2-(bromomethyl)-1-fluoro-4-methoxybenzene

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 2,2-dimethyl-propionic acid 8-(4-acetylamino-benzyl)-3-butyl-2,6-dioxo-1,2,3,6-tetrahydro-purin-7-ylmethyl ester (100 mg, 0.21 mmol) and 2-bromomethyl-1-fluoro-4-methoxy-benzene (56 mg, 0.25 mmol) in acetonitrile (2.0 mL) was treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (0.06 mL, 0.45 mmol). The reaction was stirred at 25° C. The reaction was diluted with ethyl acetate and was washed with a 1N aqueous hydrochloric acid solution and a saturated aqueous sodium chloride solution. The organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 1:1 ethyl acetate/petroleum ether) afforded 2,2-dimethyl-propionic acid 8-(4-acetylamino-benzyl)-3-butyl-1-(2-fluoro-5-methoxy-benzyl)-2,6-dioxo-1,2,3,6-tetrahydro-purin-7-ylmethyl ester (26 mg, 20%) as a yellow solid. This material was taken on without further purification or characterization. was washed with a 1N aqueous hydrochloric acid solution The organics were dried over magnesium sulfate filtered concentrated in vacuo

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 2,2-dimethyl-propionic acid 8-(4-acetylamino-benzyl)-3-butyl-2,6-dioxo-1,2,3,6-tetrahydro-purin-7-ylmethyl ester (100 mg, 0.21 mmol) and 2-bromomethyl-1-fluoro-4-methoxy-benzene (56 mg, 0.25 mmol) in acetonitrile (2.0 mL) was treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (0.06 mL, 0.45 mmol). The reaction was stirred at 25° C. The reaction was diluted with ethyl acetate and was washed with a 1N aqueous hydrochloric acid solution and a saturated aqueous sodium chloride solution. The organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 1:1 ethyl acetate/petroleum ether) afforded 2,2-dimethyl-propionic acid 8-(4-acetylamino-benzyl)-3-butyl-1-(2-fluoro-5-methoxy-benzyl)-2,6-dioxo-1,2,3,6-tetrahydro-purin-7-ylmethyl ester (26 mg, 20%) as a yellow solid. This material was taken on without further purification or characterization. was washed with a 1N aqueous hydrochloric acid solution The organics were dried over magnesium sulfate filtered concentrated in vacuo

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

Procedure: To a solution of 1-fluoro-4-methoxy-2-methylbenzene (2.0 g, 14.29 mmol) in CCl4, NBS (2.55 g, 14.29 mmol) and PhCO3H (80 mg) were added. The reaction mixture was heated at reflux for 2 h, cooled to room temperature, and the solid was filtered off. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (eluting with PE/EA=20/1) to give the target compound (3.0 g) as an oil. 1H NMR (CDCl3): δ 6.97-6.83 (m, 3H), 4.48 (s, 2H), 3.78 (s, 3H). The reaction mixture was heated at reflux for 2 h the solid was filtered off The filtrate was concentrated the residue was purified by silica gel column chromatography (eluting with PE/EA=20/1)

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

Procedure: To a solution of 1-fluoro-4-methoxy-2-methylbenzene (2.0 g, 14.29 mmol) in CCl4, NBS (2.55 g, 14.29 mmol) and PhCO3H (80 mg) were added. The reaction mixture was heated at reflux for 2 h, cooled to room temperature, and the solid was filtered off. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (eluting with PE/EA=20/1) to give the target compound (3.0 g) as an oil. 1H NMR (CDCl3): δ 6.97-6.83 (m, 3H), 4.48 (s, 2H), 3.78 (s, 3H). The reaction mixture was heated at reflux for 2 h the solid was filtered off The filtrate was concentrated the residue was purified by silica gel column chromatography (eluting with PE/EA=20/1)

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

Procedure: To a solution of 1-fluoro-4-methoxy-2-methylbenzene (2.0 g, 14.29 mmol) in CCl4, NBS (2.55 g, 14.29 mmol) and PhCO3H (80 mg) were added. The reaction mixture was heated at reflux for 2 h, cooled to room temperature, and the solid was filtered off. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (eluting with PE/EA=20/1) to give the target compound (3.0 g) as an oil. 1H NMR (CDCl3): δ 6.97-6.83 (m, 3H), 4.48 (s, 2H), 3.78 (s, 3H). The reaction mixture was heated at reflux for 2 h the solid was filtered off The filtrate was concentrated the residue was purified by silica gel column chromatography (eluting with PE/EA=20/1)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a cold (10° C.) stirred solution of 2-fluoro-5-methoxybenzyl bromide (35, 50 mg, 0.23 mmol), t-butylglycinate Schiff base 3 (68 mg, 0.23 mmol) and potassium iodide (4.2 mg, 0.05 mmol) in dioxane (2.0 mL) was added dropwise over 30–45 min. benzyltrimethylammonium hydroxide (0.069 mL, 0.23 mmol, 40% aqueous). The reaction mixture was then brought to room temperature and stirred for an additional 3 h. After cooling to 0° C., water (2.0 mL) was added and the mixture was extracted with toluene (6×10 mL). The organic extracts were washed with water (20 mL) and dried over sodium sulfate. Evaporation of the solvent afforded a colorless oil, which was not purified (33%) and the alkylated product 40 was not obtained. was then brought to room temperature the mixture was extracted with toluene (6×10 mL) The organic extracts were washed with water (20 mL) dried over sodium sulfate Evaporation of the solvent afforded a colorless oil, which was not purified (33%)

