5-bromo-2,3-dihydroisoindol-1-one

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

Procedure: A suspension of sodium hydride (130 mg, 60% dispersion in mineral oil, 3.2 mmol) and tetra-nbutylammonium iodide (243 mg, 0.68 mmol) in THF (20 mL) is stirred at rt and a solution of 5-bromo-2,3-dihydroisoindol-1-one (675 mg, 3.2 mmol) in THF (20 mL) and DMF (4 mL) is added. After 75 min 4-methoxybenzyl bromide (460 μL, 3.2 mmol) is added and stirring is continued for 4 h. Sodium hydride (635 mg, 60% dispersion in mineral oil, 15.9 mmol) is then added and stirring is continued for 30 min before iodomethane (1.19 mL, 19 mmol) is added and the mixture heated to 70° C. for 30 min. After cooling, NH4Cl (sat. aq.) is added and the mixture is diluted with ethyl acetate (120 mL). The layers are separated, the organic phase is dried over MgSO4 and the solvents removed under reduced pressure. The residue is purified by silica chromatography, eluting with 5% to 10% ethyl acetate in petroleum ether to afford the title compound as a yellow oil (640 mg, 1.78 mmol). stirring stirring is added the mixture heated to 70° C. for 30 min After cooling The layers are separated the organic phase is dried over MgSO4 the solvents removed under reduced pressure The residue is purified by silica chromatography eluting with 5% to 10% ethyl acetate in petroleum ether

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

Procedure: 4-Bromo-2-bromomethyl-benzoic acid methyl ester (0.5 g, 16.2 mmol) is treated with methanolic ammonia (10 mL, 7 N NH3 in MeOH) for 5 minutes at 90° C. After cooling to room temperature a precipitate is formed, collected by filtration and washed with a small amount of methanol to afford the title compound as a colourless solid (224 mg, 65%). 1H-NMR (400 MHz, d6-DMSO) δ (ppm) 4.41 (2H, s), 7.64 (1H, d), 7.70 (1H, d), 7.87 (1H, s), 8.67 (1H, br s). LCMS: Rt 2.49 min, (99.6%), m/z (APCI) 212 (M+H)+. is formed collected by filtration washed with a small amount of methanol

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

Procedure: Under nitrogen atmosphere, 1.5 mg of 5-bromo-1-oxo-isoindoline was dissolved in 20 ml of tetrahydrofuran, cooled down to 0° C. Then, 85 mg of N,N-dimethylaminopyridine and 3.0 ml of tert-butylcarbonate were added, and the mixture was stirred at room temperature for 30 min. Methanol was added to the reaction solution, and the solvents were distilled outunder reduced pressure. Water was added to the residues, extracted with ethyl acetate. Ethyl acetate layer was washed with saturated saline solution, and dried with anhydrous sodium sulfate. After distilling out the solvents under reduced pressure, the residues were separated and purified by silicagel column chromatography (ethyl acetate/hexane=1/2), to obtain 300 mg of the above compound as a white solid. the solvents were distilled outunder reduced pressure Water was added to the residues extracted with ethyl acetate Ethyl acetate layer was washed with saturated saline solution dried with anhydrous sodium sulfate After distilling out the solvents under reduced pressure the residues were separated purified by silicagel column chromatography (ethyl acetate/hexane=1/2)

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

Procedure: Under nitrogen atmosphere, 1.5 mg of 5-bromo-1-oxo-isoindoline was dissolved in 20 ml of tetrahydrofuran, cooled down to 0° C. Then, 85 mg of N,N-dimethylaminopyridine and 3.0 ml of tert-butylcarbonate were added, and the mixture was stirred at room temperature for 30 min. Methanol was added to the reaction solution, and the solvents were distilled outunder reduced pressure. Water was added to the residues, extracted with ethyl acetate. Ethyl acetate layer was washed with saturated saline solution, and dried with anhydrous sodium sulfate. After distilling out the solvents under reduced pressure, the residues were separated and purified by silicagel column chromatography (ethyl acetate/hexane=1/2), to obtain 300 mg of the above compound as a white solid. the solvents were distilled outunder reduced pressure Water was added to the residues extracted with ethyl acetate Ethyl acetate layer was washed with saturated saline solution dried with anhydrous sodium sulfate After distilling out the solvents under reduced pressure the residues were separated purified by silicagel column chromatography (ethyl acetate/hexane=1/2)

