Ethyl Acetate → 2-(4-Fluoropyridin-2-yl)-4-methylthiazole

HRID 523164Notes

Reaction equation

HRID 523164 reaction equation
Br[C:2]1[S:3][CH:4]=[C:5]([CH3:7])[N:6]=1.C([Li])CCC.Cl[C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][N:15]=1.CCOC(C)=O>C1COCC1.CCOCC.[Cl-].[Zn+2].[Cl-].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:20][C:18]1[CH:17]=[CH:16][N:15]=[C:14]([C:2]2[S:3][CH:4]=[C:5]([CH3:7])[N:6]=2)[CH:19]=1

Participants

9

Reactant 4

HCID 8857Ethyl AcetateHCID 5515412-Bromo-4-methyl-1,3-thiazoleHCID 27827922-Chloro-4-fluoropyridineHCID 178418339Butyllithium

Product 1

HCID 901181702-(4-Fluoropyridin-2-yl)-4-methylthiazoleYield 24.4%

Reagents, catalysts & solvents 4

HCID 3007855ZincchlorideCatalystHCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 3283Diethyl EtherSolventHCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-78 °C

Procedure

To a dry 10 mL Schlenk flask equipped with a stir bar and placed under N2 atmosphere was added 2-bromo-4-methylthiazole (244 mg, 1.37 mmol) in THF (5 mL). The flask was cooled to −78° C. To the solution was added n-butyllithium in hexanes (0.55 mL, 1.37 mmol). The solution was stirred for 5 minutes. To the solution was added zinc(II) chloride in THF (2.74 mL, 1.37 mmol). A thick ppt. immediately formed which hindered stirring. The flask was immediately transfered to a r.t. water bath and the solution was allowed to warm to r.t. with stirring for 30 min. To the solution was added 2-chloro-4-fluoropyridine (150 mg, 1.14 mmol), then Pd(dppf)Cl2 (42 mg, 0.057 mmol). The vial was placed in a 60° C. heating block with stirring (t=0). The reaction mixture was transfered to a 125 mL separatory funnel and was diluted with Et2O:EtOAc (25 mL:25 mL). The solution was washed with water:brine (25 mL:25 mL). The aq. phase was extracted with EtOAc (25 mL). The combined organics were washed with brine (25 mL); dried over MgSO4; filtered; then concentrated in vacuo. The residue was subjected to silica gel chromatography to afford 2-(4-fluoropyridin-2-yl)-4-methylthiazole as an orange solid (54 mg, 24%).

Workup

  1. customTo a dry 10 mL Schlenk flask equipped with a stir bar
  2. customimmediately formed which
  3. stirringhindered stirring
  4. customwas immediately transfered to a r.t.
  5. temperatureto warm to r.t.
  6. stirringwith stirring for 30 min
  7. customwas placed in a 60° C.
  8. temperatureheating block
  9. stirringwith stirring (t=0)
  10. customThe reaction mixture was transfered to a 125 mL separatory funnel
  11. washThe solution was washed with water
  12. extractionThe aq. phase was extracted with EtOAc (25 mL)
  13. washThe combined organics were washed with brine (25 mL)
  14. dry with materialdried over MgSO4
  15. filtrationfiltered
  16. concentrationthen concentrated in vacuo

Sources & evidence

ORD record
ord-c41830255c3844bbb4ef231f29390064
Source dataset
uspto-grants-2016_05
Patent number
US09334279B2

Reaction notes

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