2-but-3-ynylisoindole-1,3-dione

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

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

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: The title compound was prepared in accordance with the general method of Example 1, from 2-iodopyridine (453 mg, 2.21 mmol) and 2-(but-3-ynyl)isoindoline-1,3-dione (400 mg, 2.01 mmol, Example 189(B)). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 70:30) to yield 250 mg (0.90 mmol, 45%) of 2-(4-pyridin-2-yl)but-3-ynyl)isoindoline-1,3-dione as. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 70:30)

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

Procedure: The title compound was prepared in accordance with the general method of Example 1; from 2-bromo-6-(fluoromethyl)pyridine (336 mg, 1.77 mmol, Example 190(E)) and 2-(but-3-ynyl)isoindoline-1,3-dione (320 mg, 1.61 mmol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 75:25) to yield 320 mg (1.04 mmol, 650%) of 2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)isoindoline-1,3-dione as a white solid. The title compound was prepared in accordance with the general method of Example 1 The crude residue was purified by flash chromatography (cyclohexane/AcOEt 75:25)

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

Procedure: 5-Iodo-2'-deoxyuridine (354 mg, 1 mmol) was dissolved in 10 mL of dimethylformamide. Cuprous iodide (76 mg, 0.4 mmol), tetrakis(triphenylphosphine)palladium(0) (230 mg, 0.2 mmol), and triethylamine (200 mg, 2.0 mmol) were added. 4-Phthalimidobut-1-yne (300 mg, 1.5 mmol) was added all at once and the reaction kept at 60° C. for three hours. The clear yellow reaction was then evaporated and methylene chloride was added. Scratching of the flask induced crystallization of nearly all of the product which was filtered and recrystallized from 95% ethanol to give 335 mg (78%) of title compound as fine, feathery needles. The clear yellow reaction was then evaporated methylene chloride was added crystallization of nearly all of the product which was filtered recrystallized from 95% ethanol

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

Procedure: The title compound was prepared in accordance with the general method of Example 1, from 2-iodopyridine (453 mg, 2.21 mmol) and 2-(but-3-ynyl)isoindoline-1,3-dione (400 mg, 2.01 mmol, Example 189(B)). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 70:30) to yield 250 mg (0.90 mmol, 45%) of 2-(4-(pyridin-2-yl)but-3-ynyl)isoindoline-1,3-dione as. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 70:30)

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

Procedure: The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-6-(fluoromethyl)pyridine (336 mg, 1.77 mmol, Example 190(E)) and 2-(but-3-ynyl)isoindoline-1,3-dione (320 mg, 1.61 mmol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 75:25) to yield 320 mg (1.04 mmol, 65%) of 2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)isoindoline-1,3-dione as a white solid. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 75:25)

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

Procedure: The title compound was prepared according to the procedure of lyer and Liebeskind (J. Amer. Chem. Soc, 1987, 109, 2759-2770) via a Mitsunobu reaction between phthalimide and 3-butyn-1-ol in 84% yield. The product was isolated as white crystals. mp=137-139° C. (lit. mp=136-137° C.). N-(Ethoxycarbonyl)but-3-ynylamine The product was isolated as white crystals

Conditions: temp:-5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Diisopropyl azodicarboxylate (316 g, 1.56 mol) was added to a solution of triphenylphosphine (PPh3) (393 g, 1.50 mol), 3-butyn-1-ol (105 g, 1.50 mol) and phthalimide (200 g, 1.36 mol) in toluene (1600 mL) which was pre-cooled with a −5° C. cooling bath at such a rate that temperature of the reaction mixture was kept between 15-25° C. The addition time was 50 min. The cooling bath was removed after the addition was finished. The reaction mixture was allowed to warm to 15-25° C. and stirred for 1 h. Then methanol (800 mL) was added. The mixture was stirred for 30 min and then filtered. The crude product was washed with methanol and dried to give a white solid (218 g) in 80% yield 99.8% purity by area. 1H NMR (DMSO-d6): δ 7.88 (m, 4 H), 3.72 (t, 2 H, J=7.0 Hz), 2.83 (t, 1 H, J=2.7 Hz), 2.55 (m, 2 H). cooling bath at such a rate that temperature of the reaction mixture was kept between 15-25° C The cooling bath was removed after the addition to warm to 15-25° C. Then methanol (800 mL) was added The mixture was stirred for 30 min filtered The crude product was washed with methanol dried

Conditions: temp:30.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Dichlorobis(triphenylphosphine)palladium (II) (43 g, 0.061 mol), copper (I) iodide (20.2 g, 0.106 mol), and triethylamine (782 g, 7.74 mol) is added to a stirred mixture of N-(4-Chloro-2-iodophenyl)-2,2,2-trifluoroacetamide (1800 g, 5.15 mol) and tetrahydrofuran (1.80 L). A solution of 2-(but-3-ynyl)-1H-isoindole-1,3(2H)-dione (1098 g, 5.51 mol) and tetrahydrofuran (11 L) is added to the reaction mixture slowly over 6 hours, maintaining a reaction temperature of 30° C. The reaction mixture is allowed to stir at room temperature overnight. The reaction mixture is filtered under reduced pressure and the triethylammonium iodide cake is washed with tetrahydrofuran (2×550 mL). The filtrate is concentrated under reduced pressure to a volume of less than 6 L, and N,N-dimethylformamide (8 L) is added to the residue. The mixture is concentrated until tetrahydrofuran is removed. Piperidine (535 g, 6.29 mol) is added to the mixture. The mixture is stirred and warmed to 100° C. The mixture is maintained at 100° C. until the product/starting material ratio is >97/3. The mixture is cooled to 32° C. Water (4.2 L) is added to the stirred mixture over >100 min, allowing the temperature of the mixture to rise to 45° C. The mixture is cooled (0-5° C.). The product is collected by filtration and dried to give 2-[2-(5-Chloro-1H-indol-2-yl)-ethyl]-isoindole-1,3-dione (1173 g, 73%, 98.1% purity, largest single impurity 1.2%. 1H NMR (DMSO-d6): δ11.35 (s, 1H), 7.83 (m, 4H), 7.41 (d, 1H, J=2.0 Hz), 7.29 (d, 1H, J=8.6 Hz), 6.99 (dd, 1H, J=2.0, 8.6 Hz), 3.94 (t, 2H, J=7.1 Hz), 3.08 (t, 2H, J=7.1 Hz). The reaction mixture is filtered under reduced pressure the triethylammonium iodide cake is washed with tetrahydrofuran (2×550 mL) The filtrate is concentrated under reduced pressure to a volume of less than 6 L, and N,N-dimethylformamide (8 L) is added to the residue The mixture is concentrated until tetrahydrofuran is removed The mixture is stirred warmed to 100° C The mixture is maintained at 100° C. until the product/starting material ratio The mixture is cooled to 32° C to rise to 45° C The mixture is cooled (0-5° C.) The product is collected by filtration dried