p-((Trimethylsilyl)oxy)benzaldehyde

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

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

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

Procedure: To a stirred solution of 122 g 4-hydroxybenzaldehyde (1.0 mol, available from Aldrich) and 111 g triethylamine (1.1 mol, available from Aldrich) in 1.0 L dichloromethane was added dropwise 108 g chlorotrimethylsilane (1.1 mol). This mixture was allowed to stand at room temperature for three days before 500 mL hexane was added. The mixture was filtered to remove triethylamine hydrochloride, and most of the solvent was removed at reduced pressure. A 200 mL portion of hexane was then added, the mixture filtered again, and solvent removed at reduced pressure to leave the desired product. was added The mixture was filtered to remove triethylamine hydrochloride most of the solvent was removed at reduced pressure A 200 mL portion of hexane was then added the mixture filtered again solvent removed at reduced pressure

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

Procedure: To a stirred solution of 122 g 4-hydroxybenzaldehyde (1.0 mol, available from Aldrich) and 111 g triethylamine (1.1 mol, available from Aldrich) in 1.0 L dichloromethane was added dropwise 108 g chlorotrimethylsilane (1.1 mol). This mixture was allowed to stand at room temperature for three days before 500 mL hexane was added. The mixture was filtered to remove triethylamine hydrochloride, and most of the solvent was removed at reduced pressure. A 200 mL portion of hexane was then added, the mixture filtered again, and solvent removed at reduced pressure to leave the desired product. was added The mixture was filtered to remove triethylamine hydrochloride most of the solvent was removed at reduced pressure A 200 mL portion of hexane was then added the mixture filtered again solvent removed at reduced pressure

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

Procedure: Triethylamine (42 ml) is added dropwise to a stirred solution of 4-hydroxybenzaldehyde (33.5 g) and chlorotrimethylsilane (42 ml) in ether (300 ml). After 15 min, the mixture is filtered through diatomaceous earth and the filtrate is concentrated and distilled in vacuo, providing 4-(trimethylsiloxy)benzaldehyde as a colorless oil (43 g). This material is reacted with methoxymethyl triphenylphosphonium chloride and potassium tert-butoxide in THF, using the procedure described in Example 1 (A) above, to provide 1-(2-methoxyethenyl)-4-(trimethylsiloxy)benzene (35%) as a colorless oil after distillation in vacuo, as a mixture of (E) and (Z) isomers. This material (3.0 g) is dissolved in methanol (30 ml) containing methanesulfonic acid (0.4 ml), and the solution is refluxed for 3 hr. Sodium bicarbonate (8 ml of 1.0N solution) is added, and the mixture is concentrated in vacuo. The residue is taken up in ethyl acetate, dried, and concentrated to provide 4-[(2,2-dimethoxy)ethyl]phenol as a pale red oil (2.4 g). the mixture is filtered through diatomaceous earth the filtrate is concentrated distilled in vacuo

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

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

Procedure: Triethylamine (42 ml) is added dropwise to a stirred solution of 4-hydroxybenzaldehyde (33.5 g) and chlorotrimethylsilane (42 ml) in ether (300 ml). After 15 min, the mixture is filtered through diatomaceous earth and the filtrate is concentrated and distilled in vacuo, providing 4-(trimethylsiloxy)benzaldehyde as a colorless oil (43 g). This material is reacted with methoxymethyl triphenylphosphonium chloride and potassium tert-butoxide in THF, using the procedure described in Example 1 (A) above, to provide 1-(2-methoxyethenyl)-4-(trimethylsiloxy)benzene (35%) as a colorless oil after distillation in vacuo, as a mixture of (E) and (Z) isomers. This material (3.0 g) is dissolved in methanol (30 ml) containing methanesulfonic acid (0.4 ml), and the solution is refluxed for 3 hr. Sodium bicarbonate (8 ml of 1.0N solution) is added, and the mixture is concentrated in vacuo. The residue is taken up in ethyl acetate, dried, and concentrated to provide 4-[(2,2-dimethoxy)ethyl]phenol as a pale red oil (2.4 g). the mixture is filtered through diatomaceous earth the filtrate is concentrated distilled in vacuo

