4-Bromo-2-fluoroanisole → tert-Butyl 4-(3-fluoro-4-methoxyphenyl)-4-hydroxypiperidine-1-carboxylate

HRID 1507190Notes

Reaction equation

HRID 1507190 reaction equation
Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([F:10])[CH:3]=1.C([Li])CCC.[O:16]=[C:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1>O1CCCC1>[F:10][C:4]1[CH:3]=[C:2]([C:17]2([OH:16])[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])[CH2:21][CH2:22]2)[CH:7]=[CH:6][C:5]=1[O:8][CH3:9]

Participants

5

Reactant 3

HCID 753784-Bromo-2-fluoroanisoleHCID 735900tert-Butyl 4-oxopiperidine-1-carboxylateHCID 178418339Butyllithium

Product 1

HCID 118207351tert-Butyl 4-(3-fluoro-4-methoxyphenyl)-4-hydroxypiperidine-1-carboxylateYield 63.4%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

To a solution of 4-bromo-2-fluoro-1-methoxybenzene (2 g, 9.7 mmol) in tetrahydrofuran (100 mL) at −78° C. was added a solution of n-butyllithium (1.6 M in hexanes, 7.9 mL, 12.7 mmol). The reaction mixture was stirred in the cold for 2 h, and then a solution of tert-butyl 4-oxopiperidine-1-carboxylate (1.94 g, 9.7 mmol) in THF (10 mL) was added dropwise. The mixture was then allowed to warm to rt and stir for 12 h. It was quenched with a saturated NH4Cl solution and diluted with ethyl acetate. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure. The crude product was purified by silica gel chromatography to provide 2.0 g (63%) of the desired compound; 1H NMR (400 MHz, DMSO-d6) δ 7.29 (dd, J=13.3, 2.3 Hz, 1H), 7.24-7.18 (m, 1H), 7.10 (t, J=8.0 Hz, 1H), 5.09 (s, 1H), 3.85 (br. s., 2H), 3.82 (s, 3H), 1.86-1.68 (m, 2H), 1.56 (d, J=12.0 Hz, 3H), 1.46-1.38 (m, 11H).

Workup

  1. stirringstir for 12 h
  2. customIt was quenched with a saturated NH4Cl solution
  3. additiondiluted with ethyl acetate
  4. customThe organic layer was separated
  5. washwashed with brine
  6. dry with materialdried over anhydrous Na2SO4
  7. filtrationfiltered
  8. customevaporated under reduced pressure
  9. customThe crude product was purified by silica gel chromatography

Sources & evidence

ORD record
ord-d3f4782624fa40eeb521fc0af4e17750
Source dataset
uspto-grants-2015_12
Patent number
US09221796B2

Reaction notes

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