Acetic Acid → tert-Butyl 4-(benzyl(methyl)amino)piperidine-1-carboxylate

HRID 365419Notes

Reaction equation

HRID 365419 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[C:23](O)(=O)C.C([BH3-])#N.[Na+].C=O.[OH-].[Na+]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:22]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]

Participants

8

Reactant 6

HCID 176Acetic AcidHCID 712FormaldehydeHCID 7504BenzylamineHCID 14798Sodium HydroxideHCID 735900tert-Butyl 4-oxopiperidine-1-carboxylateHCID 5003444Sodium cyanoborohydride

Product 1

HCID 23292008tert-Butyl 4-(benzyl(methyl)amino)piperidine-1-carboxylateYield 87.4%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent2×

Procedure

To a stirred solution of 1-tert-butyloxycarbonyl-4-piperidone (3.30 g, 16.5 mmol) and benzylamine (1.64 ml, 15.0 mmol) in a mixture of methanol (150 ml) and glacial acetic acid (3.4 ml, 60 mmol) was added sodium cyanoborohydride (1.04 g, 16.5 mmol), and the resulting mixture was stirred at room temperature for 2 hours 15 minutes. A solution of formaldehyde (38% w/v aqueous solution; 1.42 ml) in methanol (5 ml) was added and stirring was continued for 16 hours. 4N Sodium hydroxide (35 ml) was added and the methanol was removed under vacuum. The residue was diluted with water (50 ml) and products were extracted with diethyl ether (2×300 ml). The combined organic phases were washed with brine (50 ml), dried (Na2SO4) and concentrated. Flash chromatography of the residue (silica gel, dichloromethane-methanol-ammonia, 97:3:0.2) followed by repurification of impure fractions on alumina (activity III, dichloromethane) afforded 3.98 g (87.4%) of the title compound as a colourless thick oil; δH (360 MHz, CDCl3) 1.46 (9H, s), 1.44-1.56 (2H, m), 1.76-1.85 (2H, m), 2.20 (3H, s), 2.52-2.76 (3H, m), 3.57 (2H, s), 4.10-4.22 (2H, m), 7.20-7.36 (5H, m); m/e (ES) 305 (M+ +1).

Workup

  1. stirringstirring
  2. waitwas continued for 16 hours
  3. customthe methanol was removed under vacuum
  4. additionThe residue was diluted with water (50 ml) and products
  5. extractionwere extracted with diethyl ether (2×300 ml)
  6. washThe combined organic phases were washed with brine (50 ml)
  7. dry with materialdried (Na2SO4)
  8. concentrationconcentrated
  9. customFlash chromatography of the residue (silica gel, dichloromethane-methanol-ammonia, 97:3:0.2) followed by repurification of impure fractions on alumina (activity III, dichloromethane)

Sources & evidence

ORD record
ord-7c7cb37a5d984d3fbb0730b11581e75f
Source dataset
uspto-grants-2000_10
Patent number
US06127388

Reaction notes

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