Hydrochloric Acid → 4-Fluoro-4-(2-methyl-4-nitro-pyrazol-3-yl)cyclohexanone

HRID 1915837Notes

Reaction equation

HRID 1915837 reaction equation
[CH3:1][N:2]1[C:6]([C:7]2(O)[CH2:16][CH2:15][C:10]3(OCC[O:11]3)[CH2:9][CH2:8]2)=[C:5]([N+:18]([O-:20])=[O:19])[CH:4]=[N:3]1.COCCN(S(F)(F)[F:31])CCOC.C([O-])(O)=O.[Na+].Cl>C(Cl)Cl.C1COCC1.O>[F:31][C:7]1([C:6]2[N:2]([CH3:1])[N:3]=[CH:4][C:5]=2[N+:18]([O-:20])=[O:19])[CH2:16][CH2:15][C:10](=[O:11])[CH2:9][CH2:8]1

Participants

8

Reactant 4

HCID 313Hydrochloric AcidHCID 516892Sodium BicarbonateHCID 2734690(Bis(2-methoxyethyl)amino)sulfur trifluorideHCID 866800488-(2-Methyl-4-nitro-pyrazol-3-yl)-1,4-dioxaspiro[4.5]decan-8-ol

Product 1

HCID 866800504-Fluoro-4-(2-methyl-4-nitro-pyrazol-3-yl)cyclohexanone

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent2×

Procedure

To a solution of 8-(2-methyl-4-nitro-pyrazol-3-yl)-1,4-dioxaspiro[4.5]decan-8-ol (3.68 g, 13.0 mmol) in dry DCM (80 mL) under nitrogen was added dropwise a solution of deoxo-Fluor® (50% in THF, 14.1 mL, 39.0 mmol). The reaction mixture was stirred at room temperature for 1 hr. After cooling to 0° C., saturated aqueous NaHCO3 (100 mL) was added, dropwise initially, and the mixture was extracted with DCM (2×75 mL). The combined organic layers were dried over MgSO4, and concentrated under reduced pressure. Purification via silica gel column chromatography (30-50% EtOAc/isohexane) gave a pale yellow oil. A portion of this oil (780 mg, 2.74 mmol) was dissolved in THF (20 mL) and treated with 2 M aqueous HCl (3 mL). The reaction mixture was stirred at room temperature for 4 hr, heated at 60° C. for 7 hr and stirred at room temperature for 18 hr. Water (10 mL) was added and the mixture extracted with EtOAc (100 mL). The organic layer was washed with brine (20 mL), separated, dried over MgSO4 and concentrated under reduced pressure. Purification via silica gel column chromatography (25-40% EtOAc/isohexane) gave 4-fluoro-4-(2-methyl-4-nitro-pyrazol-3-yl)cyclohexanone as a white solid (490 mg, 30% over two steps). 1H NMR (400 MHz, CDCl3) δ 8.10 and 8.09 (2s, 1H), 4.17 and 4.15 (2s, 3H), 3.16-2.94 (m, 2H), 2.84-2.72 (m, 2H), 2.51 (dd, J=15.4, 5.6 Hz, 2H), 2.43-2.33 (m, 2H).

Workup

  1. temperatureAfter cooling to 0° C.
  2. extractiondropwise initially, and the mixture was extracted with DCM (2×75 mL)
  3. dry with materialThe combined organic layers were dried over MgSO4
  4. concentrationconcentrated under reduced pressure
  5. customPurification via silica gel column chromatography (30-50% EtOAc/isohexane)
  6. customgave a pale yellow oil
  7. stirringThe reaction mixture was stirred at room temperature for 4 hr
  8. temperatureheated at 60° C. for 7 hr
  9. stirringstirred at room temperature for 18 hr
  10. extractionthe mixture extracted with EtOAc (100 mL)
  11. washThe organic layer was washed with brine (20 mL)
  12. customseparated
  13. dry with materialdried over MgSO4
  14. concentrationconcentrated under reduced pressure
  15. customPurification via silica gel column chromatography (25-40% EtOAc/isohexane)

Sources & evidence

ORD record
ord-e42812a883b5478d9efa120946101118
Source dataset
uspto-grants-2013_12
Patent number
US08614206B2

Reaction notes

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