Ethyl Acetate → (3R,4R)-tert-butyl 3-fluoro-4-(4-hydroxyphenyl)piperidine-1-carboxylate

HRID 1507230Notes

Reaction equation

HRID 1507230 reaction equation
O[C@@H:2]1[C@@H:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1.CCN(S(F)(F)[F:28])CC.C(OCC)(=O)C>C(Cl)Cl>[F:28][C@@H:2]1[C@@H:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1

Participants

5

Reactant 3

HCID 8857Ethyl AcetateHCID 123472(Diethylamino)sulfur trifluorideHCID 11483231(3R,4R)-tert-Butyl 3-hydroxy-4-(4-hydroxyphenyl)piperidine-1-carboxylate

Product 1

HCID 118207316(3R,4R)-tert-butyl 3-fluoro-4-(4-hydroxyphenyl)piperidine-1-carboxylateYield 80.4%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a solution of (3R,4R)-tert-butyl 3-hydroxy-4-(4-hydroxyphenyl)piperidine-1-carboxylate (MG Bursavich et al; Organic Letters 2001, 3, 2317, 150 mg, 0.51 mmol) in 5 mL of DCM at −78° C. under nitrogen was added DAST (0.2 mL, 1.5 mmol). The mixture was allowed to warm up to rt with stirring over 3 h. To the mixture was added 100 mL of ethyl acetate and the organic layer was separated, washed with a saturated NaHCO3 solution, and then evaporated under vacuum. The residue was purified via silica gel chromatography eluting with 0-100% ethyl acetate/hexanes to give (3R,4R)-tert-butyl 3-fluoro-4-(4-hydroxyphenyl)piperidine-1-carboxylate (120 mg, 0.41 mmol); LCMS (Method T) RT 3.09 min, m/z 294.3. (M−H)−; 1H NMR (500 MHz, chloroform-d) δ 7.11 (d, J=8.5 Hz, 2H), 6.93 (br. s., 1H), 6.89-6.82 (m, 2H), 4.56-4.47 (m, 1H), 4.45-4.38 (m, 1H), 4.16 (d, J=7.2 Hz, 1H), 2.89-2.69 (m, 3H), 1.89-1.83 (m, 1H), 1.76-1.65 (m, 1H), 1.53 (s, 9H).

Workup

  1. customthe organic layer was separated
  2. washwashed with a saturated NaHCO3 solution
  3. customevaporated under vacuum
  4. customThe residue was purified via silica gel chromatography
  5. washeluting with 0-100% ethyl acetate/hexanes

Sources & evidence

ORD record
ord-3d0a81f4648a479eb23156bfe8cb1723
Source dataset
uspto-grants-2015_12
Patent number
US09221796B2

Reaction notes

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