Toluene → Ethyl 1-(5-fluoropyridin-2-yl)piperidine-4-carboxylate

HRID 1891326Notes

Reaction equation

HRID 1891326 reaction equation
[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].Cl[C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][N:14]=1.C1(C)C=CC=CC=1.CC([O-])(C)C.[Na+]>CCOC(C)=O.O.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][N:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]

Participants

8

Reactant 4

HCID 1140TolueneHCID 70770Ethyl 4-piperidinecarboxylateHCID 27828012-Chloro-5-fluoropyridineHCID 23676156Sodium t-butoxide

Product 1

HCID 58302994Ethyl 1-(5-fluoropyridin-2-yl)piperidine-4-carboxylateYield 65.2%

Reagents, catalysts & solvents 3

HCID 634876Binap, (A+-)-CatalystHCID 962WaterSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
75 °C

Procedure

To a stirred solution of piperidine-4-carboxylic acid ethyl ester (14.3 g, 0.091 mol) and 2-chloro-5-fluoro-pyridine (10 g, 0.076 mol) in toluene (100 mol) was added NaOtBu (8.77 g, 0.091 mol), BINAP (1.42 g, 2.28 mmol) and tris(dibenilideneacetone)dipalladium(0) (1.39 g, 1.52 mmol). The reaction mixture was heated at 75° C. for 2 hours, cooled down to RT, and diluted with AcOEt (100 mL) and H2O (100 mL). The organic layer was separated and washed with brine, dried over Na2SO4 and concentrated under vacuo. Column chromatography (SiO2, EtOAc/heptane, 1:9 to 1:1) yielded 12.5 g (65%) of 5′-fluoro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid ethyl ester as a yellow oil. ES-MS m/e: 253.3 (M+H+).

Workup

  1. temperaturecooled down to RT
  2. customThe organic layer was separated
  3. washwashed with brine
  4. dry with materialdried over Na2SO4
  5. concentrationconcentrated under vacuo

Sources & evidence

ORD record
ord-83ba09ed02ec4bd1b7108682c416973d
Source dataset
uspto-grants-2013_08
Patent number
US08507535B2

Reaction notes

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