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

HRID 1260906Notes

Reaction equation

HRID 1260906 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.[Cu]I.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

9

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 3

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 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 one-tenth 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. When the reaction started, the rest of the 3,4-dichlorobromobenzene/diethyl ether solution was added slowly while cooling the reaction mixture to 35-40° C. When all was added, the mixture was stirred at 40° C. for 1 hr, and then cooled to 0° C. To the reaction mixture was added copper(I) iodide (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 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 mixture was washed with aqueous ammonium chloride solution and 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. additionWhen all was added
  2. stirringthe mixture was stirred at 40° C. for 1 hr
  3. temperaturecooled to 0° C
  4. stirringThe reaction mixture was stirred at 0° C. for 1 hr
  5. additionwas added
  6. customthe precipitate was removed by decantation
  7. washThe reaction mixture was washed with aqueous ammonium chloride solution and brine
  8. customdried
  9. customthe solvent was evaporated under reduced pressure
  10. 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-02069762a3954bb8a80f7578f85e7431
Source dataset
uspto-grants-2013_06
Patent number
US08470816B2

Reaction notes

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