Chloromethyl ethyl ether → methyl 1-(ethoxymethyl)-1H-indole-4-carboxylate

HRID 1886735Notes

Reaction equation

HRID 1886735 reaction equation
[NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:10]([O:12][CH3:13])=[O:11])[C:4]=2[CH:3]=[CH:2]1.C[Si](C)(C)[N-][Si](C)(C)C.[K+].[CH2:24]([O:26][CH2:27]Cl)[CH3:25]>C1COCC1>[CH2:24]([O:26][CH2:27][N:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:10]([O:12][CH3:13])=[O:11])[C:4]=2[CH:3]=[CH:2]1)[CH3:25]

Participants

5

Reactant 3

HCID 18523Chloromethyl ethyl etherHCID 2733668methyl 1H-indole-4-carboxylateHCID 3251421Potassium bis(trimethylsilyl)amide

Product 1

HCID 67468002methyl 1-(ethoxymethyl)-1H-indole-4-carboxylateYield 75%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

Under nitrogen, to a solution of methyl 1H-indole-4-carboxylate (80 g, 0.46 mol) in THF (700 mL) is added potassium hexamethyldisilazide (1 M in THF, 550 mL, 0.55 mol) in drops at 0° C. The mixture is stirred at 0° C. for 30 minutes (min) and chloromethyl ethyl ether (51 mL, 0.55 mol) is then added at 0-5° C. After the addition, the reaction mixture is stirred at ambient temperature for another 3 hours (h), quenched carefully with 300 mL of water and extracted with ethyl acetate (EA, 3×300 mL). The combined extracts are washed with aqueous saturated sodium chloride (2×400 mL), then dried over Na2SO4, filtered and concentrated. The residue is purified by chromatography on silica gel to give the title compound (80 g, 75%). MS (m/z): 234 (M+H)+.

Workup

  1. additionis then added at 0-5° C
  2. additionAfter the addition
  3. customquenched carefully with 300 mL of water
  4. extractionextracted with ethyl acetate (EA, 3×300 mL)
  5. washThe combined extracts are washed with aqueous saturated sodium chloride (2×400 mL)
  6. dry with materialdried over Na2SO4
  7. filtrationfiltered
  8. concentrationconcentrated
  9. customThe residue is purified by chromatography on silica gel

Sources & evidence

ORD record
ord-c8024654c063418d8beaff8dc7c1b1ba
Source dataset
uspto-grants-2013_08
Patent number
US08501166B2

Reaction notes

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