Sodium hydride → methyl 6-bromo-1-cyclobutyl-1H-indole-4-carboxylate

HRID 873464Notes

Reaction equation

HRID 873464 reaction equation
[Br:1][C:2]1[CH:3]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[C:5]2[CH:6]=[CH:7][NH:8][C:9]=2[CH:10]=1.[Cl-].C(C[P+](C)(C)C)#N.[CH:23]1(O)[CH2:26][CH2:25][CH2:24]1.[H-].[Na+]>C1COCC1.CCOC(C)=O.CCCCCC>[Br:1][C:2]1[CH:3]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[C:5]2[CH:6]=[CH:7][N:8]([CH:23]3[CH2:26][CH2:25][CH2:24]3)[C:9]=2[CH:10]=1

Participants

8

Reactant 4

HCID 24758Sodium hydrideHCID 76218CyclobutanolHCID 13770009methyl 6-bromo-1H-indole-4-carboxylateHCID 57431663(Cyanomethyl)trimethylphosphonium chloride

Product 1

HCID 67469195methyl 6-bromo-1-cyclobutyl-1H-indole-4-carboxylateYield 25%

Reagents, catalysts & solvents 3

HCID 8028TetrahydrofuranSolventHCID 8058HexaneSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
50 °C

Procedure

In an oven dried 100 ml RBF, equipped with a stir bar, septum, nitrogen inlet was added methyl 6-bromo-1H-indole-4-carboxylate (1.0 g, 3.94 mmol) and (cyanomethyl)(trimethyl)phosphonium chloride (1.491 g, 9.84 mmol). Added in THF (40 mL) and stirred suspension for 5 min. The reaction was cooled with an ice bath for 10 min, then was added cyclobutanol (0.616 mL, 7.87 mmol), followed by sodium hydride (0.346 g, 8.66 mmol) portionwise. The ice bath was removed and the reaction stirred at ambient temperature for 45 min, then heated at 50° C. for 18 h. LCMS showed mostly SM. Heated at 75° C. for 24 h. The reaction was allowed to cool to RT, then poured into water (200 ml) and extracted with EtOAc (2×). The combined organics were dried over magnesium sulfate, filtered, and concentrated. Purification of the residue by column chromatography (40 g Isco silica column; gradient B: 2-25%; A:hexane, B: EtOAc) gave methyl 6-bromo-1-cyclobutyl-1H-indole-4-carboxylate (0.3 g, 25% yield, ˜45% pure by HPLC). MS(ES) [M+H]+ 308.2.

Workup

  1. customIn an oven dried 100 ml RBF
  2. customequipped with a stir bar
  3. temperatureThe reaction was cooled with an ice bath for 10 min
  4. customThe ice bath was removed
  5. stirringthe reaction stirred at ambient temperature for 45 min
  6. temperatureHeated at 75° C. for 24 h
  7. temperatureto cool to RT
  8. additionpoured into water (200 ml)
  9. extractionextracted with EtOAc (2×)
  10. dry with materialThe combined organics were dried over magnesium sulfate
  11. filtrationfiltered
  12. concentrationconcentrated
  13. customPurification of the residue by column chromatography (40 g Isco silica column

Sources & evidence

ORD record
ord-9bfcf678878b4d3dbac34ce5219f3364
Source dataset
uspto-grants-2015_03
Patent number
US08975291B2

Reaction notes

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