Acetyl chloride → 3-(4-Isopropoxy-3-methoxy-benzoyl)-11-oxa-3-azaspiro[5.5]undec-9-en-8-one

HRID 1478429Notes

Reaction equation

HRID 1478429 reaction equation
[CH:1]([O:4][C:5]1[CH:19]=[CH:18][C:8]([C:9]([N:11]2[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]2)=[O:10])=[CH:7][C:6]=1[O:20][CH3:21])([CH3:3])[CH3:2].[Si]([O:29][C:30](=[CH2:36])/[CH:31]=[CH:32]/N(C)C)(C(C)(C)C)(C)C.C(Cl)(=O)C>CC(O)CC>[CH:1]([O:4][C:5]1[CH:19]=[CH:18][C:8]([C:9]([N:11]2[CH2:16][CH2:15][C:14]3([O:17][CH:32]=[CH:31][C:30](=[O:29])[CH2:36]3)[CH2:13][CH2:12]2)=[O:10])=[CH:7][C:6]=1[O:20][CH3:21])([CH3:3])[CH3:2]

Participants

5

Reactant 3

HCID 6367Acetyl chlorideHCID 6060661[(1E)-3-[(tert-butyldimethylsilyl)oxy]buta-1,3-dien-1-yl]dimethylamineHCID 897046151-(4-Isopropoxy-3-methoxy-benzoyl)piperidin-4-one

Product 1

HCID 897085073-(4-Isopropoxy-3-methoxy-benzoyl)-11-oxa-3-azaspiro[5.5]undec-9-en-8-oneYield 591.2%

Reagents, catalysts & solvents 1

HCID 6568(+-)-2-ButanolSolvent

Procedure

A suspension of 1-(4-isopropoxy-3-methoxy-benzoyl)piperidin-4-one (12.8 g, 44.0 mmol) in 2-butanol (100 mL) was purged with argon gas for 5 minutes. (1E)-3-[tert-butyl(dimethyl)silyl]oxy-N,N-dimethyl-buta-1,3-dien-1-amine (10.0 g, 4.0 mmol) was added dropwise at room temperature under argon gas. The reaction mixture was stirred at room temperature overnight. The mixture turned to a dark brown clear solution. Solvent was removed. The residue was redissolved in THF (200 mL) and cooled to −78° C. Acetyl chloride (3.75 mL, 52.8 mmol) was added dropwise. The mixture was stirred at −78° C. for 30 min. The reaction was quenched with saturated sodium bicarbonate (25 mL). The organic layer was separated. The aqueous layer was extracted with diethyl ether (3×). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated. The crude material was purified by column chromatography (40-60% ethyl acetate-Hex) to provide 3-(4-isopropoxy-3-methoxy-benzoyl)-11-oxa-3-azaspiro[5.5]undec-9-en-8-one (8.5 g) as a light yellow thick oil. 1H NMR (400 MHz, CDCl3) δ 7.28 (d, J=6.1 Hz, 1H), 6.99 (d, J=1.9 Hz, 1H), 6.94 (dd, J=8.2, 1.9 Hz, 1H), 6.87 (d, J=8.3 Hz, 1H), 5.44 (d, J=6.1 Hz, 1H), 4.57 (dt, J=12.2, 6.1 Hz, 1H), 4.25-4.00 (m, 2H), 3.87 (s, 3H), 3.34 (s, 2H), 2.56 (s, 2H), 2.15 (d, J=14.1 Hz, 2H), 1.62 (s, 2H), 1.39 (t, J=5.3 Hz, 6H). ESI-MS m/z calc. 359.17, found 360.3 (M+1)+; Retention time: 1.18 minutes (3 minute run).

Workup

  1. customwas purged with argon gas for 5 minutes
  2. customSolvent was removed
  3. dissolutionThe residue was redissolved in THF (200 mL)
  4. temperaturecooled to −78° C
  5. stirringThe mixture was stirred at −78° C. for 30 min
  6. customThe reaction was quenched with saturated sodium bicarbonate (25 mL)
  7. customThe organic layer was separated
  8. extractionThe aqueous layer was extracted with diethyl ether (3×)
  9. washThe combined organic layers were washed with brine
  10. dry with materialdried over MgSO4
  11. filtrationfiltered
  12. concentrationconcentrated
  13. customThe crude material was purified by column chromatography (40-60% ethyl acetate-Hex)

Sources & evidence

ORD record
ord-ec985e42e13b4cc19f6c293cb658db7f
Source dataset
uspto-grants-2016_08
Patent number
US09403839B2

Reaction notes

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