Methanamine, N-methoxy-, hydrochloride (1:1) → N-methoxy-N-methyl-1-phenylbicyclo[2.2.2]octane-4-carboxamide

HRID 2353068Notes

Reaction equation

HRID 2353068 reaction equation
[C:1]1([C:7]23[CH2:14][CH2:13][C:10]([C:15](OCC)=[O:16])([CH2:11][CH2:12]2)[CH2:9][CH2:8]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:21][NH:22][O:23][CH3:24].C([Mg]Cl)(C)C>C1COCC1>[CH3:24][O:23][N:22]([CH3:21])[C:15]([C:10]12[CH2:11][CH2:12][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)([CH2:14][CH2:13]1)[CH2:8][CH2:9]2)=[O:16]

Participants

5

Reactant 3

HCID 81138Methanamine, N-methoxy-, hydrochloride (1:1)HCID 21627803Ethyl 4-phenylbicyclo[2.2.2]octane-1-carboxylate2×HCID 178418918HCID 178418918, compound

Product 1

HCID 59379799N-methoxy-N-methyl-1-phenylbicyclo[2.2.2]octane-4-carboxamideYield 55%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
-20 °C

Procedure

To a mixture of ethyl 1-phenylbicyclo[2.2.2]octane-4-carboxylate (Intermediate 4; 15 g, 58.06 mmol) and N,O-dimethylhydroxylamine hydrochloride (8.87 g, 89.99 mmol) in anhydrous THF (130 mL) cooled to −20° C. was added isopropylmagnesium chloride (2M solution in THF; 87 mL) dropwise over 30 mins maintaining the internal temp at −10° C. The mixture was stirred at −10° C. for 1 hr and then quenched by adding 20% ammonium chloride solution. The mixture was extracted into EtOAc (2×200 mL), the organic phase was separated and dried and evaporated to leave a white solid. This was purified on a 330 g Crawford silica cartridge, loading in DCM and eluting with 20-40% EtOAc-isohexane, to provide the title compound as a white solid (8.66 g, 31.67 mmol, 55%); 1H NMR (CDCl3) δ 1.75-1.90 (6H, m), 2.01-2.06 (6H, m), 3.19 (3H, s), 3.70 (3H, s), 7.15-7.20 (1H, m), 7.28-7.36 (4H, m); GC-MS EI+ m/e 243 (M-CH2O), MH+ not seen

Workup

  1. temperaturemaintaining the internal temp at −10° C
  2. customquenched
  3. additionby adding 20% ammonium chloride solution
  4. extractionThe mixture was extracted into EtOAc (2×200 mL)
  5. customthe organic phase was separated
  6. customdried
  7. customevaporated
  8. customto leave a white solid
  9. customThis was purified on a 330 g Crawford silica cartridge, loading in DCM
  10. washeluting with 20-40% EtOAc-isohexane

Sources & evidence

ORD record
ord-07d858825c07422f814236c6ccbf53a2
Source dataset
uspto-grants-2010_07
Patent number
US07749997B2

Reaction notes

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