Methyl iodide → HCID 12638749, compound

HRID 1912628Notes

Reaction equation

HRID 1912628 reaction equation
[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([O:12]C)=[O:11])=[C:2]1[C:14]([O:16]C)=[O:15].[H-].[Na+].[CH3:20]I.[OH-].[K+]>CN(C)C=O.CCO.CCOC(C)=O>[CH3:20][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=[O:11])=[C:2]1[C:14]([OH:16])=[O:15]

Participants

8

Reactant 4

HCID 6328Methyl iodideHCID 14797Potassium HydroxideHCID 24758Sodium hydrideHCID 143197Dimethyl indole-2,3-dicarboxylate

Product 1

HCID 12638749HCID 12638749, compoundYield 100.1%

Reagents, catalysts & solvents 3

HCID 702EthanolSolventHCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
75 °C

Procedure

An ice cold solution of dimethyl 1H-indole-2,3-dicarboxylate (3 g, 12.86 mmol) in N,N-dimethylformamide (DMF) (31.5 ml) was treated with NaH (0.617 g, 15.44 mmol) and methyl iodide (0.881 ml, 14.15 mmol) and warmed to 75° C. After 8 h, the reaction mixture was partitioned between EtOAc and sat. aq. NH4Cl. The combined organics were washed with water (3×), brine, dried (MgSO4), filtered and concentrated. The residue was treated with a solution of KOH (8.66 g, 154 mmol) in EtOH (200 mL) and heated to reflux (95° C. bath temp). After 8 h, the reaction mixture was cooled to ambient temperature, diluted with EtOAc and the layers partitioned. The aqueous layer was extracted with EtOAc (2×) and acidified with 1 M HCl to pH 3. The aqueous layer was then extracted with EtOAc and the organics were washed with brine, dried (MgSO4), filtered and concentrated to afford 1-methyl-1H-indole-2,3-dicarboxylic acid (2.82 g, 12.87 mmol, 100% yield) as a white solid. The acid was suspended in DCM (30 mL) and treated dropwise with TFAA (4.39 ml, 32.2 mmol). After 2 h, the reaction mixture was concentrated in vacuo to afford 4-methyl-1H-furo[3,4-b]indole-1,3(4H)-dione as a purple solid. The anhydride was suspended in MeOH (100 mL) and stirred at ambient temperature. After 18 h, the reaction mixture was concentrated in vacuo to afford 3-(methoxycarbonyl)-1-methyl-1H-indole-2-carboxylic acid (2.95 g, 12.65 mmol, 98% yield) as a brown solid: 1H NMR (400 MHz, DMSO-d6) δ=8.00 (s, 1 H), 7.64 (d, J=8.4 Hz, 1 H), 7.40-7.33 (m, 1 H), 7.28 (s, 1 H), 3.82 (d, J=5.7 Hz, 6 H); LCMS (m/z) ES+=234 (M+1).

Workup

  1. customthe reaction mixture was partitioned between EtOAc and sat. aq. NH4Cl
  2. washThe combined organics were washed with water (3×), brine
  3. dry with materialdried (MgSO4)
  4. filtrationfiltered
  5. concentrationconcentrated
  6. temperatureheated
  7. temperatureto reflux (95° C. bath temp)
  8. waitAfter 8 h
  9. temperaturethe reaction mixture was cooled to ambient temperature
  10. customthe layers partitioned
  11. extractionThe aqueous layer was extracted with EtOAc (2×)
  12. extractionThe aqueous layer was then extracted with EtOAc
  13. washthe organics were washed with brine
  14. dry with materialdried (MgSO4)
  15. filtrationfiltered
  16. concentrationconcentrated

Sources & evidence

ORD record
ord-8a467a68ace94ef89602d226cdbda7fc
Source dataset
uspto-grants-2013_12
Patent number
US08609653B2

Reaction notes

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