HCID 58593059, compound → HCID 58593038, compound

HRID 1292852Notes

Reaction equation

HRID 1292852 reaction equation
[CH2:1]([Mg]Br)[CH3:2].[CH2:5]([N:12]([CH:27]1[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]1)[C:13]([CH:15]1[CH2:19][CH2:18][N:17]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:16]1)=O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C1COCC1.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH2:5]([N:12]([C:13]1([CH:15]2[CH2:19][CH2:18][N:17]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:16]2)[CH2:2][CH2:1]1)[CH:27]1[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1

Participants

5

Reactant 2

HCID 58593059HCID 58593059, compoundHCID 178418443HCID 178418443, compound2×

Product 1

HCID 58593038HCID 58593038, compoundYield 61.5%

Reagents, catalysts & solvents 2

HCID 11026Titanium isopropoxideCatalyst2×HCID 8028TetrahydrofuranSolvent4×

Procedure

A solution of ethylmagnesium bromide (3.0 M in ethyl ether, 13.0 mL, 39.1 mmol, 2.5 equiv) in THF (100 mL) was cooled to −78° C. To this was added a solution of titanium (IV) isopropoxide (4.8 mL, 16.3 mmol, 1.04 equiv) in THF (10 mL) dropwise with the temperature below −70° C. After stirring for thirty minutes, a solution of (R/S)-N-benzyl-N-(1-tert-butoxycarbonylpiperidin-4-yl)-1-benzylpyrrolidine-3-carboxamide (7.5 g, 15.6 mmol) in THF (10 mL) was added. The resulting solution was warmed to RT, heated at reflux for one hour. The mixture was then cooled to 8° C., and ethylmagnesium bromide (3.0 M in ethyl ether, 11.0 mL, 33.1 mmol, 2.1 equiv) was added, followed immediately by a solution of titanium (IV) isopropoxide (4.2 mL, 14.2 mmol, 0.91 equiv) in THF (10 mL). The reaction mixture was stirred at room temperature for one hour then partitioned between 1:1 EtOAc—H2O (500 mL). The organic layer was washed with brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by chromatography (5:1 hexanes-EtOAc to 100% EtOAc) to give a pale yellow oil (4.7 g, 61%). ESI MS m/z 490.3 (M+H). 1H NMR (400 MHz, CDCl3) δ 7.34-7.11 (m, 10H), 4.18-3.98 (br m, 1H), 3.92 (app s, 2H), 3.64 (app t, J=13.2, 1H), 3.55 (d, J=12.5, 1H), 3.00-2.78 (m, 4H), 2.75-2.37 (m, 4H), 2.33-2.21 (m, 1H), 2.10-1.89 (m, 2H), 1.73-1.62 (m, 2H), 1.50-1.37 (s+m, 11H), 1.37-1.14 (m, 2H), 0.71 (app s, 1H), 0.60-0.49 (m, 1H). 13C NMR (400 MHz, CDCl3) δ 154.20 (C═O), 143.1 (Ph), 138.8 (Ph), 128.5 (Ph), 128.4 (Ph), 127.9 (Ph), 127.7 (Ph), 126.6 (Ph), 125.9 (Ph), 78.8 (t-Bu), 60.6, 58.4, 55.5, 53.2, 48.9, 45.2, 43.3 (br), 42.7 (br), 38.6, 32.1 (br), 28.1 (t-Bu), 7.6 (c-Pr).

Workup

  1. temperatureheated
  2. temperatureat reflux for one hour
  3. temperatureThe mixture was then cooled to 8° C.
  4. stirringThe reaction mixture was stirred at room temperature for one hour
  5. customthen partitioned between 1:1 EtOAc—H2O (500 mL)
  6. washThe organic layer was washed with brine
  7. dry with materialdried (Na2SO4)
  8. concentrationconcentrated in vacuo
  9. customThe residue was purified by chromatography (5:1 hexanes-EtOAc to 100% EtOAc)

Sources & evidence

ORD record
ord-6109eeb79ce348a9a188d9ef94d92cc1
Source dataset
uspto-grants-2007_07
Patent number
US07238694B2

Reaction notes

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