Conditions: temp:-40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of 2-bromo-5-methylpyridine (3.45 g, 20 mmol) in THF (10 mL) was added dropwise 1.6 M solution in hexanes n-BuLi (12 mL, 19.2 mmol) over a 10-min period at −78° C. The mixture was stirred at −78° C. for 2 min before 4-trimethylsilyloxybenzaldehyde (4.2 g, 21.6 mmol) dissolved in THF (10 mL) was added. The mixture was allowed to warm to −40° C. and quenched with water. The pH of the aqueous phase was adjusted to 7 which causes precipitation of 4-[hydroxy-(5-methyl-pyridin-2-yl)-methyl]phenol. This was isolated by filtration to give 1.13 g (27%) of 4-[hydroxy-(5-methyl-pyridin-2-yl)-methyl]phenol as crystals. This intermediate was dissolved in CH2Cl2 (15 mL) and stirred with triethylsilane (4 mL) and TFA (5 mL) for 16 h at 50° C. Evaporation gave 99% of 4-(5-methyl-pyridin-2-ylmethyl)phenol as a hygroscopic solid. This was carbamoylated using general procedure 1 (CH2Cl2 was used as solvent and N-phenyl-N-methyl carbamoyl chlorid) to give 99% of the title product as its crystalline hydrochloride after purification by flash chromatography (Quad flash 12, EtOAc-heptane) and treatment with HCl in Et2O. was added quenched with water precipitation of 4-[hydroxy-(5-methyl-pyridin-2-yl)-methyl]phenol This was isolated by filtration

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

Procedure: A solution of 2-(dimethylamino)ethanol (32 mmol) in hexane (120 mL) was cooled to −5° C. and n-BuLi (64 mmol) was added. After 30 min 4-(dimethylamine=pyridine (16 mmol) was added and the red-orange mixture was stirred for further 1 h. The solution was cooled to −78° C. and 4-(trimethylsilyloxy)benzaldehyde (40 mmol) dissolved in hexane (80 mL) was added and the suspention was allowed to warm to rt over 20 min. The reaction mixture was quenched with water, and the aqueous phase was washed with CH2Cl2. The aqueous phase was evaporated to dryness, added NaI (96 mmol) and dissolved in MeCN (160 mL). Addition of trimethylsilylchloride (96 mmol) and stirring at rt for 16 h. The purple reaction mixture was evaporated to dryness and treated with an aqueous solution of Na2SO3 and pH was adjusted to 8. Extraction with CH2Cl2 gave after evaporation 560 mg (15%) slightly impure 4-(4-dimethylamino-pyridin-2-ylmethyl)phenol as yellow crystals. This was carbamoylated using general procedure 1 (CH2Cl2 was used as solvent) to give the title product as its hydrochloride after purification by preparative HPLC (Gilson) and treatment with HCl in Et2O (48%, ligt yellow crystals). was added to warm to rt over 20 min The reaction mixture was quenched with water the aqueous phase was washed with CH2Cl2 The aqueous phase was evaporated to dryness stirring at rt for 16 h The purple reaction mixture was evaporated to dryness treated with an aqueous solution of Na2SO3 and pH Extraction with CH2Cl2 gave after evaporation 560 mg (15%) slightly impure 4-(4-dimethylamino-pyridin-2-ylmethyl)phenol as yellow crystals

