methoxyphenyl bromide (3.45 g) in dry tetrahydrofuran (30 mL) at -70° C. and the solution is then stirred at -70° C. for 1 hour. It is then treated dropwise with 2,6-dichlorophenylacetaldehyde (2.4 g), while keeping the temperature below -60° C. When the addition is complete the temperature is allowed to rise to room temperature and the solution is stirred for a further 2 hours. The reaction mixture is treated with aqueous ammonium chloride solution (50 mL) and the solution is extracted with diethyl ether (2×200 mL). The combined extracts are dried and concentrated, to give a yellow oil, which is subjected to flash chromatography, eluting with a mixture of diethyl ether and pentane (1:8 v/v), to give 1-(3-cyclopentyloxy-4-methoxyphenyl)-2-(2,6-dichlorophenyl)ethanol (1.6 g),in the form of a white solid, m.p. 87°-89° C. the temperature below -60° C When the addition to rise to room temperature the solution is stirred for a further 2 hours the solution is extracted with diethyl ether (2×200 mL) The combined extracts are dried concentrated to give a yellow oil, which eluting with a mixture of diethyl ether and pentane (1:8 v/v)

Conditions: temp:83.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of sodium hydroxide (0.672 g, 16.8 mmol) and hydroxylamine hydrochloride (1.17 g, 16.8 mmol) in water (11 mL) was added to a solution of (2,6-dichlorophenyl)acetaldehyde (2.78 g, 14.7 mmol) in ethanol (21 mL). The resulting solution was heated in an 83° C. oil bath overnight. The sample was concentrated and filtered. The resulting solid was dried with P2O5 in a vacuum oven at 45° C. under reduced pressure to provide the oxime as a mixture of isomers (2.21 g yield, 74%). A solution of (2,6-dichlorophenyl)acetaldehyde oxime (1.05 g, 4.82 mmol) in dimethylformamide (3.8 mL) was stirred as N-chlorosuccinimide (0.64 g, 4.82 mmol) was added and the resulting solution was allowed to stir for one hour. The solution was poured into water and extracted with ether. The organic layer was washed with brine, dried with magnesium sulfate, filtered and concentrated to yield the title compound (2.60 g, 77%). 1H NMR (DMSO-d6): δ 11.78 (s, 1H), 7.47 (d, J=8 Hz, 2H), 7.33 (t, J=8 Hz, 1H), 4.08 (s, 2H). The sample was concentrated filtered The resulting solid was dried with P2O5 in a vacuum oven at 45° C. under reduced pressure

Conditions: temp:83.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of sodium hydroxide (0.672 g, 16.8 mmol) and hydroxylamine hydrochloride (1.17 g, 16.8 mmol) in water (11 mL) was added to a solution of (2,6-dichlorophenyl)acetaldehyde (2.78 g, 14.7 mmol) in ethanol (21 mL). The resulting solution was heated in an 83° C. oil bath overnight. The sample was concentrated and filtered. The resulting solid was dried with P2O5 in a vacuum oven at 45° C. under reduced pressure to provide the oxime as a mixture of isomers (2.21 g yield, 74%). A solution of (2,6-dichlorophenyl)acetaldehyde oxime (1.05 g, 4.82 mmol) in dimethylformamide (3.8 mL) was stirred as N-chlorosuccinimide (0.64 g, 4.82 mmol) was added and the resulting solution was allowed to stir for one hour. The solution was poured into water and extracted with ether. The organic layer was washed with brine, dried with magnesium sulfate, filtered and concentrated to yield the title compound (2.60 g, 77%). 1H NMR (DMSO-d6): δ 11.78 (s, 1H), 7.47 (d, J=8 Hz, 2H), 7.33 (t, J=8 Hz, 1H), 4.08 (s, 2H). The sample was concentrated filtered The resulting solid was dried with P2O5 in a vacuum oven at 45° C. under reduced pressure

