2-phenoxyisoindole-1,3-dione

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

Procedure: A 20 mL scintillation vial was charged with N-hydroxyphthalimide (163 mg, 1.0 mmol), copper (I) chloride (99 mg, 1.0 mmol), freshly activated 4 Å molecular sieves (˜250 mg), and phenylboronic acid (244 mg, 2.0 mmol). 1,2-Dichloroethane (5 mL) was added followed by pyridine (90 μL, 1.1 mmol), resulting in a light brown suspension. The cap was loosely applied such that the reaction suspension was open to air and stirred at room temperature until completion as detected by analytical RP-HPLC (mixture color turned from brown to emerald green as the reaction proceeded). Upon completion (˜48 h), the mixture was adsorbed onto silica gel and concentrated to a powder. Flash chromatographic purification over silica (25% EtOAc in hexanes) afforded N-phenoxyphthalimide 9 as a white solid (216 mg, 90%); see below for characterization data. resulting in a light brown suspension Upon completion (˜48 h) concentrated to a powder Flash chromatographic purification over silica (25% EtOAc in hexanes)

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

Procedure: A 20 mL scintillation vial was charged with N-hydroxyphthalimide (163 mg, 1.0 mmol), copper (I) chloride (99 mg, 1.0 mmol), freshly activated 4 Å molecular sieves (˜250 mg), and phenylboronic acid (244 mg, 2.0 mmol). 1,2-Dichloroethane (5 mL) was added followed by pyridine (90 μL, 1.1 mmol), resulting in a light brown suspension. The cap was loosely applied such that the reaction suspension was open to air and stirred at room temperature until completion as detected by analytical RP-HPLC (mixture color turned from brown to emerald green as the reaction proceeded). Upon completion (˜48 h), the mixture was adsorbed onto silica gel and concentrated to a powder. Flash chromatographic purification over silica (25% EtOAc in hexanes) afforded N-phenoxyphthalimide 9 as a white solid (216 mg, 90%); see below for characterization data. resulting in a light brown suspension Upon completion (˜48 h) concentrated to a powder Flash chromatographic purification over silica (25% EtOAc in hexanes)

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

Procedure: To a 50 mL single neck RB flask wash charged with 2-hydroxy-1H-isoindole-1,3(2H)-dione (1 g, 6.13 mmol), 4 A° molecular sieves (1 g) and copper (I) chloride (0.61 g, 0.06 mmol) in DCE under open atmosphere. To the stirred reaction mixture, was added phenyl boronic acid (1.5 g, 12.2 mmol) followed by pyridine (0.53 g, 6.7 mmol) drop wise. Resulting mixture was stirred at RT for 12 h. The Reaction mixture was diluted with DCM and then filtered through celite pad. The organic layer was washed with saturated brine solution (50 mL) and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure to afford off white solid. 1H NMR (300 MHz, CDCl3): δ 7.83-7.86 (q, 2H), 7.73-7.77 (m, 2H), 7.28-7.30 (m, 2H), 7.07-7.11 (m, 3H). To a 50 mL single neck RB flask wash To the stirred reaction mixture Resulting mixture filtered through celite pad The organic layer was washed with saturated brine solution (50 mL) dried over anhydrous Na2SO4 The solvent was removed under reduced pressure to afford off white solid

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

Procedure: To a 50 mL single neck RB flask wash charged with 2-hydroxy-1H-isoindole-1,3(2H)-dione (1 g, 6.13 mmol), 4 A° molecular sieves (1 g) and copper (I) chloride (0.61 g, 0.06 mmol) in DCE under open atmosphere. To the stirred reaction mixture, was added phenyl boronic acid (1.5 g, 12.2 mmol) followed by pyridine (0.53 g, 6.7 mmol) drop wise. Resulting mixture was stirred at RT for 12 h. The Reaction mixture was diluted with DCM and then filtered through celite pad. The organic layer was washed with saturated brine solution (50 mL) and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure to afford off white solid. 1H NMR (300 MHz, CDCl3): δ 7.83-7.86 (q, 2H), 7.73-7.77 (m, 2H), 7.28-7.30 (m, 2H), 7.07-7.11 (m, 3H). To a 50 mL single neck RB flask wash To the stirred reaction mixture Resulting mixture filtered through celite pad The organic layer was washed with saturated brine solution (50 mL) dried over anhydrous Na2SO4 The solvent was removed under reduced pressure to afford off white solid