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

Procedure: To a stirred solution of 1-[2-(4-bromo-phenoxy)-ethyl]-pyrrolidine (2.89 g, 10.7 mmol) in THF (30 mL) was added dropwise 1.6 M solution in hexanes n-BuLi (7 mL, 10.2 mmol) over a 5-min period at −78° C. The mixture was stirred at −78° C. for 15 min before 4-trimethylsilyloxybenzaldehyde (2.08 g, 10.7 mmol) was added. The mixture was allowed to warm to rt during 20 min and quenched with water. Extraction with CH2Cl2, drying (MgSO4), filtration and evaporation provided the crude diarylmethanol which was dissolved in CH2Cl2 (30 mL) and stirred with triethylsilane (4 mL) and TFA (5 mL) for 16 h at rt. Evaporation gave 3.0 g (84%) 4-[4-(2-pyrrolidin-1-yl-ethoxy)-benzyl]-phenol. This was carbamoylated using general procedure 1 (CH2Cl2 was used as solvent) to give the title product after purification by preparative HPLC (Gilson) (35%, oil). was added quenched with water Extraction with CH2Cl2 drying (MgSO4), filtration and evaporation provided the crude diarylmethanol which Evaporation

Conditions: temp:-40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of 2-bromo-5-methylpyridine (3.45 g, 20 mmol) in THF (10 mL) was added dropwise 1.6 M solution in hexanes n-BuLi (12 mL, 19.2 mmol) over a 10-min period at −78° C. The mixture was stirred at −78° C. for 2 min before 4-trimethylsilyloxybenzaldehyde (4.2 g, 21.6 mmol) dissolved in THF (10 mL) was added. The mixture was allowed to warm to −40° C. and quenched with water. The pH of the aqueous phase was adjusted to 7 which causes precipitation of 4-[hydroxy-(5-methyl-pyridin-2-yl)-methyl]phenol. This was isolated by filtration to give 1.13 g (27%) of 4-[hydroxy-(5-methyl-pyridin-2-yl)-methyl]phenol as crystals. This intermediate was dissolved in CH2Cl2 (15 mL) and stirred with triethylsilane (4 mL) and TFA (5 mL) for 16 h at 50° C. Evaporation gave 99% of 4-(5-methyl-pyridin-2-ylmethyl)phenol as a hygroscopic solid. This was carbamoylated using general procedure 1 (CH2Cl2 was used as solvent and N-phenyl-N-methyl carbamoyl chlorid) to give 99% of the title product as its crystalline hydrochloride after purification by flash chromatography (Quad flash 12, EtOAc-heptane) and treatment with HCl in Et2O. was added quenched with water precipitation of 4-[hydroxy-(5-methyl-pyridin-2-yl)-methyl]phenol This was isolated by filtration

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

Procedure: A solution of 2-(dimethylamino)ethanol (32 mmol) in hexane (120 mL) was cooled to −5° C. and n-BuLi (64 mmol) was added. After 30 min 4-(dimethylamine=pyridine (16 mmol) was added and the red-orange mixture was stirred for further 1 h. The solution was cooled to −78° C. and 4-(trimethylsilyloxy)benzaldehyde (40 mmol) dissolved in hexane (80 mL) was added and the suspension was allowed to warm to rt over 20 min. The reaction mixture was quenched with water, and the aqueous phase was washed with CH2Cl2. The aqueous phase was evaporated to dryness, added Nal (96 mmol) and dissolved in MeCN (160 mL). Addition of trimethylsilylchloride (96 mmol) and stirring at rt for 16 h. The purple reaction mixture was evaporated to dryness and treated with an aqueous solution of Na2SO3 and pH was adjusted to 8. Extraction with CH2Cl2 gave after evaporation 560 mg (15%) slightly impure 4-(4-dimethylamino-pyridin-2-ylmethyl)phenol as yellow crystals. This was carbamoylated using general procedure 1 (CH2Cl2 was used as solvent) to give the title product as its hydrochloride after purification by preparative HPLC (Gilson) and treatment with HCl in Et2O (48%, light yellow crystals). was added to warm to rt over 20 min The reaction mixture was quenched with water the aqueous phase was washed with CH2Cl2 The aqueous phase was evaporated to dryness stirring at rt for 16 h The purple reaction mixture was evaporated to dryness treated with an aqueous solution of Na2SO3 and pH Extraction with CH2Cl2 gave after evaporation 560 mg (15%) slightly impure 4-(4-dimethylamino-pyridin-2-ylmethyl)phenol as yellow crystals