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

Procedure: Under nitrogen atmosphere, 70 mg of 5-bromo-1-oxo-isoindoline was dissolved in 2 ml of tetrahydrofuran, cooled down to 0° C., and then 4 mg of N,N-dimethylaminopyridine and 144 mg of di-tert-butylcarbonate were added. The mixture was stirred at room temperature for 30 min. Methanol was added to the reaction solution, and the solvents were distilled outunder reduced pressure. Water was added to the residues, extracted with ethyl acetate. Ethyl acetate layer was washed with saturated saline solution, and dried with anhydrous sodium sulfate. After distilling out the solvents under reduced pressure, the residues were separated and purified by silicagel column chromatography (ethyl acetate/hexane=1/2), to obtain 51.2 mg of the above compound as a white solid. the solvents were distilled outunder reduced pressure Water was added to the residues extracted with ethyl acetate Ethyl acetate layer was washed with saturated saline solution dried with anhydrous sodium sulfate After distilling out the solvents under reduced pressure the residues were separated purified by silicagel column chromatography (ethyl acetate/hexane=1/2)

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

Procedure: 5-Bromo-2,3-dihydro-1H-isoindol-1-one (100 mg, 0.47 mmol) was dissolved in DMF (4.7 mL) and stirred at 0° C. NaH (38 mg, 0.94 mmol, 60% dispersion in oil) was carefully added in two portions, and the resulting mixture was allowed to stir at 0° C. for 15 minutes before tert-butyl bromoacetate (92 mg, 0.47 mmol) was added. The mixture was allowed to stir at 0° C. for 30 minutes before saturated aqueous NaHCO3 (10 mL) was carefully added. The mixture was extracted with EtOAc, and the organic layer was washed with water, brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The residue was purified by MPLC on silica gel (using a gradient elution of 0-20% EtOAc/hexanes). Desired fractions were identified, combined, and concentrated in vacuo to afford the title compound. LRMS (ESI) calc'd for C14H16BrNO3 [M+Na]+: 348. Found: 348. was added was carefully added The mixture was extracted with EtOAc the organic layer was washed with water, brine dried over anhydrous MgSO4 filtered concentrated in vacuo The residue was purified by MPLC on silica gel ( a gradient elution of 0-20% EtOAc/hexanes) concentrated in vacuo

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

Procedure: 5-Bromo-2,3-dihydro-1H-isoindol-1-one (100 mg, 0.47 mmol) was dissolved in DMF (4.7 mL) and stirred at 0° C. NaH (38 mg, 0.94 mmol, 60% dispersion in oil) was carefully added in two portions, and the resulting mixture was allowed to stir at 0° C. for 15 minutes before 2,2,2-trifluoroethyl trifluoromethanesulfonate (110 mg, 0.47 mmol) was added. The mixture was allowed to stir at 0° C. for 30 minutes before saturated aqueous NaHCO3 (10 mL) was carefully added, and the mixture was extracted with EtOAc. The organic layer was washed with water, brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The residue was purified by MPLC on silica gel (using a gradient elution of 0-20% EtOAc/hexanes). Desired fractions were identified, combined, and concentrated in vacuo to afford the title compound. was added was carefully added the mixture was extracted with EtOAc The organic layer was washed with water, brine dried over anhydrous MgSO4 filtered concentrated in vacuo The residue was purified by MPLC on silica gel ( a gradient elution of 0-20% EtOAc/hexanes) concentrated in vacuo

