Methyl iodide → 2-[(1R,2R)-2-methoxy-2,3-dihydro-1H-inden-1-yl]-1H-isoindole-1,3(2H)-dione

HRID 222201Notes

Reaction equation

HRID 222201 reaction equation
[OH:1][C@@H:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@H:3]1[N:11]1[C:19](=[O:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]1=[O:21].[CH3:22][Si](C)(C)[N-][Si](C)(C)C.[Li+].CI>C1COCC1>[CH3:22][O:1][C@@H:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@H:3]1[N:11]1[C:12](=[O:21])[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:19]1=[O:20]

Participants

5

Reactant 3

HCID 6328Methyl iodide2×HCID 2733832Lithium Hexamethyldisilazide2×HCID 666181792-[(1R,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]-1H-isoindole-1,3(2H)-dione

Product 1

HCID 666179892-[(1R,2R)-2-methoxy-2,3-dihydro-1H-inden-1-yl]-1H-isoindole-1,3(2H)-dioneYield 46%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent3×

Procedure

To a solution of 2-[(1R,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]-1H-isoindole-1,3(2H)-dione (0.860 g, 0.00308 mol) in THF (30 mL) at 0° C. under an atmosphere of nitrogen was added a 1.0 M solution of lithium hexamethyldisilazide in THF (3.39 mL, 0.00339 mol). The reaction mixture was stirred for 20 minutes, followed by the addition of methyl iodide (0.575 mL, 0.00924 mol). The cold bath was removed, and the reaction mixture was allowed to stir and warm to rt over 18 h. The reaction was monitored by 1H NMR. The reaction mixture was then re-cooled to 0° C. To the reaction mixture was added 1.0 M solution of lithium hexamethyldisilazide in THF (3.39 mL, 0.00339 mol). The reaction mixture was stirred for 15 minutes, followed by addition of methyl iodide (0.575 mL, 0.00924 mol). The cold bath was removed, and the reaction mixture was allowed to stir at rt for 22 h. 1H NMR indicated 80:20 product/starting material. The reaction was quenched with aqueous 1N HCl solution and then concentrated in vacuo. The residue was partitioned between EtOAc and water. The organic phase was washed with saturated NaHCO3 and brine, dried over Na2SO4, filtered, and concentrated. The oil was purified by silica gel chromatography, eluting with a gradient of hexanes to 10% EtOAc in hexanes) to obtain product (4.18 g, 46%). LC/MS: Rt=1.90 min, ES+ 294 (AA standard).

Workup

  1. customThe cold bath was removed
  2. stirringto stir
  3. temperatureThe reaction mixture was then re-cooled to 0° C
  4. stirringThe reaction mixture was stirred for 15 minutes
  5. customThe cold bath was removed
  6. stirringto stir at rt for 22 h
  7. customThe reaction was quenched with aqueous 1N HCl solution
  8. concentrationconcentrated in vacuo
  9. customThe residue was partitioned between EtOAc and water
  10. washThe organic phase was washed with saturated NaHCO3 and brine
  11. dry with materialdried over Na2SO4
  12. filtrationfiltered
  13. concentrationconcentrated
  14. customThe oil was purified by silica gel chromatography
  15. washeluting with a gradient of hexanes to 10% EtOAc in hexanes)

Sources & evidence

ORD record
ord-8e9446f7733047e9b5988b41f6cd93f7
Source dataset
uspto-grants-2012_06
Patent number
US08207177B2

Reaction notes

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