Acetone → 3-Bromo-5-methoxy-α,α-dimethylbenzenemethanol

Temperature

-70 °C

To a solution of 1,3-dibromo-5-methoxy-benzene (20.7 g, 78 mmol) in dry THF (100 mL) was added under nitrogen a 1.6 M solution of nBuLi in hexane (48.7 mL, 78 mmol) at such a rate that the reaction temperature did not rise above −50° C. After the addition the mixture was cooled to −70° C. and acetone (6.86 mL, 78 mmol) was added over a 5 min period. After 2 min the reaction was quenched with saturated NH4Cl solution and stirred for 10 min. The mixture was diluted with water and extracted with TBME. The organic layer was dried with MgSO4, filtered and evaporated. Chromatographic purification over silica gel (hexane-EtOAc 95:5 to 85:15) provided impure 2-(3-bromo-5-methoxy-phenyl)-propan-2-ol as a yellow oil: TLC (hexane-AcOEt 6:1) Rf=0.22; HPLC RtH1=2.35 min; ESIMS [M−OH]−=227,229; 1H NMR (400 MHz, CDCl3): δ 7.27 (t, 1H), 7.02 (dd, 1H), 6.97 (dd, 1H), 3.83 (s, 3H), 1.59 (s, 6H). This material was treated with (±) camphor sulfonic acid (70 mg) in refluxing hexane with the azeotropical removal of water. After 1 h the cooled reaction mixture is diluted with TBME, washed with 5% aq. NaHCO3, dried with MgSO4, filtered and evaporated. Chromatographic purification over silica gel (hexane-toluene 0-10%) gave impure 1-bromo-3-iso-propenyl-5-methoxy-benzene as a slightly yellow oil: 1H NMR (400 MHz, CDCl3): δ 7.27 (t, 1H), 7.07 (s, 1H), 6.99 (s, 1H), 5.48 (s, 1H), 5.16 (s, 1H), 3.75 (s, 3H), 2.07 (s, 3H). This material was stirred in the presence of Ra—Ni catalyst (5 g) in EtOH (15 mL) under a hydrogen atmosphere for 18 h. The mixture was filtered over a bed of Celite and evaporated to obtain a yellow oil that contained still some starting material. It was taken up in CH2Cl2 (10 mL) and treated with meta-chlorperbenzoic acid (250 mg). The mixture was washed with sodium sulfite solution, followed by water and evaporated. Chromatography over silica gel (hexane-CH2Cl2 100:1 to 9:1) gave the title compound as a colorless oil: TLC (hexane-EtOAc 9:1) Rf=0.50; HPLC RtH1=3.79 min; 1H NMR (400 MHz, CDCl3): δ 6.97 (t, 1H), 6.86 (t, 1H), 6.69 (t, 1H), 3.78 (s, 3H), 2.84 (heptet, 1H), 1.22 (d, 6H).

1. customdid not rise above −50° C
2. additionAfter the addition the mixture
3. customAfter 2 min the reaction was quenched with saturated NH4Cl solution
4. additionThe mixture was diluted with water
5. extractionextracted with TBME
6. dry with materialThe organic layer was dried with MgSO4
7. filtrationfiltered
8. customevaporated
9. customChromatographic purification over silica gel (hexane-EtOAc 95:5 to 85:15)

ORD record

ord-4d25460066ec49cd95a9875c49e59d7d

Source dataset

uspto-grants-2012_01

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08093406B2