1-Benzyl-4-piperidone → 1-Benzyl-4-(2-fluorobenzyl)piperidin-4-ol

HRID 1004398Notes

Reaction equation

HRID 1004398 reaction equation
[CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:15][C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1[CH2:18][Mg]Br>C(OCC)C>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([CH2:18][C:17]2[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=2[F:15])([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1

Participants

4

Reactant 2

HCID 192201-Benzyl-4-piperidoneHCID 178505626HCID 178505626, compound

Product 1

HCID 127332241-Benzyl-4-(2-fluorobenzyl)piperidin-4-olYield 56.7%

Reagents, catalysts & solvents 1

HCID 3283Diethyl EtherSolvent

Conditions

Temperature
-4 °C

Procedure

1-Benzyl-4-piperidone (10 g, 53 mmol) in diethyl ether (80 ml) was added dropwise to a cooled (-4° C.), stirred mixture of 2-fluorobenzyl magnesium bromide (prepared from magnesium and 2-fluorobenzyl bromide (9.56 ml, 80 mmol) in diethyl ether (65 ml)) under an atmosphere of nitrogen. The reaction mixture was stirred whilst warming to room temperature (30 minutes) then at room temperature for 20 minutes. The reaction mixture was quenched with 2M hydrochloric acid (100 ml). The aqueous was separated and washed with diethyl ether (100 ml). The aqueous was basified with 2M sodium hydroxide solution then exhaustively extracted with dichloromethane. The combined organics were dried (sodium sulphate) then evaporated to give crude 1-benzyl-4-(2-fluorobenzyl)-4-hydroxypiperidine as a gum (9.0 g). This crude product in methanol (100 ml) was treated with formic acid (6 ml), ammonium formate (9.5 g, 0.15 mol) and 10% palladium on carbon (900 mg). The mixture was stirred whilst heating at reflux for 4 hours, cooled, filtered then evaporated to afford 4-(2-fluorobenzyl)-4-hydroxypiperidine as a gum (3.4 g); m/z (ES) 210 (M+ +1). This amine (3.35 g, 16 mmol) in dichloromethane (75 ml) was treated with di-t-butyldicarbonate (3.5 g, 16 mmol) and stirred at ambient temperature for 18 hours, washed with aqueous 10% citric acid, dried (potassium carbonate), evaporated to give a gum which was purified by column chromatography on silica using ethyl acetate/n-hexane (1:1) to afford the title compound as a colourless, viscous gum (3.62 g, 73%). δH (360 MHz, CDCl3) 1.46 (9H, s, (CH3)3C), 1.48 (2H, d, J=13 Hz, 2×CH), 1.63 (2H, ddd, J1 =5, J2 =13, J3 =17 Hz, 2×CH), 2.82 (2H, d, J=1 Hz, CH2Ph), 3.11 (2H, ddd, J1 =3, J2 =J3 =13 Hz, 2×CH), 3.84 (2H, d, J=13 Hz, 2×CH), 7.02-7.27 (4H, m, C6H4); m/z (ES) 310 (M+ +1).

Workup

  1. stirringThe reaction mixture was stirred
  2. temperaturewhilst warming to room temperature (30 minutes)
  3. customThe reaction mixture was quenched with 2M hydrochloric acid (100 ml)
  4. customThe aqueous was separated
  5. washwashed with diethyl ether (100 ml)
  6. extractionthen exhaustively extracted with dichloromethane
  7. dry with materialThe combined organics were dried (sodium sulphate)
  8. customthen evaporated

Sources & evidence

ORD record
ord-4b63cd5862d1446abf17c9b4c202ef95
Source dataset
uspto-grants-2000_04
Patent number
US06048878

Reaction notes

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