Tris(1,1-dimethylethyl)phosphine → 1,1-Dimethylethyl 4-(6-amino-3,4-dihydro-1(2H)-quinolinyl)-1-piperidinecarboxylate

HRID 1922450Notes

Reaction equation

HRID 1922450 reaction equation
P(C(C)(C)C)(C(C)(C)C)C(C)(C)C.Br[C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]([CH:25]1[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]1)[CH2:20][CH2:19][CH2:18]2.[F-].C([N+:43](CCCC)(CCCC)CCCC)CCC>C1COCC1.CO.C(Cl)Cl.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]>[NH2:43][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]([CH:25]1[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]1)[CH2:20][CH2:19][CH2:18]2

Participants

7

Reactant 3

HCID 83681Tris(1,1-dimethylethyl)phosphineHCID 2724141Tetrabutylammonium FluorideHCID 53392352HCID 53392352, compound

Product 1

HCID 533924481,1-Dimethylethyl 4-(6-amino-3,4-dihydro-1(2H)-quinolinyl)-1-piperidinecarboxylateYield 76.6%

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 8028TetrahydrofuranSolvent3×HCID 21226129Dichloromethane methanolSolvent

Procedure

A suspension of Pd2(dba)3 (29 mg, 0.032 mmol) in 2 mL anhydrous THF was treated with PtBu3 (400 μL of a 10% wt in hexanes solution, 0.13 mmol) and stirred at room temperature for 5 minutes. To this mixture was added tert-butyl 4-(6-bromo-3,4-dihydroquinolin-1(2H)-yl)piperidine-1-carboxylate (250 mg, 0.63 mmol) followed by lithium hexamethyldisilizane (1.3 mL of a 1 M solution in THF, 1.3 mmol). The resulting dark brown suspension was heated at 95° C. for 3 hours. The mixture was cooled to room temperature and treated with 5 ml of a 1M tetrabutylammonium fluoride solution in THF then stirred at room temperature for 30 minutes. The mixture was partitioned between ethyl acetate (100 mL) and H2O (20 mL). After extraction, the organic layer was separated, dried over Na2SO4, filtered and concentrated to give a dark brown residue. This residue was subjected to flash chromatography on silica gel using 2.5% 2M NH3 in methanol/CH2Cl2 to give a viscous dark brown residue (160 mg, 76.6%). 1H-NMR (CDCl3) δ 6.56 (d, J=8.4 Hz, 1H), 6.48 (dd, J=2.7, 8.7 Hz, 1H), 6.43-6.42 (m, 1H), 4.25-4.21 (m, 2H), 3.69-3.59 (m, 1H), 3.24 (br s, 2H), 3.07 (t, J=5.4 Hz, 2H), 2.78-2.72 (m, 2H), 2.66 (t, J=6.6 Hz, 2H), 1.93-1.83 (m, 2H), 1.76-1.55 (m, 4H), 1.47 (s, 9H). MS (ESI): 332.2 (M+1, 100%).

Workup

  1. temperatureThe resulting dark brown suspension was heated at 95° C. for 3 hours
  2. temperatureThe mixture was cooled to room temperature
  3. stirringthen stirred at room temperature for 30 minutes
  4. customThe mixture was partitioned between ethyl acetate (100 mL) and H2O (20 mL)
  5. extractionAfter extraction
  6. customthe organic layer was separated
  7. dry with materialdried over Na2SO4
  8. filtrationfiltered
  9. concentrationconcentrated
  10. customto give a dark brown residue

Sources & evidence

ORD record
ord-85ccace87ec94ae29e72660017315408
Source dataset
uspto-grants-2012_05
Patent number
US08173813B2

Reaction notes

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