2-pent-4-ynylisoindole-1,3-dione

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

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

Procedure: A mixture of methyl 4-iodo-2-methoxynicotinate (400 mg, 1.36 mmol), 2-(pent-4-ynyl)isoindoline-1,3-dione (318 mg, 1.5 mmol), Pd(PPh3)2Cl2 (47 mg, 0.068 mmol), CuI (7.7 mg, 0.04 mmol) and triethylamine (400 uL) is stirred at room temperature for 20 hours. The mixture is diluted with water, made alkaline with K2CO3 and extracted with CHCl3. The organic layer is washed with brine, water and concentrated under vacuum. The title compound is purified by silica gel column chromatography using hexane/ethyl acetate as eluent. MS m/z 379.1 (M+1). extracted with CHCl3 The organic layer is washed with brine, water concentrated under vacuum The title compound is purified by silica gel column chromatography

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

Procedure: 1-Bromo-3-fluoro-benzene (1.0 mL, 7.8 mmol), 2-pent-4-ynyl-isoindole-1,3-dione (1.8 g, 8.6 mmol), Pd(PPh3)2Cl2 (191 mg, 0.27 mmol), CuI (118 mg, 0.62 mmol), and triethylamine (4.4 mL, 31.3 mmol) were taken up into DMF (10 mL) and stirred at room temperature for four hours. The reaction was then quenched with saturated NaHCO3 and the resulting mixture extracted with EtOAc and washed with brine, then dried over sodium sulfate and the solvent removed in vacuo. The resulting residue was purified on normal phase chromatography (Heptane/EtOAc) to yield 2-(5-(3-bromophenyl)pent-4-ynyl)isoindoline-1,3-dione. MH+ 368, 370 The reaction was then quenched with saturated NaHCO3 the resulting mixture extracted with EtOAc washed with brine dried over sodium sulfate the solvent removed in vacuo The resulting residue was purified on normal phase chromatography (Heptane/EtOAc)

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

Procedure: 1-Bromo-3-fluoro-benzene (1.0 mL, 7.8 mmol), 2-pent-4-ynyl-isoindole-1,3-dione (1.8 g, 8.6 mmol), Pd(PPh3)2Cl2 (191 mg, 0.27 mmol), CuI (118 mg, 0.62 mmol), and triethylamine (4.4 mL, 31.3 mmol) were taken up into DMF (10 mL) and stirred at room temperature for four hours. The reaction was then quenched with saturated NaHCO3 and the resulting mixture extracted with EtOAc and washed with brine, then dried over sodium sulfate and the solvent removed in vacuo. The resulting residue was purified on normal phase chromatography (Heptane/EtOAc) to yield 2-(5-(3-bromophenyl)pent-4-ynyl)isoindoline-1,3-dione. MH+ 368, 370 The reaction was then quenched with saturated NaHCO3 the resulting mixture extracted with EtOAc washed with brine dried over sodium sulfate the solvent removed in vacuo The resulting residue was purified on normal phase chromatography (Heptane/EtOAc)

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

Conditions: temp:45.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2-chloro-5-iodo-6-methyl-N-propylpyrimidin-4-amine (T2, 150 mg) in N,N-dimethylformamide (3 mL), N-(4-pentynyl)phthalimide (133 mg), bis(triphenylphosphine)palladium(II) dichloride (34 mg), copper(I) iodide (18 mg) and triethylamine (334 μL) were added at room temperature, and the mixture was stirred at 45° C. for 1 hour under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, and then saturated aqueous ammonium chloride and ethyl acetate were added to the reaction mixture. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, washed with saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent, 90 to 70% hexane in ethyl acetate) to obtain 2-(5-(2-chloro-4-methyl-6-(propylamino)pyrimidin-5-yl)-4-pentyn-1-yl)isoindoline-1,3-dione (T3, 131 mg). The reaction mixture was cooled to room temperature The organic layer was separated the aqueous layer was extracted with ethyl acetate washed with saturated aqueous sodium chloride dried over anhydrous sodium sulfate the solvent was evaporated under reduced pressure The obtained residue was purified by silica gel column chromatography (eluent, 90 to 70% hexane in ethyl acetate)

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2-chloro-5-iodo-N-propylpyrimidin-4-amine (F1, 1.45 g), N-(4-pentynyl)phthalimide (2.08 g), bis(triphenylphosphine)palladium(II) dichloride (171 mg) and copper(I) iodide (47 mg) in N,N-dimethylformamide (15 mL), triethylamine (3.4 mL) was added at room temperature, and the mixture was stirred at 60° C. for 1 hour and 15 minutes. The reaction mixture was cooled to room temperature, and then water and ethyl acetate were added to the reaction mixture. The organic layer was separated, washed successively with saturated aqueous sodium hydrogencarbonate, water and saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (eluent, 70 to 40% hexane in ethyl acetate) to obtain 2-(5-(2-chloro-4-(propylamino)pyrimidin-5-yl)-4-pentyn-1-yl)isoindoline-1,3-dione (K1, 2.00 g). The reaction mixture was cooled to room temperature The organic layer was separated washed successively with saturated aqueous sodium hydrogencarbonate, water and saturated aqueous sodium chloride dried over anhydrous sodium sulfate the solvent was evaporated under reduced pressure The obtained residue was purified by basic silica gel column chromatography (eluent, 70 to 40% hexane in ethyl acetate)

