2-Methylindole → 4-(5-Fluoro-2-methoxyphenyl)-2-(indol-2-ylmethyl)-4-methylpentan-2-ol

HRID 1510893Notes

Reaction equation

HRID 1510893 reaction equation
[CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.C([Li])CCC.CC(C)([O-])C.[K+].[F:22][C:23]1[CH:24]=[CH:25][C:26]([O:36][CH3:37])=[C:27]([C:29]([CH3:35])([CH3:34])[CH2:30][C:31](=[O:33])[CH3:32])[CH:28]=1>C1COCC1>[F:22][C:23]1[CH:24]=[CH:25][C:26]([O:36][CH3:37])=[C:27]([C:29]([CH3:34])([CH3:35])[CH2:30][C:31]([CH2:1][C:2]2[NH:3][C:4]3[C:9]([CH:10]=2)=[CH:8][CH:7]=[CH:6][CH:5]=3)([OH:33])[CH3:32])[CH:28]=1

Participants

6

Reactant 4

HCID 72242-MethylindoleHCID 222849224-(5-Fluoro-2-methoxyphenyl)-4-methylpentan-2-oneHCID 23665647Potassium tert-butoxideHCID 178418339Butyllithium

Product 1

HCID 223985264-(5-Fluoro-2-methoxyphenyl)-2-(indol-2-ylmethyl)-4-methylpentan-2-olYield 31.2%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-20 °C

Procedure

To a solution of 2-methylindole (130 mg) in THF (2 mL) stirred under argon cooled on dry ice/acetone was added n-butyl lithium (2M in pentane, 1.6 mL). After 2 minutes, potassium tert-butoxide (1M in THF, 2 mL) was added and the mixture was allowed to warm to approximately −20° C. After 5 minutes, precipitate was noted and the mixture was cooled to −70° C. 4-(5-Fluoro-2-methoxyphenyl)-4-methylpentan-2-one (Example 17) (440 mg) in THF (1.5 mL) was added all at once. The cooling bath was removed and the mixture was stirred for 10 minutes and then quenched with EtOH (0.5 mL). The mixture was diluted with EtOAc, washed with water, dried, filtered, and evaporated. Chromatography over silica gel (EtOAc-hexanes (1:9)) gave product which solidified on trituration with hexanes-ether. The solid was recrystallized from ether-hexanes, collected by filtration and dried under vacuum to give 0.11 g of the title compound, m.p. 118° C.-120° C.

Workup

  1. temperaturecooled on dry ice/acetone
  2. waitAfter 5 minutes
  3. temperaturethe mixture was cooled to −70° C
  4. customThe cooling bath was removed
  5. customquenched with EtOH (0.5 mL)
  6. additionThe mixture was diluted with EtOAc
  7. washwashed with water
  8. customdried
  9. filtrationfiltered
  10. customevaporated
  11. customChromatography over silica gel (EtOAc-hexanes (1:9)) gave product which
  12. customThe solid was recrystallized from ether-hexanes
  13. filtrationcollected by filtration
  14. customdried under vacuum

Sources & evidence

ORD record
ord-c38237a653f346d09984409fb17f7c58
Source dataset
uspto-grants-2012_07
Patent number
US08212040B2

Reaction notes

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