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of 6-chloro-pyrimidine-4,5-diamine (100 mg, 0.694 mmol), (2,6-dichloro-phenyl)-acetaldehyde (260 mg, 1.38 mmol) and 1,4-dioxane (7 mL) was added 5% FeCl3.SiO2 (150 mg). The resulting mixture was heated to 100° C. in a sealed tube. After 24 h, the mixture was cooled to rt and filtered through a pad of diatomaceous earth, washing with EtOAc (3×10 mL). The filtrate was concentrated and the residue was purified by preparative reverse-phase HPLC to afford the title compound as a white solid (25 mg, 36%). MS (ESI): mass calcd. for C12H7Cl3N4, 311.9; m/z found, 313.0 [M+H]+. 1H NMR (CDCl3): 8.65 (s, 1H), 7.46 (d, J=8.1 Hz, 2H), 7.34-7.29 (m, 1H), 4.78 (s, 2H). the mixture was cooled to rt filtered through a pad of diatomaceous earth washing with EtOAc (3×10 mL) The filtrate was concentrated the residue was purified by preparative reverse-phase HPLC

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

Procedure: To a solution of 2,6-dichlorophenylethylalcohol (2.0 g, 10.5 mmol) and CH2Cl2 (50 mL) was added acetic acid 1,1-diacetoxy-3-oxo-1λ5-ioda-2-oxa-indan-1-yl ester (Dess-Martin periodinane; 4.9 g, 11.5 mmol) at rt. After 30 min. the mixture was diluted with satd. aq. NaHCO3 (10 mL) and satd. aq. Na2S2O3 (10 mL) and was stirred at rt for 1 h. The mixture was extracted with CH2Cl2 (3×15 mL) and the combined organic layers were dried (MgSO4), concentrated, and purified by FCC to afford a colorless solid (1.4 g, 70%). 1H NMR (CDCl3): 9.76 (dd, J=2.24, 1.12 Hz, 1H), 7.38 (d, J=8.1 Hz, 2H), 7.25-7.20 (m, 1H), 4.14 (d, J=0.93 Hz, 1H). After 30 min. the mixture was diluted with satd The mixture was extracted with CH2Cl2 (3×15 mL) the combined organic layers were dried (MgSO4) concentrated purified by FCC

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

Procedure: To a solution of 2,6-dichlorophenylethylalcohol (2.0 g, 10.5 mmol) and CH2Cl2 (50 mL) was added acetic acid 1,1-diacetoxy-3-oxo-1λ5-ioda-2-oxa-indan-1-yl ester (Dess-Martin periodinane; 4.9 g, 11.5 mmol) at rt. After 30 min. the mixture was diluted with satd. aq. NaHCO3 (10 mL) and satd. aq. Na2S2O3 (10 mL) and was stirred at rt for 1 h. The mixture was extracted with CH2Cl2 (3×15 mL) and the combined organic layers were dried (MgSO4), concentrated, and purified by FCC to afford a colorless solid (1.4 g, 70%). 1H NMR (CDCl3): 9.76 (dd, J=2.24, 1.12 Hz, 1H), 7.38 (d, J=8.1 Hz, 2H), 7.25-7.20 (m, 1H), 4.14 (d, J=0.93 Hz, 1H). After 30 min. the mixture was diluted with satd The mixture was extracted with CH2Cl2 (3×15 mL) the combined organic layers were dried (MgSO4) concentrated purified by FCC

Conditions: temp:-70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of butyl lithium in hexane (5.1 mL; 2.5 M) is treated with a solution of 3-cyclopentyloxy-4-methoxyphenyl bromide (3.45 g) in dry tetrahydrofuran (30 mL) at -70° C. and the solution is then stirred at -70° C. for 1 hour. It is then treated dropwise with 2,6-dichlorophenylacetaldehyde (2.4 g), while keeping the temperature below -60° C. When the addition is complete the temperature is allowed to rise to room temperature and the solution is stirred for a further 2 hours. The reaction mixture is treated with aqueous ammonium chloride solution (50 mL) and the solution is extracted with diethyl ether (2×200 mL). The combined extracts are dried and concentrated, to give a yellow oil, which is subjected to flash chromatography, eluting with a mixture of diethyl ether and pentane (1:8 v/v), to give 1-(3-cyclopentyloxy-4-methoxyphenyl)-2-(2,6-dichlorophenyl)ethanol (1.6 g),in the form of a white solid, m.p. 87°-89° C. the temperature below -60° C When the addition to rise to room temperature the solution is stirred for a further 2 hours the solution is extracted with diethyl ether (2×200 mL) The combined extracts are dried concentrated to give a yellow oil, which eluting with a mixture of diethyl ether and pentane (1:8 v/v)