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2-chloro-5-iodo-N-propylpyrimidin-4-amine (F1, 1.45 g), N-(4-pentynyl)phthalimide (2.08 g), bis(triphenylphosphine)palladium(II) dichloride (171 mg) and copper(I) iodide (47 mg) in N,N-dimethylformamide (15 mL), triethylamine (3.4 mL) was added at room temperature, and the mixture was stirred at 60° C. for 1 hour and 15 minutes. The reaction mixture was cooled to room temperature, and then water and ethyl acetate were added to the reaction mixture. The organic layer was separated, washed successively with saturated aqueous sodium hydrogencarbonate, water and saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (eluent, 70 to 40% hexane in ethyl acetate) to obtain 2-(5-(2-chloro-4-(propylamino)pyrimidin-5-yl)-4-pentyn-1-yl)isoindoline-1,3-dione (K1, 2.00 g). The reaction mixture was cooled to room temperature The organic layer was separated washed successively with saturated aqueous sodium hydrogencarbonate, water and saturated aqueous sodium chloride dried over anhydrous sodium sulfate the solvent was evaporated under reduced pressure The obtained residue was purified by basic silica gel column chromatography (eluent, 70 to 40% hexane in ethyl acetate)

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

Procedure: To a solution of 4-((4-chloro-5-iodopyrimidin-2-yl)amino)benzonitrile (J12, 53 mg) and N-(4-pentynyl)phthalimide (47 mg) in N,N-dimethylformamide (1 mL), triethylamine (103 μL), copper(I) iodide (14 mg), and bis(triphenylphosphine)palladium(II) dichloride (10 mg) were added at room temperature, and the mixture was stirred overnight at the same temperature. To the reaction mixture, ethyl acetate and water were added. The organic layer was separated, washed successively with water and saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained solid matter was washed with chloroform, and then dried under reduced pressure to obtain 4-((4-chloro-5-(5-(1,3-dioxoisoindolin-2-yl)-1-pentyn-1-yl)pyrimidin-2-yl)amino)benzonitrile (J13, 44 mg) as white solid. The organic layer was separated washed successively with water and saturated aqueous sodium chloride dried over anhydrous sodium sulfate the solvent was evaporated under reduced pressure The obtained solid matter was washed with chloroform dried under reduced pressure

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

Procedure: To a solution of 4-(benzyloxy)-N-(3-fluorophenyl)-5-iodopyrimidin-2-amine (J2, 60 mg) and N-(4-pentynyl)phthalimide (76 mg) in N,N-dimethylformamide (500 μL), triethylamine (98 μL), copper(I) iodide (14 mg) and bis(triphenylphosphine)palladium(II) dichloride (10 mg) were added at room temperature, and the mixture was stirred at the same temperature for 1 hour. To the reaction mixture, ethyl acetate and water were added. The organic layer was separated, washed successively with water and saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 2-(5-(4-(benzyloxy)-2-((3-fluorophenyl)amino)pyrimidin-5-yl)-4-pentyn-1-yl)isoindoline-1,3-dione (J3, 69 mg) as pale green solid. The organic layer was separated washed successively with water and saturated aqueous sodium chloride dried over anhydrous sodium sulfate the solvent was evaporated under reduced pressure The obtained residue was purified by silica gel column chromatography

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

Procedure: To a solution of 4-(benzyloxy)-N-(3-fluorophenyl)-5-iodopyrimidin-2-amine (J2, 60 mg) and N-(4-pentynyl)phthalimide (76 mg) in N,N-dimethylformamide (500 μL), triethylamine (98 μL), copper(I) iodide (14 mg) and bis(triphenylphosphine)palladium(II) dichloride (10 mg) were added at room temperature, and the mixture was stirred at the same temperature for 1 hour. To the reaction mixture, ethyl acetate and water were added. The organic layer was separated, washed successively with water and saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 2-(5-(4-(benzyloxy)-2-((3-fluorophenyl)amino)pyrimidin-5-yl)-4-pentyn-1-yl)isoindoline-1,3-dione (J3, 69 mg) as pale green solid. The organic layer was separated washed successively with water and saturated aqueous sodium chloride dried over anhydrous sodium sulfate the solvent was evaporated under reduced pressure The obtained residue was purified by silica gel column chromatography

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

Procedure: To a suspension of bis(triphenylphosphine)palladium(II) dichloride (1.02 g) and copper(I) iodide (558 mg) in N,N-dimethylformamide (90 mL), triethylamine (10.2 mL), 2-chloro-5-iodo-4-(pyrrolidin-1-yl)pyrimidine (H1, 4.49 g), and N-(4-pentynyl)phthalimide (4.65 g) were added at room temperature under a nitrogen atmosphere, and the mixture was stirred at the same temperature for 4 hours. To the reaction mixture, water was added. The solid matter was taken by filtration, washed with water, then dried under reduced pressure, and purified by silica gel column chromatography. The obtained solid matter was washed with ethyl acetate, and then dried under reduced pressure to obtain 2-(5-(2-chloro-4-(pyrrolidin-1-yl)pyrimidin-5-yl)-4-pentyn-1-yl)isoindoline-1,3-dione (H2, 3.66 g). were added at room temperature under a nitrogen atmosphere The solid matter was taken by filtration washed with water dried under reduced pressure purified by silica gel column chromatography The obtained solid matter was washed with ethyl acetate dried under reduced pressure