Tetrahydrofuran → 2-(2,4-Dimethoxy-benzyl)-4-(3-morpholin-4-yl-propoxy)-2,3-dihydro-1H-isoindole

HRID 424074

Reaction equation

HRID 424074 reaction equation
[CH3:1][O:2][C:3]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:4]=1[CH2:5][N:6]1[C:14](=O)[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[O:16][CH2:17][CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[C:7]1=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].C1COCC1>>[CH3:1][O:2][C:3]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:4]=1[CH2:5][N:6]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[O:16][CH2:17][CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[CH2:7]1

Participants

4

Reactant 3

HCID 8028TetrahydrofuranHCID 21226445Aluminium lithium hydrideHCID 592631552-(2,4-Dimethoxy-benzyl)-4-(3-morpholin-4-yl-propoxy)-isoindole-1,3-dione

Product 1

HCID 592631052-(2,4-Dimethoxy-benzyl)-4-(3-morpholin-4-yl-propoxy)-2,3-dihydro-1H-isoindoleYield 83.1%

Procedure

2-(2,4-Dimethoxy-benzyl)-4-(3-morpholin-4-yl-propoxy)-isoindole-1,3-dione (298 mg, 0.68 mmol) was treated with a 1M solution of lithium aluminium hydride in THF (5 mL, 5 mmol) and maintained at r.t. for 21 hours. The mixture was heated to 75° C. for 1 hour then cooled in ice and quenched by the dropwise addition of water (0.2 mL), 2N sodium hydroxide solution (0.4 mL) and water (0.4 mL). Magnesium sulfate was added, followed by ethyl acetate and then the mixture was stirred at r.t. for 1 hour. The solids were removed by filtration, being well washed with ethyl acetate. Concentration of the filtrate gave a crude product which was purified by flash chromatography on silica, eluting with 5% methanol in DCM. This afforded the title compound (233 mg, 83%) as a red oil. 1H NMR (methanol-d4) 7.24 (1H, d), 7.15 (1H, t), 6.80 (1H, d), 6.78 (1H, d), 6.56 (1H, d), 6.52 (1H, dd), 4.05 (2H, t), 3.94 (2H, s), 3.88 (2H, s), 3.87 (2H, s), 3.83 (3H, s), 3.80 (3H, s), 3.70-3.68 (4H, m), 2.54-2.50 (2H, m), 2.49-2.47 (4H, m), 2.00-1.93 (2H, m). MS: [M+H]+ 413.

Workup

  1. temperatureThe mixture was heated to 75° C. for 1 hour
  2. temperaturethen cooled in ice
  3. customquenched by the dropwise addition of water (0.2 mL), 2N sodium hydroxide solution (0.4 mL) and water (0.4 mL)
  4. additionMagnesium sulfate was added
  5. customThe solids were removed by filtration
  6. washbeing well washed with ethyl acetate
  7. customConcentration of the filtrate gave a crude product which
  8. customwas purified by flash chromatography on silica
  9. washeluting with 5% methanol in DCM

Sources & evidence

ORD record
ord-9a027a1155a140bd8fe115d1191d5422
Source dataset
uspto-grants-2012_01
Patent number
US08101648B2

Linked notes

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