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

Procedure: Hydrazine monohydrate (5.45 mg, 0.109 mmol) was added to a solution of 2-phenoxyisoindoline-1,3-dione (Organic Lett, 2001, 31, 139) (30.8 mg, 0.129 mmol) in 10 mL of MeOH. The solution was heated at reflux for 2 h and then cooled to rt. White precipitate was filtered off and 1-(3-(quinolin-6-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone (41.2) (30 mg, 0.1 mmol) was added. The pH value of solution was adjusted to 5-6 with 1N HCl solution. The reaction solution was then stirred at it overnight. Solvent was evaporated and the crude was purified by HPLC (acidic with 0.05% TFA) to give 23 mg (59%) of the title compound as a white solid (TFA salt). 1H-NMR (400 MHz, CDCl3) δ ppm 9.23 (d, 1H), 8.68 (d, 1H), 8.53 (d, 1H), 8.15 (m, 3H), 8.04 d, 1H), 7.83 (m, 1H), 7.40 (t, 2H), 7.29 (m, 2H), 7.15 (t, 1H), 4.92 (s, 2H), 2.56 (s, 3H). LC-MS (method H): [MH]+=395.2, tR=2.42 min. The solution was heated at reflux for 2 h White precipitate was filtered off Solvent was evaporated the crude was purified by HPLC (acidic with 0.05% TFA)

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

Procedure: A 20 mL scintillation vial was charged with N-hydroxyphthalimide (163 mg, 1.0 mmol), copper (I) chloride (99 mg, 1.0 mmol), freshly activated 4 Å molecular sieves (˜250 mg), and phenylboronic acid (244 mg, 2.0 mmol). 1,2-Dichloroethane (5 mL) was added followed by pyridine (90 μL, 1.1 mmol), resulting in a light brown suspension. The cap was loosely applied such that the reaction suspension was open to air and stirred at room temperature until completion as detected by analytical RP-HPLC (mixture color turned from brown to emerald green as the reaction proceeded). Upon completion (˜48 h), the mixture was adsorbed onto silica gel and concentrated to a powder. Flash chromatographic purification over silica (25% EtOAc in hexanes) afforded N-phenoxyphthalimide 9 as a white solid (216 mg, 90%); see below for characterization data. resulting in a light brown suspension Upon completion (˜48 h) concentrated to a powder Flash chromatographic purification over silica (25% EtOAc in hexanes)

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

Procedure: To a 50 mL single neck RB flask wash charged with 2-hydroxy-1H-isoindole-1,3(2H)-dione (1 g, 6.13 mmol), 4 A° molecular sieves (1 g) and copper (I) chloride (0.61 g, 0.06 mmol) in DCE under open atmosphere. To the stirred reaction mixture, was added phenyl boronic acid (1.5 g, 12.2 mmol) followed by pyridine (0.53 g, 6.7 mmol) drop wise. Resulting mixture was stirred at RT for 12 h. The Reaction mixture was diluted with DCM and then filtered through celite pad. The organic layer was washed with saturated brine solution (50 mL) and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure to afford off white solid. 1H NMR (300 MHz, CDCl3): δ 7.83-7.86 (q, 2H), 7.73-7.77 (m, 2H), 7.28-7.30 (m, 2H), 7.07-7.11 (m, 3H). To a 50 mL single neck RB flask wash To the stirred reaction mixture Resulting mixture filtered through celite pad The organic layer was washed with saturated brine solution (50 mL) dried over anhydrous Na2SO4 The solvent was removed under reduced pressure to afford off white solid