Tris(1,1-dimethylethyl)phosphine → 1-(8-Methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-indol-5-amine

HRID 1668477Notes

Reaction equation

HRID 1668477 reaction equation
Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:17][CH:16]3[N:18]([CH3:19])[CH: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-:37][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>[CH3:19][N:18]1[CH:16]2[CH2:15][CH2:14][CH:13]1[CH2:12][CH:11]([N:7]1[C:8]3[C:4](=[CH:3][C:2]([NH2:37])=[CH:10][CH:9]=3)[CH:5]=[CH:6]1)[CH2:17]2

Participants

6

Reactant 3

HCID 83681Tris(1,1-dimethylethyl)phosphineHCID 2733832Lithium HexamethyldisilazideHCID 590046405-Bromo-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole

Product 1

HCID 590046691-(8-Methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-indol-5-amineYield 89%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 8028TetrahydrofuranSolvent2×

Procedure

Compound 84 (73 mg, 0.2287 mmol), tris(dibenzylideneacetone)dipalladium (0) (20.9 mg, 0.0229 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, 92.5 mg, 0.0457 mmol) is added followed by dropwise addition of a 1M tetrahydrofuran solution of lithium bis(trimethylsilyl)amide (0.686 ml, 0.686 mmol) and mixture refluxed for a period of 90 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 to yield crude. The crude amine was combined with a second crude from an identical reaction and the residue purified via chromatography on silica gel (EtOAc:methanol:Et3N, 8:1:1) to yield a brown solid 85 (52 mg, 37.6%) as a 5:1 or 1:5 mixture of endo/exo stereoisomers. 1H NMR (major isomer-DMSO-d6) δ 1.53-1.70 (m, 4H), 2.00-2.09 (m, 2H), 2.18 (s, 3H), 3.17-3.32 (m, 2H), 4.54 (quintuplet, 1H, J=8.2 Hz), 6.11 (d, 1H, J=3.1 Hz), 6.49 (dd, 1H, J=8.6, 2.1 Hz), 6.65 (d, 1H, J=1.9 Hz), 7.05 (d, 1H, J=8.7 Hz), 7.26 (d, 1H, J=3.2 Hz); ESI-MS (m/z, %): 256 (MH+, 100%).

Workup

  1. customfitted with magnetic stir bar and condenser
  2. temperaturerefluxed for a period of 90 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. customto yield crude
  14. customthe residue purified via chromatography on silica gel (EtOAc:methanol:Et3N, 8:1:1)

Sources & evidence

ORD record
ord-7b0c636bee364b30b41ace7c66cdeed8
Source dataset
uspto-grants-2011_08
Patent number
US07989447B2

Reaction notes

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