Tetrahydrofuran → HCID 60055231, compound

HRID 544799Notes

Reaction equation

HRID 544799 reaction equation
Br[C:2]1[C:3]([CH3:15])=[C:4]([C:8]2[O:9][CH2:10][C:11]([CH3:14])([CH3:13])[N:12]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:16]1[CH2:20]OC[CH2:17]1.C([Mg]Cl)(C)C>[Ni].Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1.CCOCC>[CH:16]([C:2]1[C:3]([CH3:15])=[C:4]([C:8]2[O:9][CH2:10][C:11]([CH3:14])([CH3:13])[N:12]=2)[CH:5]=[CH:6][CH:7]=1)([CH3:20])[CH3:17]

Participants

7

Reactant 3

HCID 8028TetrahydrofuranHCID 60055238HCID 60055238, compoundHCID 178418918HCID 178418918, compound2×

Product 1

HCID 60055231HCID 60055231, compound

Reagents, catalysts & solvents 3

HCID 935NickelCatalystHCID 178418745HCID 178418745, compoundCatalyst2×HCID 3283Diethyl EtherSolvent

Conditions

Temperature
15 °C

Procedure

A dry 3-neck 250 mL round bottom flask equipped with magnetic stirring and held under a nitrogen atmosphere was charged with 5.0 g 2-(3-bromo-2-methyl-phenyl)-4,4-dimethyl-4,5-dihydro-oxazole, 60 mL anhydrous THF, and 100 mg Ni(dppp)Cl2. The mixture was cooled to 15° C., and isopropyl magnesium chloride (11 mL, 2M in ethyl ether) was added. A mild exotherm took place, and the mixture darkened slightly. The reaction was stirred overnight at room temperature, at which point 1H NMR indicated 50% completion. Addition of ca 75 mg Ni(dppp)Cl2 and reflux for 3 hours resulted in no further progression of the reaction. The mixture was cooled to 15° C., and an additional 13 mL of isopropyl magnesium chloride (2M in ethyl ether) and 100 mg of nickel catalyst were added and the mixture was stirred overnight at room temperature. The reaction was quenched with saturated aqueous NH4Cl, the organic layer was removed, the aqueous layer was extracted, and the organic phases were combined and dried. The solvent was removed in vacuo to yield 3.84 g crude product as a yellow oil. Column chromatography on silica gel using 4:1 hexanes: ether as eluant yielded 0.79 g of 2-(3-isopropyl-2-methyl-phenyl)-4,4-dimethyl-4,5-dihydro-oxazole as a colorless oil. 1H NMR (CDCl3, 200 MHz), δ (ppm): 7.5 (d, 1H), 7.37 (d, 1H), 7.22 (t, 1H), 4.13 (s, 2H), 3.23 (m, 1H), 2.5 (s, 3H), 1.45 (s, 6H), 1.22 (d, 6H). The oxazoline was suspended in 34 mL of 6N HCl and refluxed in an oil bath for 6 hours. The mixture was cooled and extracted with CH2Cl2. The extract was dried over Na2SO4 and evaporated to yield 0.76 g of 3-isopropyl-2-methyl-benzoic acid, suitably pure for the next step. 1H NMR (CDCl3, 300 MHz), δ (ppm): 7.8 (d, 1H), 7.48 (d, 1H), 7.3 (t, 1H), 3.3 (m, 1H), 2.55 (s, 3H), 1.2 (d, 6H).

Workup

  1. customA dry 3-neck 250 mL round bottom flask equipped
  2. stirringThe reaction was stirred overnight at room temperature, at which point 1H NMR
  3. temperaturereflux for 3 hours
  4. customresulted in no further progression of the reaction
  5. temperatureThe mixture was cooled to 15° C.
  6. stirringthe mixture was stirred overnight at room temperature
  7. customThe reaction was quenched with saturated aqueous NH4Cl
  8. customthe organic layer was removed
  9. extractionthe aqueous layer was extracted
  10. customdried
  11. customThe solvent was removed in vacuo
  12. customto yield 3.84 g crude product as a yellow oil

Sources & evidence

ORD record
ord-f472c7b653234c02983d72c766833476
Source dataset
uspto-grants-2011_05
Patent number
US07935510B2

Reaction notes

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