Ammonium Chloride → HCID 67513649, compound

HRID 1508481Notes

Reaction equation

HRID 1508481 reaction equation
Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[F:10].[Li]CCCC.[O:16]=[C:17]1[CH2:20][CH:19]([C:21]([O:23][CH3:24])=[O:22])[CH2:18]1.[NH4+].[Cl-]>C1COCC1.CCOCC>[F:10][C:3]1[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=1[C:17]1([OH:16])[CH2:20][CH:19]([C:21]([O:23][CH3:24])=[O:22])[CH2:18]1

Participants

7

Reactant 4

HCID 25517Ammonium ChlorideHCID 37184441-Bromo-2-fluoro-4-methoxybenzeneHCID 13992367Methyl 3-oxocyclobutane-1-carboxylateHCID 178418339Butyllithium

Product 1

HCID 67513649HCID 67513649, compoundYield 45.4%

Reagents, catalysts & solvents 2

HCID 3283Diethyl EtherSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
-78 °C

Procedure

To a dry and N2 flashed flask was added 4-bromo-3-fluoroanisole (1.04 g, 5.07 mmol) in THF (6 mL) under N2. This was cooled to −78° C., and n-BuLi (1.72 mL, 4.29 mmol) was added. The reaction was stirred at −78° C. for 30 min. The mixture above was added via cannula to a stirred solution of methyl 3-oxocyclobutane carboxylate (500 mg, 3.90 mmol) in dry Et2O (35 mL) at −78° C. under N2. The reaction mixture was allowed to warm to room temperature and was stirred for 1 h. Satd aq. NH4Cl was added and the mixture was stirred until a clear solution resulted. This mixture was extracted with Et2O (3×). The combined extracts were dried (MgSO4) and concentrated in vacuo to give the crude product, which was purified by flash chromatography (Biotage Horizon, 40M, Si, ˜30 mL/min, 100% hexanes for 260 mL, gradient to 40% EtOAc in hexanes over 5184 mL) to afford methyl 3-(2-fluoro-4-methoxyphenyl)-3-hydroxycyclobutanecarboxylate (450 mg, 45%). 1H NMR (500 MHz, CDCl3): δ 7.32 (t, J=8.9 Hz, 1H); 6.69-6.63 (m, 2H); 3.80 (s, 3H); 3.74 (s, 3H); 3.40 (s, 1H); 3.03-2.93 (m, 2H); 2.90-2.82 (m, 1H); 2.67-2.61 (m, 2H).

Workup

  1. customTo a dry
  2. temperatureto warm to room temperature
  3. stirringwas stirred for 1 h
  4. stirringthe mixture was stirred until a clear solution
  5. customresulted
  6. extractionThis mixture was extracted with Et2O (3×)
  7. dry with materialThe combined extracts were dried (MgSO4)
  8. concentrationconcentrated in vacuo
  9. customto give the crude product, which
  10. customwas purified by flash chromatography (Biotage Horizon, 40M, Si, ˜30 mL/min, 100% hexanes for 260 mL, gradient to 40% EtOAc in hexanes over 5184 mL)

Sources & evidence

ORD record
ord-adb2621a9ba5443093d670a3d50ca9e3
Source dataset
uspto-grants-2015_12
Patent number
US09221834B2

Reaction notes

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