Hexane → HCID 178501138, compound

HRID 446748Notes

Reaction equation

HRID 446748 reaction equation
CCCCCC.[F:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1.[CH3:14][O:15][C:16]([C@H:18]1[CH2:23][CH2:22][C@H:21]([C:24](Cl)=[O:25])[CH2:20][CH2:19]1)=[O:17]>C(OCC)C.[Cl-].[Zn+2].[Cl-].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:14][O:15][C:16]([C@H:18]1[CH2:23][CH2:22][C@H:21]([C:24]([C:9]2[C:8]([F:7])=[CH:13][CH:12]=[CH:11][N:10]=2)=[O:25])[CH2:20][CH2:19]1)=[O:17].[CH3:14][O:15][C:16]([C@H:18]1[CH2:23][CH2:22][C@H:21]([C:24]([C:13]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[F:7])=[O:25])[CH2:20][CH2:19]1)=[O:17]

Participants

8

Reactant 3

HCID 8058HexaneHCID 677943-FluoropyridineHCID 178501148HCID 178501148, compound

Product 2

HCID 178501138HCID 178501138, compoundYield 8.4%HCID 178501139HCID 178501139, compoundYield 7.9%

Reagents, catalysts & solvents 3

HCID 3007855ZincchlorideCatalystHCID 178418397HCID 178418397, compoundCatalystHCID 3283Diethyl EtherSolvent

Conditions

Temperature
-20 °C

Procedure

To a solution of N,N,N′N′-tetramethylethylenediamine (1.20 g, 10.3 mmol) in diethyl ether (50 ml) at −78° C. was added 1.6M N-butyl lithium solution in n-hexane (6.40 ml, 10.3 mmol). Stirring for 1 h at −20° C. was followed by addition of 3-fluoropyridine (1.00 g, 10.3 mmol) at −78° C. After stirring at −60 to −70° C. for 3 h a solution of zinc chloride (2.81 g, 20.6 mmol), which had previously been dried by melting in vacuo followed by cooling under argon, in diethyl ether (20 ml) was added dropwise at max. −60° C. The reaction mixture was allowed to warm to room temperature 45 minutes after completed addition. Addition of tetrakis(triphenylphosphine)palladium(0) (0.59 g, 0.51 mmol) and trans-4-chlorocarbonyl-cyclohexanecarboxylic acid methyl ester (2.10 g, 10.3 mmol) was followed by stirring for 16 h. The reaction was quenched with aqueous saturated ammonium chloride solution and the mixture was extracted with three 100-ml portions of tert-butyl methyl ether. The combined organic layers were washed with one 50-ml portion of 2 M aqueous sodium carbonate solution and one 50-ml portion of brine, dried over anhydrous sodium sulfate and concentrated to dryness. Separation by flash-chromatography with n-heptane/ethyl acetate as eluent gave trans-4-(3-fluoro-pyridine-2-carbonyl)-cyclohexanecarboxylic acid methyl ester (0.22 g, 7.9%) as yellow oil and trans-4-(3-fluoro-pyridine-4-carbonyl)-cyclohexanecarboxylic acid methyl ester (0.23 g, 8.4%) as yellow solid.

Workup

  1. customhad previously been dried
  2. temperatureby cooling under argon, in diethyl ether (20 ml)
  3. additionwas added dropwise at max
  4. custom−60° C
  5. temperatureto warm to room temperature 45 minutes
  6. additionaddition
  7. stirringby stirring for 16 h
  8. customThe reaction was quenched with aqueous saturated ammonium chloride solution
  9. extractionthe mixture was extracted with three 100-ml portions of tert-butyl methyl ether
  10. washThe combined organic layers were washed with one 50-ml portion of 2 M aqueous sodium carbonate solution and one 50-ml portion of brine
  11. dry with materialdried over anhydrous sodium sulfate
  12. concentrationconcentrated to dryness
  13. customSeparation by flash-chromatography with n-heptane/ethyl acetate as eluent

Sources & evidence

ORD record
ord-be35437329e84665b7c60b45000e811b
Source dataset
uspto-grants-2013_07
Patent number
US08481528B2

Reaction notes

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