Hexane → N-Methyl-6-amino-4a-(3-methoxyphenyl)-8a-methyloctahydroisoquinoline

HRID 1453971Notes

Reaction equation

HRID 1453971 reaction equation
[CH3:1][N:2]1[CH2:11][CH2:10][C:9]2([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=3)[C:4]([CH3:22])([CH2:5][CH2:6][C:7](=[N:20]O)[CH2:8]2)[CH2:3]1.CCCCCC.[H][H]>C(O)(C)C.C1(C)C=CC=CC=1>[CH3:1][N:2]1[CH2:11][CH2:10][C:9]2([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=3)[C:4]([CH3:22])([CH2:5][CH2:6][CH:7]([NH2:20])[CH2:8]2)[CH2:3]1

Participants

6

Reactant 3

HCID 8058HexaneHCID 729884842,8a-Dimethyl-4a-(3-methoxyphenyl)octahydroisoquinolin-6-one OximeHCID 178418361HCID 178418361, compound

Product 1

HCID 68828064N-Methyl-6-amino-4a-(3-methoxyphenyl)-8a-methyloctahydroisoquinolineYield 94%

Reagents, catalysts & solvents 2

HCID 1140TolueneSolventHCID 3776IsopropanolSolvent

Conditions

Temperature
50 °C

Procedure

A slurry of oxime 19 (2.35 g, 0.077 mol) in anhydrous isopropanol (100 mL) and anhydrous toluene (200 mL) was heated to reflux until the solution became clear. The heat was turned off, and Na (20 g, 0.87 mol) was added carefully in a such rate that a steady reflux was maintained (make 30-40 pieces and store under hexane) over 1.5 h. The first addition was kept small. (Note hydrogen evolution!). At the end the reaction was slower, so the heating mantle was turned back on to speed things up. The reaction mixture was heated to reflux until all Na was consumed followed by cooling to 50° C. and quenching with careful addition of water (250 mL). The toluene layer was separated and the aqueous layer extracted with EtOAc (3×100 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated under reduced pressure yielding crude product. The crude product was purified by flash chromatography (50% CMA80 in CHCl3) to afford 2.11 g (94%) of 20 as a colorless oil: LCMS (APCI): m/z 289.4 (M+H)+; 1H NMR (CDCl3, 300 MHz) δ 7.14-7.44 [m, 3H], 6.71-6.74 [m, 1H], 3.80 [s, 3H], 3.05 [m, 1H], 2.77 [m, 1H], 2.64 [d, J=12 Hz, 1H], 2.27-2.30 [m, 2H], 2.26 [s, 3H], 2.02-2.12 [m, 3H], 1.68-1.71 [m, 2H], 1.46-1.49 [m, 2H], 1.24 [m, 3H], 1.20 [s, 3H]; 13C NMR (CDCl3, 300 MHz) δ 159.2, 150.2, 128.5, 121.8, 116.5, 110.0, 65.4, 55.5, 53.0, 47.1, 46.7, 43.8, 43.3, 36.6, 36.2, 32.2, 25.8.

Workup

  1. temperatureto reflux until the solution
  2. temperaturea steady reflux
  3. additionThe first addition
  4. temperatureThe reaction mixture was heated
  5. temperatureto reflux until all Na
  6. customwas consumed
  7. customquenching with careful addition of water (250 mL)
  8. customThe toluene layer was separated
  9. extractionthe aqueous layer extracted with EtOAc (3×100 mL)
  10. dry with materialThe combined organic layers were dried (MgSO4)
  11. filtrationfiltered
  12. concentrationconcentrated under reduced pressure
  13. customyielding crude product
  14. customThe crude product was purified by flash chromatography (50% CMA80 in CHCl3)

Sources & evidence

ORD record
ord-39a82fe02ae54a8e9e2225243b82c784
Source dataset
uspto-grants-2009_01
Patent number
US07476679B2

Reaction notes

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