Diethyl Ether → 3-(4-fluorophenyl)-3-isobutylfuro[3,4-c]pyridin-1(3H)-one

HRID 1747728Notes

Reaction equation

HRID 1747728 reaction equation
[Li+].C[CH:3]([N-:5][CH:6]([CH3:8])C)[CH3:4].[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:21])[CH2:17][CH:18]([CH3:20])[CH3:19])=[CH:12][CH:11]=1.[CH2:22]([O:24]CC)[CH3:23]>>[F:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2([CH2:17][CH:18]([CH3:19])[CH3:20])[C:8]3[CH:6]=[N:5][CH:3]=[CH:4][C:23]=3[C:22](=[O:24])[O:21]2)=[CH:14][CH:15]=1

Participants

4

Reactant 3

HCID 3283Diethyl Ether3×HCID 2724682Lithium diisopropylamideHCID 206446201-(4-Fluorophenyl)-3-methyl-1-butanone

Product 1

HCID 716102803-(4-fluorophenyl)-3-isobutylfuro[3,4-c]pyridin-1(3H)-oneYield 7%

Conditions

Temperature
-78 °C

Procedure

To a solution of 4-diisopropylamidopyridine (3.2 g, 15.54 mmol) in anhydrous diethyl ether (160 mL) at −78° C. was added a 1M solution of LDA in diethyl ether (23.27 mL) and the reaction mixture stirred at −78° C. for 2 hours. A solution of 1-(4-fluorophenyl)-3-methylbutan-1-one (3.5 g, 19.42 mmol) in anhydrous diethyl ether (5 mL) was added dropwise, and the reaction was stirred at −78° C. for 30 min. The reaction mixture was quenched with brine (100 mL), extracted with ethyl acetate (3×50 mL), dried (MgSO4), and concentrated. The crude mixture was stirred with 6 N HCl (50 mL) for 12 hours, then cooled to 0° C. Sodium hydroxyde (15 g, 37.5 mmol) was added in 3 portions, the reaction mixture was stirred at 0° C. for 30 min, then extracted with ethyl acetate (3×100 mL). The organic layers were dried (MgSO4), concentrated and purified by column chromatography (40 g, SiO2, 0 to 40% ethyl acetate in hexanes) to provide 3-(4-fluorophenyl)-3-isobutylfuro[3,4-c]pyridin-1(3H)-one (296 mg, 7%) as an off-white solid. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.80-0.91 (m, 6H), 1.54-1.66 (m, 1H), 2.06 (dd, J=14.88, 6.97 Hz, 1H), 2.48 (dd, J=15.07, 5.27 Hz, 1H), 7.04-7.14 (m, 2H), 7.46-7.56 (m, 2H), 7.77 (dd, J=5.09, 0.94 Hz, 1H), 8.85 (d, J=4.90 Hz, 1H), 9.01 (s, 1H); MS m/z 286 (M+H)+.

Workup

  1. stirringthe reaction was stirred at −78° C. for 30 min
  2. customThe reaction mixture was quenched with brine (100 mL)
  3. extractionextracted with ethyl acetate (3×50 mL)
  4. dry with materialdried (MgSO4)
  5. concentrationconcentrated
  6. stirringThe crude mixture was stirred with 6 N HCl (50 mL) for 12 hours
  7. temperaturecooled to 0° C
  8. additionSodium hydroxyde (15 g, 37.5 mmol) was added in 3 portions
  9. stirringthe reaction mixture was stirred at 0° C. for 30 min
  10. extractionextracted with ethyl acetate (3×100 mL)
  11. dry with materialThe organic layers were dried (MgSO4)
  12. concentrationconcentrated
  13. custompurified by column chromatography (40 g, SiO2, 0 to 40% ethyl acetate in hexanes)

Sources & evidence

ORD record
ord-0e49da4bcc8041f489fba08f49c75334
Source dataset
uspto-grants-2015_10
Patent number
US09150582B2

Reaction notes

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