Methanol → 3-(4-Methoxy-benzyl)-8-(3-methoxy-phenyl)-3-aza-bicyclo[3.2.1]octane

HRID 1295501Notes

Reaction equation

HRID 1295501 reaction equation
Cl[C:2]1([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=2)[CH:7]2[CH2:8][CH2:9][CH:3]1[CH2:4][N:5]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)[CH2:6]2.C(O)(C)(C)C.[Na].CO>O1CCOCC1>[CH3:18][O:17][C:14]1[CH:13]=[CH:12][C:11]([CH2:10][N:5]2[CH2:4][CH:3]3[CH:2]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=4)[CH:7]([CH2:8][CH2:9]3)[CH2:6]2)=[CH:16][CH:15]=1

Participants

6

Reactant 4

HCID 887MethanolHCID 6386tert-ButanolHCID 5360545SodiumHCID 694314818-Chloro-3-(4-methoxy-benzyl)-8-(3-methoxy-phenyl)-3-aza-bicyclo[3.2.1]octane

Product 1

HCID 694276763-(4-Methoxy-benzyl)-8-(3-methoxy-phenyl)-3-aza-bicyclo[3.2.1]octaneYield 35%

Reagents, catalysts & solvents 1

HCID 312751,4-DioxaneSolvent

Conditions

Temperature
110 °C

Procedure

8-Chloro-3-(4-methoxy-benzyl)-8-(3-methoxy-phenyl)-3-aza-bicyclo[3.2.1]octane (2.46 g, 6.61 mmol) and t-butanol (9.48 mL, 99.1 mmol) in dioxane (25 mL) was heated to a gentle reflux with an oil bath (110° C.). Sodium (1.52 g, 66.1 mmol) was pre-washed sequentially with hexanes/ethanol/THF/hexanes then added portionwise to the above refluxing mixture over 20 min. The reaction mixture was heated overnight then cooled to room temperature. To this was added methanol (50 mL) to quench residual sodium. The solvent was removed in vacuo, and the product was partitioned between water (100 mL) and EtOAc (100 mL). The layers were separated and the product was further extracted with EtOAc (3×40 mL), washed with saturated aqueous NaCl solution (1×50 mL), dried over Na2SO4, filtered and concentrated to a light brown oil. Flash chromatography provided the title compound (780 mg, 35%). (TLC 20% EtOAc/hexanes Rf 0.60); 1H NMR (400 MHz, CDCl3) δ 7.29 (d, J=8.7 Hz, 2H), 7.23 (t, J=7.7 Hz, 1H), 6.89 (d, J=8.7 Hz, 2H), 6.88 (m, 1H), 6.84 (s, 1H), 6.74 (dd, J=7.9, 2.5 Hz, 1H), 3.82 (s, 3H), 3.81 (s, 3H), 3.52 (s, 2H), 2.86 (dd, J=10.8, 3.7 Hz, 2H), 2.75 (s, 1H), 2.51 (br s, 2H), 2.28 (d, J=10.0 Hz, 2H), 1.79 (dd, J=12.7, 5.8 Hz, 2H), 1.63 (m, 2H); GCMS m/z 337 (M)+.

Workup

  1. additionthen added portionwise to the above refluxing mixture over 20 min
  2. temperatureThe reaction mixture was heated overnight
  3. temperaturethen cooled to room temperature
  4. customto quench residual sodium
  5. customThe solvent was removed in vacuo
  6. customthe product was partitioned between water (100 mL) and EtOAc (100 mL)
  7. customThe layers were separated
  8. extractionthe product was further extracted with EtOAc (3×40 mL)
  9. washwashed with saturated aqueous NaCl solution (1×50 mL)
  10. dry with materialdried over Na2SO4
  11. filtrationfiltered
  12. concentrationconcentrated to a light brown oil

Sources & evidence

ORD record
ord-06bc1e66882440849e44c1be101b2bce
Source dataset
uspto-grants-2007_07
Patent number
US07241887B2

Reaction notes

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