Tris(1,1-dimethylethyl)phosphine → 1-(Quinuclidin-3-yl)-1H-indol-5-amine

HRID 1668463Notes

Reaction equation

HRID 1668463 reaction equation
Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH:16]3[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]3)[CH2:12]1)[CH:6]=[CH:5]2.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C[Si]([N-:36][Si](C)(C)C)(C)C.[Li+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCCC1>[N:13]12[CH2:18][CH2:17][CH:16]([CH2:15][CH2:14]1)[CH:11]([N:7]1[C:8]3[C:4](=[CH:3][C:2]([NH2:36])=[CH:10][CH:9]=3)[CH:5]=[CH:6]1)[CH2:12]2

Participants

6

Reactant 3

HCID 83681Tris(1,1-dimethylethyl)phosphineHCID 2733832Lithium HexamethyldisilazideHCID 590046503-(5-Bromo-1H-indol-1-yl)quinuclidine

Product 1

HCID 590046571-(Quinuclidin-3-yl)-1H-indol-5-amineYield 79.9%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 8028TetrahydrofuranSolvent2×

Procedure

Compound 69 (95 mg, 0.311 mmol), Tris(dibenzylideneacetone)dipalladium (0) (28.5 mg, 0.031 mmol) and anhydrous tetrahydrofuran (10 mL) were charged to a dry argon purged flask fitted with magnetic stir bar and condenser. A solution of tri-tert-butylphosphine (10 wt % in hexane, 125.9 mg, 0.062 mmol) is added followed by dropwise addition of a 1M tetrahydrofuran solution of Lithium bis(trimethylsilyl)amide (0.993 ml, 0.993 mmol) and mixture refluxed for a period of 45 minutes. The mixture was cooled to room temperature then to 0° C., quenched with 1M HCl (10 mL) and stirred for 15 minutes. The solution was diluted with ethyl acetate and conc. NH4OH added to adjust pH to 9. The mixture was transferred to a separatory funnel and the organic layer collected. The aqueous layer was further extracted with ethyl acetate and the combined organic layers were washed with brine, dried over magnesium sulphate, filtered, concentrated and the residue purified via chromatography on silica gel (2M NH3 in methanol:CH2Cl2, 5:95) to yield a yellow residue 70 (60 mg, 79.9%). 1H NMR (DMSO-d6) δ 1.22-1.47 (m, 2H), 1.57-1.70 (m, 1H), 1.73-1.90 (2×m, 2H), 2.66-2.84 (2×m, 3H), 2.97-3.04 (m, 1H), 3.09-3.20 (m, 2H), 4.41-4.54 (2×m, 3H), 6.17 (d, 1H, J=3.1 Hz), 6.51 (dd, 1H, J=8.8, 2.0 Hz), 6.68 (d, 1H, J=2.0 Hz), 7.12 (d, 1H, J=8.7 Hz), 7.50 (d, 1H, J=3.2 Hz); ESI-MS (m/z, %): 242 (MH+, 100%).

Workup

  1. customfitted with magnetic stir bar and condenser
  2. temperaturerefluxed for a period of 45 minutes
  3. customto 0° C., quenched with 1M HCl (10 mL)
  4. additionThe solution was diluted with ethyl acetate and conc. NH4OH
  5. additionadded
  6. customThe mixture was transferred to a separatory funnel
  7. customthe organic layer collected
  8. extractionThe aqueous layer was further extracted with ethyl acetate
  9. washthe combined organic layers were washed with brine
  10. dry with materialdried over magnesium sulphate
  11. filtrationfiltered
  12. concentrationconcentrated
  13. customthe residue purified via chromatography on silica gel (2M NH3 in methanol:CH2Cl2, 5:95)

Sources & evidence

ORD record
ord-465289a4b4f4479992df7c8494a1e595
Source dataset
uspto-grants-2011_08
Patent number
US07989447B2

Reaction notes

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