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

Procedure: KHMDS (550 μl of a 0.5 M solution in toluene, 0.55 mmol) diluted with dry THF (1.5 mL) was added to a solution of t-butylglycinate Schiff base 3 (68 mg, 0.23 mmol) in THF (1.5 mL). A mixture containing 2-fluoro-5-methoxybenzyl bromide (35, 50 mg, 0.23 mmol) in THF (1.0 mL) was immediately added to the resulting enolate solution at −78° C. The combined mixture was warmed to room temperature, stirred for 2 h, diluted with 1:1 ether/pentane (20 mL), washed with brine (3×10 mL), dried (sodium sulfate), filtered and then concentrated to afford 40 as a crude yellow oil (115%). Interestingly, a lower yield of 22% (40 mg) was obtained compared to using LiHMDS. washed with brine (3×10 mL) dried (sodium sulfate) filtered concentrated

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

Procedure: LHMDS (92 mg, 0.55 mmol) was added to a solution of t-butylglycinate Schiff base 3 (136 mg, 0.46 mmol) in THF (1.5 mL) A mixture containing 2-fluoro-5-methoxy-benzyl bromide (35, 100 mg, 0.46 mmol) and sodium iodide (138 mg, 0.92 mmol) in THF (2.0 mL) was immediately added to the resulting enolate solution at −78° C. The combined mixture was warmed to room temperature, stirred for 2 h, diluted with 1:1 ether/pentane (25 mL), washed with brine (3×15 mL), dried (sodium sulfate) and concentrated to afford 40 as a crude yellow oil (108%). Once examined, the pure product was made in 97% yield (193 mg). washed with brine (3×15 mL) dried (sodium sulfate) concentrated

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

Procedure: t-Butylglycinate Schiff base 3 (136 mg, 0.46 mmol) in a mixture of dry THF-DMPU 60:40 (2.5 mL) at −78° C. was treated with a 2.0 M LDA solution (0.23 mL, 0.46 mmol) and the mixture was stirred for one h at the same temperature. 2-Fluoro-5-methoxybenzyl bromide (35, 100 mg, 0.46 mmol) in dry THF (2.5 mL) was added dropwise at −78° C. and then the mixture was stirred overnight at room temperature. The reaction was quenched with saturated aqueous ammonium chloride (10 mL), and the product was extracted with diethyl ether (2×15 mL). The combined organic layers were washed with saturated aqueous ammonium chloride (4×10 mL), dried over sodium sulfate, filtered and evaporated to give 40 as a crude yellow oil (110%). When examined, the pure product 40 was made in 80% yield (175 mg). the mixture was stirred overnight at room temperature The reaction was quenched with saturated aqueous ammonium chloride (10 mL) the product was extracted with diethyl ether (2×15 mL) The combined organic layers were washed with saturated aqueous ammonium chloride (4×10 mL) dried over sodium sulfate filtered evaporated

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

Procedure: Tetrabutylammonium sulfate (156.2 mg, 0.46 mmol) was added to a two-phase mixture consisting of 10% NaOH (2.5 mL), t-butylglycinate Schiff base 3 (142.7 mg, 0.48 mmol), and 2-fluoro-5-methoxybenzyl bromide 35 (100 mg, 0.46 mmol) in dichloromethane (2.0 mL). After 5 h of vigorous stirring at ambient temperature, the reaction mixture was diluted with ether (10 mL) and the layers were separated. The organic layer was washed with water (3×3.0 mL), dried over sodium sulfate, filtered, and evaporated in vacuo. A crude yellow oil of 40 was obtained in 90% yield. The pure product 40 was made as a residue in 83% (149 mg). the layers were separated The organic layer was washed with water (3×3.0 mL) dried over sodium sulfate filtered evaporated in vacuo

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 2,2-dimethyl-propionic acid 8-(4-acetylamino-benzyl)-3-butyl-2,6-dioxo-1,2,3,6-tetrahydro-purin-7-ylmethyl ester (100 mg, 0.21 mmol) and 2-bromomethyl-1-fluoro-4-methoxy-benzene (56 mg, 0.25 mmol) in acetonitrile (2.0 mL) was treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (0.06 mL, 0.45 mmol). The reaction was stirred at 25° C. The reaction was diluted with ethyl acetate and was washed with a 1N aqueous hydrochloric acid solution and a saturated aqueous sodium chloride solution. The organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 1:1 ethyl acetate/petroleum ether) afforded 2,2-dimethyl-propionic acid 8-(4-acetylamino-benzyl)-3-butyl-1-(2-fluoro-5-methoxy-benzyl)-2,6-dioxo-1,2,3,6-tetrahydro-purin-7-ylmethyl ester (26 mg, 20%) as a yellow solid. This material was taken on without further purification or characterization. was washed with a 1N aqueous hydrochloric acid solution The organics were dried over magnesium sulfate filtered concentrated in vacuo