Methyl Isocyanate → 6-Methoxy-2-methyl-1H-indol-3-carboxylic acid methylamide

HRID 1825091Notes

Reaction equation

HRID 1825091 reaction equation
[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[C:8]([CH3:12])[NH:9]2)=[CH:5][CH:4]=1.C[Mg]Br.[CH3:16][N:17]=[C:18]=[O:19]>C1COCC1.[Cl-].[Zn+2].[Cl-]>[CH3:16][NH:17][C:18]([C:7]1[C:6]2[C:10](=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[NH:9][C:8]=1[CH3:12])=[O:19]

Participants

6

Reactant 3

HCID 12228Methyl IsocyanateHCID 108447096-methoxy-2-methyl-1H-indoleHCID 178418573HCID 178418573, compound

Product 1

HCID 207678716-Methoxy-2-methyl-1H-indol-3-carboxylic acid methylamideYield 30%

Reagents, catalysts & solvents 2

HCID 3007855ZincchlorideCatalystHCID 8028TetrahydrofuranSolvent2×

Procedure

To a stirred solution of 6-methoxy-2-methyl-1H-indole (500 mg, 3.1 mmol) (prepared according to JACS 1988, 110, 2242) in 8 mL anhydrous THF maintained at room temperature was added methylmagnesium bromide (1.13 ml, 3.0 M solution in diethyl ether, 3.41 mmol). After stirring for 1 hour at room temperature, a solution of 0.5M zinc chloride in THF (7.44 ml, 3.72 mmol) was introduced and the mixture was stirred for 1 hour at room temperature before addition of methyl isocyanate (424 mg, 7.44 mmol). The resulting mixture was stirred at ambient temperature overnight, quenched with water, and extracted with EtOAc. The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography eluting with 2–5% MeOH in CH2Cl2 to give 200 mg product (30% yield). 1H NMR (300 MHz, CD3OD) δ 7.55 (1H, d, J=8.6 Hz), 6.78 (1H, d, J=2.2 Hz), 6.70 (1H, dd, J=2.2, 8.6 Hz), 3.73 (3H, s), 2.90 (3H, s), 2.52 (3H, s). LCMS (ESI+) [M+H]/z Calc'd 219. found 219.

Workup

  1. stirringThe resulting mixture was stirred at ambient temperature overnight
  2. customquenched with water
  3. extractionextracted with EtOAc
  4. washThe combined organic layer was washed with brine
  5. dry with materialdried over Na2SO4
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customThe residue was purified by flash column chromatography
  9. washeluting with 2–5% MeOH in CH2Cl2

Sources & evidence

ORD record
ord-6d28bd25f24543c190ad5c3156a7b50e
Source dataset
uspto-grants-2006_05
Patent number
US07045528B2

Reaction notes

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