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of 6-chloro-pyrimidine-4,5-diamine (100 mg, 0.694 mmol), (2,6-dichloro-phenyl)-acetaldehyde (260 mg, 1.38 mmol) and 1,4-dioxane (7 mL) was added 5% FeCl3.SiO2 (150 mg). The resulting mixture was heated to 100° C. in a sealed tube. After 24 h, the mixture was cooled to rt and filtered through a pad of diatomaceous earth, washing with EtOAc (3×10 mL). The filtrate was concentrated and the residue was purified by preparative reverse-phase HPLC to afford the title compound as a white solid (25 mg, 36%). MS (ESI): mass calcd. for C12H7Cl3N4, 311.9; m/z found, 313.0 [M+H]+. 1H NMR (CDCl3): 8.65 (s, 1H), 7.46 (d, J=8.1 Hz, 2H), 7.34-7.29 (m, 1H), 4.78 (s, 2H). the mixture was cooled to rt filtered through a pad of diatomaceous earth washing with EtOAc (3×10 mL) The filtrate was concentrated the residue was purified by preparative reverse-phase HPLC

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

Procedure: To a solution of 2,6-dichlorophenylethylalcohol (2.0 g, 10.5 mmol) and CH2Cl2 (50 mL) was added acetic acid 1,1-diacetoxy-3-oxo-1λ5-ioda-2-oxa-indan-1-yl ester (Dess-Martin periodinane; 4.9 g, 11.5 mmol) at rt. After 30 min. the mixture was diluted with satd. aq. NaHCO3 (10 mL) and satd. aq. Na2S2O3 (10 mL) and was stirred at rt for 1 h. The mixture was extracted with CH2Cl2 (3×15 mL) and the combined organic layers were dried (MgSO4), concentrated, and purified by FCC to afford a colorless solid (1.4 g, 70%). 1H NMR (CDCl3): 9.76 (dd, J=2.24, 1.12 Hz, 1H), 7.38 (d, J=8.1 Hz, 2H), 7.25-7.20 (m, 1H), 4.14 (d, J=0.93 Hz, 1H). After 30 min. the mixture was diluted with satd The mixture was extracted with CH2Cl2 (3×15 mL) the combined organic layers were dried (MgSO4) concentrated purified by FCC

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

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of 6-chloro-pyrimidine-4,5-diamine (100 mg, 0.694 mmol), (2,6-dichloro-phenyl)-acetaldehyde (260 mg, 1.38 mmol) and 1,4-dioxane (7 mL) was added 5% FeCl3.SiO2 (150 mg). The resulting mixture was heated to 100° C. in a sealed tube. After 24 h, the mixture was cooled to rt and filtered through a pad of diatomaceous earth, washing with EtOAc (3×10 mL). The filtrate was concentrated and the residue was purified by preparative reverse-phase HPLC to afford the title compound as a white solid (25 mg, 36%). MS (ESI): mass calcd. for C12H7Cl3N4, 311.9; m/z found, 313.0 [M+H]+. 1H NMR (CDCl3): 8.65 (s, 1H), 7.46 (d, J=8.1 Hz, 2H), 7.34-7.29 (m, 1H), 4.78 (s, 2H). the mixture was cooled to rt filtered through a pad of diatomaceous earth washing with EtOAc (3×10 mL) The filtrate was concentrated the residue was purified by preparative reverse-phase HPLC