Iodine → Ethyl 3-(3,4-dichlorophenyl)-1-methylpiperidine-4-carboxylate

HRID 2047432Notes

Reaction equation

HRID 2047432 reaction equation
[Mg].II.[Cl:4][C:5]1[CH:6]=[C:7](Br)[CH:8]=[CH:9][C:10]=1[Cl:11].ClC1C=C(Br)C=CC=1Cl.C(OCC)C.[CH3:27][N:28]1[CH2:33][CH:32]=[C:31]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:30][CH2:29]1>C(OCC)C.O>[Cl:4][C:5]1[CH:6]=[C:7]([CH:32]2[CH:31]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:30][CH2:29][N:28]([CH3:27])[CH2:33]2)[CH:8]=[CH:9][C:10]=1[Cl:11]

Participants

8

Reactant 5

HCID 807IodineHCID 290134-Bromo-1,2-dichlorobenzeneHCID 566021Ethyl 1-methyl-1,2,3,6-tetrahydro-4-pyridinecarboxylateHCID 5462224MagnesiumHCID 672334723,4-Dichlorobromobenzene diethyl ether

Product 1

HCID 67231835Ethyl 3-(3,4-dichlorophenyl)-1-methylpiperidine-4-carboxylateYield 71.9%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 3283Diethyl EtherSolvent3×

Conditions

Temperature
37.5 °C

Procedure

To a suspension of magnesium (10.76 g) in diethyl ether (110 mL) was added a trace amount of iodine. About 1/10 amount of a solution of 3,4-dichlorobromobenzene (100 g) in diethyl ether (110 ml) was added slowly at 35-40° C., and the mixture was vigorously stirred until the reaction started. Once the initiation was occurred, the rest of 3,4-dichlorobromobenzene/diethyl ether solution was added slowly with cooling to maintain the reaction temperature at 35-40° C. When everything was added, and the mixture was stirred at 40° C. for 1 hr, then cooled to 0° C. To the reaction mixture was added copper iodide(I) (12.6 g), and the compound (56.2 g) obtained in step 1 was slowly added dropwise at 0° C. The reaction mixture was stirred at 0° C. for 1 hr, and further at room temperature for 1 hr. The reaction mixture was poured into water (40 mL), diethyl ether (500 mL) was added, and the precipitate was removed by decantation. The reaction solution was washed with aqueous ammonium chloride solution and saturated brine and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 20% ethyl acetate/hexane→>2.5% aqueous ammonia/17.5% methanol/ethyl acetate) to give crude ethyl 3-(3,4-dichlorophenyl)-1-methylpiperidine-4-carboxylate (cis/trans mixture) (75.5 g) as a brown oil.

Workup

  1. temperaturewith cooling
  2. additionWhen everything was added
  3. stirringthe mixture was stirred at 40° C. for 1 hr
  4. temperaturecooled to 0° C
  5. stirringThe reaction mixture was stirred at 0° C. for 1 hr
  6. additionwas added
  7. customthe precipitate was removed by decantation
  8. washThe reaction solution was washed with aqueous ammonium chloride solution and saturated brine
  9. customdried
  10. customthe solvent was evaporated under reduced pressure
  11. customThe obtained residue was purified by silica gel column chromatography (solvent gradient; 20% ethyl acetate/hexane→>2.5% aqueous ammonia/17.5% methanol/ethyl acetate)

Sources & evidence

ORD record
ord-c6da8e71da744a49810663f6d53966f6
Source dataset
uspto-grants-2013_11
Patent number
US08592454B2

Reaction notes

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