Diisopropylamine → 4-Benzyloxy-1-[4-(4-chloro-benzenesulfonyl)-5,8-difluoro-chroman-3-yl]-butan-2-one

HRID 564321Notes

Reaction equation

HRID 564321 reaction equation
C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([O:20][CH2:21][CH2:22][C:23](=[O:25])[CH3:24])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([S:33]([C:36]2[C:45]3[C:40](=[C:41]([F:47])[CH:42]=[CH:43][C:44]=3[F:46])[O:39][CH2:38][CH:37]=2)(=[O:35])=[O:34])=[CH:29][CH:28]=1>C1COCC1.C(OCC)(=O)C.O>[CH2:13]([O:20][CH2:21][CH2:22][C:23](=[O:25])[CH2:24][CH:37]1[CH:36]([S:33]([C:30]2[CH:29]=[CH:28][C:27]([Cl:26])=[CH:32][CH:31]=2)(=[O:35])=[O:34])[C:45]2[C:40](=[C:41]([F:47])[CH:42]=[CH:43][C:44]=2[F:46])[O:39][CH2:38]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1

Participants

8

Reactant 4

HCID 7912DiisopropylamineHCID 2345114-(Benzyloxy)butan-2-oneHCID 582522424-((4-Chlorophenyl)sulfonyl)-5,8-difluoro-2H-chromeneHCID 178418339Butyllithium

Product 1

HCID 670063444-Benzyloxy-1-[4-(4-chloro-benzenesulfonyl)-5,8-difluoro-chroman-3-yl]-butan-2-one

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent3×HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
0 °C

Procedure

Diisopropylamine (1.23 g, 12.2 mmole) was dissolved in 150 ml dry THF and the reaction was cooled to 0° C. n-Butyllithium (2.5 ml in Hexane, 4.5 ml, 11.2 mmole) was added and the reaction was stirred at 0° C. for 10 minutes. The reaction was cooled to −100° C. and 4-benzyloxy-2-butanone (1.83 g, 10.3 mmole) in 50 ml dry THF (pre-cooled to −78° C.) was added. The reaction was stirred for 30 minutes at −78° C. 4-(4-Chloro-benzenesulfonyl)-5,8-difluoro-2H-chromene (3.2 g, 9.36 mmole) in 20 ml THF (pre-cooled to −78° C.) was added. The reaction was stirred at −78° C. for 1 hour. 20 ml water was added at −78° C. to quench the reaction. After the reaction was warmed up to room temperature, 200 ml EtOAc was added. The organic layer washed with brine (2×100 ml), dried over Na2SO4 and concentrated. The product was purified by column chromatography (EtOAc/hexane from 0/100 to 40/60 in 45 minute). Yield, 2.6 g, 53%. 1H NMR (CDCl3 400 MHz δ 7.82 (d, J=8.8 Hz, 2H), 7.54 (d, J=8.1 Hz, 2H), 7.20-7.35 (m, 5H), 7.05 (m, 1H), 6.47 (m, 1H), 4.89 (dd, J=11.7 and 2.9 Hz, 1H), 4.42 (s, 3H), 4.24 (dt, J=12.4 and 2.2 Hz, 1H), 3.65 (t, J=5.9 Hz, 2H), 3.31 (m, 1H), 2.33-2.67 (m, 4H).

Workup

  1. additionwas added
  2. temperatureThe reaction was cooled to −100° C.
  3. stirringThe reaction was stirred for 30 minutes at −78° C
  4. stirringThe reaction was stirred at −78° C. for 1 hour
  5. customto quench
  6. customthe reaction
  7. temperatureAfter the reaction was warmed up to room temperature
  8. washThe organic layer washed with brine (2×100 ml)
  9. dry with materialdried over Na2SO4
  10. concentrationconcentrated
  11. customThe product was purified by column chromatography (EtOAc/hexane from 0/100 to 40/60 in 45 minute)
  12. customYield

Sources & evidence

ORD record
ord-49058df9a06c4822a65559889913bc09
Source dataset
uspto-grants-2011_11
Patent number
US08067621B2

Reaction notes

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