tert-Butanol → 8,8-Dimethoxy-3-(4-methoxy-benzyl)-3-aza-bicyclo[3.2.1]oct-6-ene

Temperature

92 °C

1,5,6,7-Tetrachloro-8,8-dimethoxy-3-(4-methoxy-benzyl)-3-aza-bicyclo[3.2.1]oct-6-ene (6.23 g, 146 mmol) and t-butanol (25.13 mL, 263 mmol) were dissolved in dioxane (75 mL) in a flame dried 3N RB equipped with a water condenser and thermometer then heated to a gentle reflux (internal temp 92° C.). Sodium (5.36 g, 233 mmol) was pre-washed sequentially with hexanes/ethanol/THF/hexanes then added portionwise to the above refluxing mixture over 45 min The reaction was heated overnight and judged complete by GCMS. The reaction solution was decanted from the unreacted sodium, then washed with methanol to fully quench residual sodium. Solvent was removed in vacuo, diluted in water (100 mL), cooled in an ice bath, then acidified with 6 N HCl (100 mL). At room temperature, the acidic aqueous layers were washed with ether (2×100 mL) then made alkaline with 1N NaOH. The product was extracted with EtOAc (3×100 mL), washed with saturated aqueous NaCl solution (1×100 mL), dried over Na2SO4, filtered and concentrated to yield the title compound (3.97 g, 94%). (TLC 5% MeOH/CH2Cl2, (NH3) Rf 0.40); 1H NMR (400 MHz, CDCl3) δ 7.16 (d, J=8.3 Hz, 2H), 6.79 (d, J=8.3 Hz, 2H), 5.97 (s, 2H), 3.76 (s, 3H), 3.56 (s, 2H), 3.20 (s, 3H), 3.13 (s, 3H), 2.59 (br s, 2H), 2.53 (d, J=10.6 Hz, 2H), 2.39 (d, J=10.6 Hz, 2H); GCMS m/z 287 (M)+.

1. customdried 3N RB
2. customequipped with a water condenser
3. temperaturethermometer then heated to
4. additionthen added portionwise to the above refluxing mixture over 45 min The reaction
5. temperaturewas heated overnight
6. customThe reaction solution was decanted from the unreacted sodium
7. washwashed with methanol to fully quench residual sodium
8. customSolvent was removed in vacuo
9. additiondiluted in water (100 mL)
10. temperaturecooled in an ice bath
11. washAt room temperature, the acidic aqueous layers were washed with ether (2×100 mL)
12. extractionThe product was extracted with EtOAc (3×100 mL)
13. washwashed with saturated aqueous NaCl solution (1×100 mL)
14. dry with materialdried over Na2SO4
15. filtrationfiltered
16. concentrationconcentrated

ORD record

ord-9041d464577f49eea24033f9e1e39da0

Source dataset

uspto-grants-2007_07

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07241887B2