Chloroiodomethane → 2-Chloro-1-(1-(4-chloro-3-methoxyphenyl)piperidin-4-yl)ethanone

HRID 1804829Notes

Reaction equation

HRID 1804829 reaction equation
[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]([O:16]CC)=O)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[O:19][CH3:20].[Cl:21][CH2:22]I.C(=O)=O.CC(C)=O.C[Li]>CCOCC.C1COCC1>[Cl:21][CH2:22][C:14]([CH:11]1[CH2:10][CH2:9][N:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([O:19][CH3:20])[CH:4]=2)[CH2:13][CH2:12]1)=[O:16]

Participants

7

Reactant 4

HCID 11644ChloroiodomethaneHCID 18522661Acetone cardiceHCID 68554705Ethyl 1-(4-chloro-3-methoxyphenyl)piperidine-4-carboxylateHCID 178418348HCID 178418348, compound

Product 1

HCID 866397972-Chloro-1-(1-(4-chloro-3-methoxyphenyl)piperidin-4-yl)ethanoneYield 43%

Reagents, catalysts & solvents 2

HCID 3283Diethyl EtherSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
-78 °C

Procedure

A dry 3-neck, 250-mL round bottom flask was charged with ethyl 1-(4-chloro-3-methoxyphenyl)piperidine-4-carboxylate (3.0 g, 10.07 mmol), anhydrous THF (50.4 mL) and chloroiodomethane (0.878 mL, 12.09 mmol). The flask was fitted with a rubber septum and pressure-equalized dropping funnel topped with an inert gas inlet and placed under a nitrogen atmosphere. The mixture was cooled to −78° C. (CO2/acetone bath). Methyllithium (7.56 mL of a 1.6 M solution in Et2O, 12.09 mmol) was added dropwise to the mixture from the dropping funnel over 10 min. The mixture was stirred at −78° C. for 1 h and then quenched with saturated NH4Cl (10 mL) and warmed to RT. The mixture was adjusted to a pH=6 and extracted with Et2O (3×75 mL). The extract was washed with brine, dried (Na2SO4) and concentrated on a rotary evaporator. The resultant residue was purified by flash chromatography using an 80 g silica gel cartridge and gradient elution from 20:1 Hex/EtOAc to 2:1 Hex/EtOAc. The fractions containing the product were pooled and concentrated on a rotary evaporator to give 2-chloro-1-(1-(4-chloro-3-methoxyphenyl)piperidin-4-yl)ethanone (1.3 g, 4.30 mmol, 43% yield) as a pale orange solid. LC/MS [M+H]+=302. 1H-NMR (400 MHz, CDCl3) δ ppm 7.19 (1 H, d, J=8.57 Hz), 6.50 (1 H, s), 6.44 (1 H, s), 4.18 (2 H, s), 3.87 (3 H, s), 3.62-3.71 (2 H, m), 2.75-2.86 (3 H, m), 1.97 (2 H, s), 1.84 (2 H, s).

Workup

  1. customThe flask was fitted with a rubber septum
  2. customtopped with an inert gas inlet
  3. customquenched with saturated NH4Cl (10 mL)
  4. temperaturewarmed to RT
  5. extractionextracted with Et2O (3×75 mL)
  6. washThe extract was washed with brine
  7. dry with materialdried (Na2SO4)
  8. concentrationconcentrated on a rotary evaporator
  9. customThe resultant residue was purified by flash chromatography
  10. washan 80 g silica gel cartridge and gradient elution from 20:1 Hex/EtOAc to 2:1 Hex/EtOAc
  11. additionThe fractions containing the product
  12. concentrationconcentrated on a rotary evaporator

Sources & evidence

ORD record
ord-ebc3728ab9ff4714b68aa67b45d766e8
Source dataset
uspto-grants-2013_01
Patent number
US08354432B2

Reaction notes

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