Aluminium lithium hydride → Indole, 3-(1-methyl-2-piperidylmethyl)-

HRID 975009Notes

Reaction equation

HRID 975009 reaction equation
CS(N[C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[C:9]2[CH2:15][C@H:16]1[CH2:20][CH2:19][CH2:18][N:17]1[CH3:21])(=O)=O.C(OC(N1CCC[C@H]1C([N:39]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH:41]=[CH:40]1)=O)=O)C1C=CC=CC=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH3:21][N:17]1[CH2:18][CH2:19][CH2:20][CH:16]1[CH2:15][C:9]1[C:8]2[C:12](=[CH:13][CH:14]=[CH:6][CH:7]=2)[NH:11][CH:10]=1.[CH3:21][N:17]1[CH2:18][CH2:20][CH:16]1[CH2:15][C:9]1[C:8]2[C:12](=[CH:13][CH:14]=[CH:6][CH:7]=2)[NH:11][CH:10]=1.[CH3:21][N:17]1[CH2:18][CH2:19][CH2:9][CH2:15][CH:16]1[CH2:20][C:41]1[C:42]2[C:47](=[CH:46][CH:45]=[CH:44][CH:43]=2)[NH:39][CH:40]=1

Participants

7

Reactant 3

HCID 21226445Aluminium lithium hydrideHCID 53691778(R)-5-methylsulfonamido-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indoleHCID 53957257(S)-(N-benzyloxycarbonylpyrrolidin-2-ylcarbonyl)-1H-indole

Product 3

HCID 58967Indole, 3-(1-methyl-2-piperidylmethyl)-HCID 199702683-(N-methylazetidin-2-ylmethyl)-1H-indoleHCID 538704423-(N-methylpyrrolidin-2-ylmethyl)-1H-indole

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

To a stirred solution of (R)- or (S)-(N-benzyloxycarbonylpyrrolidin-2-ylcarbonyl)-1H-indole, (R)-, (S), or (R,S)-(N-benzyloxycarbonylazetidin-2-ylcarbonyl)-1H-indole, or (R)-, (S)-, or (R,S)-(N-benzyloxycarbonylpiperidin-2-ylcarbonyl)-1H-indole, (5.00 mmol) in anhydrous tetrahydrofuran (20 mL) at room temperature under nitrogen was carefully added lithium aluminum hydride (0.57 g, 15.0 mmol, 3.0 eq) as a powder, and the resulting mixture was stirred at room temperature under nitrogen for 1 hour. The mixture was then heated at reflux (66° C.) under nitrogen for 12 hours. The reaction was then quenched with successive additions of water (0.5 mL), aqueous sodium hydroxide (20%, 0.5 mL), and then additional water (1.0 mL), and the resulting mixture filtered through diatomaceous earth (Celite (trademark)). The solids were then washed with copious amounts of ethyl acetate (50 mL). The combined filtrate was then washed with water (20 mL), dried (MgSO4), and evaporated under reduced pressure. The residue was then column chromatographed using silica gel (50 g) and elution with the appropriate solvent system to afford the 3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole, 3-(N-methylazetidin-2-ylmethyl)-1H-indole, or 3-(N-methylpiperidin-2-ylmethyl)-1H-indole. Following this procedure the following compounds were prepared:

Workup

  1. customat room temperature
  2. temperatureThe mixture was then heated
  3. temperatureat reflux (66° C.) under nitrogen for 12 hours
  4. customThe reaction was then quenched with successive additions of water (0.5 mL), aqueous sodium hydroxide (20%, 0.5 mL)
  5. filtrationadditional water (1.0 mL), and the resulting mixture filtered through diatomaceous earth (Celite (trademark))
  6. washThe solids were then washed with copious amounts of ethyl acetate (50 mL)
  7. washThe combined filtrate was then washed with water (20 mL)
  8. dry with materialdried (MgSO4)
  9. customevaporated under reduced pressure
  10. customcolumn chromatographed
  11. washsilica gel (50 g) and elution with the appropriate solvent system

Sources & evidence

ORD record
ord-dd566a1f88134e52a9a9fc9d4cd4b75f
Source dataset
uspto-grants-1997_03
Patent number
US05607951

Reaction notes

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