Tetrahydrothiopyran-4-one → 4-{4-[4-(4-Hydroxy-tetrahydro-thiopyran-4-yl)-3-methyl-phenoxymethyl]-phenyl}-piperidine-1-carboxylic acid tert-butyl ester

HRID 2100673Notes

Reaction equation

HRID 2100673 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25](Br)=[C:24]([CH3:29])[CH:23]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.[S:35]1[CH2:40][CH2:39][C:38](=[O:41])[CH2:37][CH2:36]1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([C:38]4([OH:41])[CH2:39][CH2:40][S:35][CH2:36][CH2:37]4)=[C:24]([CH3:29])[CH:23]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]

Participants

5

Reactant 3

HCID 66173Tetrahydrothiopyran-4-oneHCID 688122784-[4-(4-Bromo-3-methyl-phenoxymethyl)-phenyl]-piperidine-1-carboxylic acid tert-butyl esterHCID 178418339Butyllithium

Product 1

HCID 688162544-{4-[4-(4-Hydroxy-tetrahydro-thiopyran-4-yl)-3-methyl-phenoxymethyl]-phenyl}-piperidine-1-carboxylic acid tert-butyl ester

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-78 °C

Procedure

To a solution of 4-[4-(4-Bromo-3-methyl-phenoxymethyl)-phenyl]-piperidine-1-carboxylic acid tert-butyl ester (409 mg, 0.8884 mmol) in dry THF (5 mL) cooled to −78° C. is added n-BuLi (1.6 M in hexanes, 1.1 eq., 0.9772 mmol, 0.61 mL). The resulting mixture is stirred at −78° C. for 30 minutes and a solution of tetrahydro-thiopyran-4-one (1.1 eq., 0.9772 mmol, 114 mg) in dry THF (0.5 mL) is then added dropwise. After 30 minutes, the reaction mixture is quenched with saturated aqueous NH4Cl and warmed to room temperature. The reaction mixture is diluted with EtOAc and washed sequentially with H2O and saturated aqueous NaCl. The organic solution is dried over Na2SO4. After concentration, the residue is partially purified by silica gel chromatography (3:1 hexanes/EtOAc) to give crude 4-{4-[4-(4-Hydroxy-tetrahydro-thiopyran-4-yl)-3-methyl-phenoxymethyl]-phenyl}-piperidine-1-carboxylic acid tert-butyl ester.

Workup

  1. waitAfter 30 minutes
  2. customthe reaction mixture is quenched with saturated aqueous NH4Cl
  3. temperaturewarmed to room temperature
  4. additionThe reaction mixture is diluted with EtOAc
  5. washwashed sequentially with H2O and saturated aqueous NaCl
  6. dry with materialThe organic solution is dried over Na2SO4
  7. concentrationAfter concentration
  8. customthe residue is partially purified by silica gel chromatography (3:1 hexanes/EtOAc)

Sources & evidence

ORD record
ord-5c16a9c4aa61408da338841f191977c4
Source dataset
uspto-grants-2009_08
Patent number
US07572811B2

Reaction notes

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