Ethyl Acetate → 2-(4-Fluoropyridin-2-yl)-5-methylthiazole

HRID 523165Notes

Reaction equation

HRID 523165 reaction equation
Br[C:2]1[S:3][C:4]([CH3:7])=[CH:5][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][C:4]([CH3:7])=[CH:5][N:6]=2)[CH:19]=1

Participants

9

Reactant 4

HCID 8857Ethyl AcetateHCID 27827922-Chloro-4-fluoropyridineHCID 219061062-Bromo-5-methyl-1,3-thiazoleHCID 178418339Butyllithium

Product 1

HCID 901179752-(4-Fluoropyridin-2-yl)-5-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-5-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 15 minutes. To the solution was added zinc(II) chloride in THF (2.74 mL, 1.37 mmol). The solution was immediately allowed to warm to r.t. (using a r.t. water bath) 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 for 2.25 h. The reaction solution was transfered to a 125 mL separatory funnel and was diluted with Et2O (20 mL). The solution was washed with sat. aq. NaHCO3 (20 mL). The aq. phase was extracted with EtOAc (25 mL). The combined organics were washed with brine (20 mL); dried over MgSO4; filtered; then concentrated in vacuo to afford an orange residue. This material was subjected to silica gel chromatography (hexanes:EtOAc, 100:0 to 80:20) to afford 2-(4-fluoropyridin-2-yl)-5-methylthiazole as a white solid (54 mg, 24%). 1H-NMR (400 MHz, CDCl3) δ 8.55 (dd, J=8.2, 5.4 Hz, 1H), 7.91-7.82 (m, 1H), 7.62-7.56 (m, 1H), 7.02 (ddd, J=8.2, 5.6, 2.5 Hz, 1H), 2.55 (d, J=1.3 Hz, 3H).

Workup

  1. customTo a dry 10 mL Schlenk flask equipped with a stir bar
  2. temperatureto warm to r.t. (
  3. customusing a r.t.
  4. stirringwith stirring for 30 min
  5. customwas placed in a 60° C.
  6. temperatureheating block
  7. stirringwith stirring for 2.25 h
  8. customThe reaction solution was transfered to a 125 mL separatory funnel
  9. washThe solution was washed with sat. aq. NaHCO3 (20 mL)
  10. extractionThe aq. phase was extracted with EtOAc (25 mL)
  11. washThe combined organics were washed with brine (20 mL)
  12. dry with materialdried over MgSO4
  13. filtrationfiltered
  14. concentrationthen concentrated in vacuo
  15. customto afford an orange residue

Sources & evidence

ORD record
ord-2409436187634bcea9a5e7047b743f94
Source dataset
uspto-grants-2016_05
Patent number
US09334279B2

Reaction notes

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