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

Procedure: 5-Bromo-2,3-dihydro-1H-isoindol-1-one (100 mg, 0.47 mmol) was dissolved in DMF (4.7 mL) and stirred at 0° C. NaH (38 mg, 0.94 mmol, 60% dispersion in oil) was carefully added in two portions, and the resulting mixture was allowed to stir at 0° C. for 15 minutes before 2,2,2-trifluoroethyl trifluoromethanesulfonate (110 mg, 0.47 mmol) was added. The mixture was allowed to stir at 0° C. for 30 minutes before saturated aqueous NaHCO3 (10 mL) was carefully added, and the mixture was extracted with EtOAc. The organic layer was washed with water, brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The residue was purified by MPLC on silica gel (using a gradient elution of 0-20% EtOAc/hexanes). Desired fractions were identified, combined, and concentrated in vacuo to afford the title compound. was added was carefully added the mixture was extracted with EtOAc The organic layer was washed with water, brine dried over anhydrous MgSO4 filtered concentrated in vacuo The residue was purified by MPLC on silica gel ( a gradient elution of 0-20% EtOAc/hexanes) concentrated in vacuo

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 5-bromo-2,3-dihydro-1H-isoindole-1-one (0.065 g, 0.22 mmol), Pd(PPh3)4 (0.025 g, 0.02 mmol), sodium cyanide (0.023 g, 0.5 mmol), and CuI (0.004 g, 0.02 mmol) in acetonitrile (4 mL) was stirred at 80° C. for 18 h. Workup and silica gel column chromatography using 2:1 hexanes-ethyl acetate (typically 2:1 hexane-EtOAc) afforded 2-benzyl-1-oxo-2,3-dihydro-1H-isoindole-5-carbonitrile (0.047 g, 85%). 1H NMR (300 MHz, CDCl3): δ (ppm) 4.32 (s, 2H), 4.81 (s, 2H), 7.33 (m, 5H), 7.68 (s, 1H), 7.76 (d, 1H), 7.98 (d, 1H). GC-MS: m/z 248 (M)+, 171 (M−77)+.

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

Procedure: 5-Bromo-2,3-dihydro-isoindol-1-one (1.0 g, 4.72 mmol), 1-bromomethyl-4-methyl-benzene (1.14 g, 6.14 mmol) and cesium carbonate (3.08 g, 9.44 mmol) were suspended in anhydrous NMP (10 mL). The mixture was immersed in a 60° C. oil bath for 16.5 hours. The cooled reaction mixture was poured into water and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over magnesium sulfate, filtered and concentrated. Column chromatography (20% to 40% ethyl acetate/hexanes) provided the title compound as a yellow solid (1.18 g, 79%). 1H NMR CDCl3: 7.76 (d, 1H), 7.62 (d, 1H), 7.55 (s, 1H), 4.76 (s, 2H), 4.24 (s, 2H), 2.35 (s, 3H). was immersed in a 60° C. for 16.5 hours The cooled reaction mixture extracted with ethyl acetate The organic phase was washed with water and brine dried over magnesium sulfate filtered concentrated

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

Procedure: 4-Bromo-2-bromomethyl-benzoic acid methyl ester (3.70 g) was suspended in 2M NH3 in MeOH (36 mL) and concentrated ammonium hydroxide (12 mL) for eighteen hours. The solid product was filtered to provide the title compound as a colourless solid (2.30 g, 90%). 1H NMR (300M, CDCl3): δ 7.68 (m, 3H), 4.44 (s, 2H). The solid product was filtered

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

Procedure: 4-Bromo-2-bromomethylbenzoic acid methyl ester (0.70 g, 2.3 mmol) and sat. NH3 in MeOH (3 mL) were placed in a sealed tube. The mixture was heated at 40° C. overnight. After cooling to rt, the solids were collected to afford 5-bromoisoindolin-1-one (0.43 g, 89%). 1H NMR (DMSO-d6, 400 MHz) δ 8.62 (br s, 1H), 7.81 (s, 1H), 7.65 (d, J=7.6 Hz, 1H), 7.58 (d, J=7.6 Hz, 1H), 4.35 (s, 2H). After cooling to rt the solids were collected