Ethyl Acrylate → tert-butyl (3RS,4RS)-4-[4-(2-ethoxycarbonyl-vinyl)-phenyl]-3-hydroxy-piperidine-1-carboxylate

HRID 1858611Notes

Reaction equation

HRID 1858611 reaction equation
Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]2[OH:21])=[CH:4][CH:3]=1.[C:22]([O:26][CH2:27][CH3:28])(=[O:25])[CH:23]=[CH2:24].C([O-])(=O)C.[Na+]>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[CH2:27]([O:26][C:22]([CH:23]=[CH:24][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]2[OH:21])=[CH:4][CH:3]=1)=[O:25])[CH3:28]

Participants

7

Reactant 3

HCID 8821Ethyl AcrylateHCID 517045Sodium AcetateHCID 54537313tert-butyl (3RS,4RS)-4-(4-bromophenyl)-3-hydroxy-piperidine-1-carboxylate

Product 1

HCID 86604399tert-butyl (3RS,4RS)-4-[4-(2-ethoxycarbonyl-vinyl)-phenyl]-3-hydroxy-piperidine-1-carboxylateYield 77.5%

Reagents, catalysts & solvents 3

HCID 80271Tri-o-tolylphosphineCatalyst2×HCID 167845palladium(II) acetateCatalyst2×HCID 6228DimethylformamideSolvent3×

Procedure

A Schlenk tube was charged under argon with 25.6 mg (0.114 mmol) of Pd(OAc)2, 69.6 mg (0.229 mmol) of tri(o-tolyl)phosphine and 20 ml of DMF (distilled under argon) and the reaction mixture was stirred at room temperature for 15 minutes. A 200 ml sulphonation flask was charged under argon and while stirring with 8.15 g (22.9 mmol) of tert-butyl (3RS,4RS)-4-(4-bromo-phenyl)-3-hydroxy-piperidine-1-carboxylate [Example 25(c)], 100 ml of DMF, 3.73 ml (34.3 mmol) of ethyl acrylate, 2.25 g (27.5 mmol) of sodium acetate and the yellow catalyst solution. The reaction mixture was stirred at 120° C. for 6 hours. In order to complete the reaction, a solution of 5.1 mg Pd(OAc)2 and 14.3 mg of tri(o-tolyl)phosphine in 5 ml of DMF was added after 5 hours. The dark reaction mixture was evaporated on a rotary evaporator. The grey solid residue was taken up in ether and the turbid solution was washed three times with water, dried over sodium sulphate and evaporated under reduced pressure. The yellow solid residue was chromatographed on 250 g of silica gel using a 2:1 mixture of hexane and ethyl acetate as the eluent. After crystallization from ethyl acetate there were obtained 6.66 g (77% of theory) of tert-butyl (3RS,4RS)-4-[4-(2-ethoxycarbonyl-vinyl)-phenyl]-3-hydroxy-piperidine-1-carboxylate as colourless crystals; MS: 376 (M+H)+.

Workup

  1. additionA 200 ml sulphonation flask was charged under argon
  2. stirringThe reaction mixture was stirred at 120° C. for 6 hours
  3. customthe reaction
  4. customThe dark reaction mixture
  5. customwas evaporated on a rotary evaporator
  6. washthe turbid solution was washed three times with water
  7. dry with materialdried over sodium sulphate
  8. customevaporated under reduced pressure
  9. customThe yellow solid residue was chromatographed on 250 g of silica gel using
  10. additiona 2:1 mixture of hexane and ethyl acetate as the eluent
  11. customAfter crystallization from ethyl acetate

Sources & evidence

ORD record
ord-1c5aa70c2c1146218b6f7cc08d9dc232
Source dataset
uspto-grants-2000_11
Patent number
US06150526

Reaction notes

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