Piperidine → (R)-((S)-1-phenylethyl)2-(2-fluorophenyl)-2-(piperidin-1-yl)acetate

HRID 417899Notes

Reaction equation

HRID 417899 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][C@H:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:13])=[O:10].[CH2:20]1[CH2:30][CH2:29][N:28]2C(=NC[CH2:26][CH2:27]2)CC1.C(Br)(Br)(Br)Br.N1CCCCC1>C1COCC1.C(OCC)C.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:8]([N:28]1[CH2:27][CH2:26][CH2:20][CH2:30][CH2:29]1)[C:9]([O:11][C@H:12]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH3:13])=[O:10]

Participants

7

Reactant 4

HCID 8082PiperidineHCID 11205Carbon tetrabromideHCID 811841,8-Diazabicyclo(5.4.0)undec-7-eneHCID 66648658(S)-1-Phenylethyl 2-(2-fluorophenyl)acetate

Product 1

HCID 59166523(R)-((S)-1-phenylethyl)2-(2-fluorophenyl)-2-(piperidin-1-yl)acetateYield 11.1%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolvent2×HCID 22238780Ether tolueneSolvent

Conditions

Temperature
-78 °C

Procedure

To a solution of (S)-1-phenylethyl 2-(2-fluorophenyl)acetate (5.00 g, 19.4 mmol) in THF (1200 mL) at 0° C. was added DBU (6.19 g, 40.7 mmol) and the solution was allowed to warn to room temperature while stirring for 30 minutes. The solution was then cooled to −78° C. and a solution of CBr4 (13.5 g, 40.7 mmol) in THF (100 mL) was added and the mixture was allowed to warn to −10° C. and stirred at this temperature for 2 hours. The reaction mixture was quenched with saturated aq. NH4Cl and the layers were separated. The aqueous layer was back-extracted with ethyl acetate (2×) and the combined organic phases were washed (H2O, brine), dried (Na2SO4), filtered, and concentrated in vacuo. To the residue was added piperidine (5.73 mL, 58.1 mmol) and the solution was stirred at room temperature for 24 hours. The volatiles were then concentrated in vacuo and the residue was purified by silica gel chromatography (Biotage/0-30% diethyl ether-hexane) to provide a pure mixture of diastereomers (2:1 ratio by 1H NMR) as a yellow oil (2.07 g, 31%), along with unreacted starting material (2.53 g, 51%). Further chromatography of the diastereomeric mixture (Biotage/0-10% diethyl ether-toluene) provided the title compound as a colorless oil (0.737 g, 11%). 1H NMR (400 MHz, CD3OD) δ 7.52 (ddd, J=9.4, 7.6, 1.8 Hz, 1H), 7.33-7.40 (m, 1), 7.23-7.23 (m, 4H), 7.02-7.23 (m, 4H), 5.86 (q, J=6.6 Hz, 1H), 4.45 (s, 1H), 2.39-2.45 (m, 4H), 1.52-1.58 (m, 4H), 1.40-1.42 (m, 1H), 1.38 (d, J=6.6 Hz, 3H). LCMS: Anal. Calcd. for C21H24FNO2: 341; found: 342 (M+H)+.

Workup

  1. customto warn to room temperature
  2. customto warn to −10° C.
  3. stirringstirred at this temperature for 2 hours
  4. customThe reaction mixture was quenched with saturated aq. NH4Cl
  5. customthe layers were separated
  6. extractionThe aqueous layer was back-extracted with ethyl acetate (2×)
  7. washthe combined organic phases were washed (H2O, brine)
  8. dry with materialdried (Na2SO4)
  9. filtrationfiltered
  10. concentrationconcentrated in vacuo
  11. stirringthe solution was stirred at room temperature for 24 hours
  12. concentrationThe volatiles were then concentrated in vacuo
  13. customthe residue was purified by silica gel chromatography (Biotage/0-30% diethyl ether-hexane)
  14. customto provide

Sources & evidence

ORD record
ord-da0b1f78e87d402e938d8c2fc36cef32
Source dataset
uspto-grants-2012_01
Patent number
US08093243B2

Reaction notes

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