2,3-Dichloro-5,6-dicyano-1,4-benzoquinone → 2-(2-(4-Fluoro-benzyl)-5-(5-chloro-2-(methylthio)pyrimidin-4-yl)thiophen-3-yl)ethanol

HRID 507569Notes

Reaction equation

HRID 507569 reaction equation
C([Li])CCC.[F:6][C:7]1[CH:21]=[CH:20][C:10]([CH2:11][C:12]2[S:13][CH:14]=[CH:15][C:16]=2[CH2:17][CH2:18][OH:19])=[CH:9][CH:8]=1.[Cl:22][C:23]1[CH:24]=[N:25][C:26]([S:29][CH3:30])=[N:27][CH:28]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.[OH-].[Na+]>O1CCCC1.O>[F:6][C:7]1[CH:21]=[CH:20][C:10]([CH2:11][C:12]2[S:13][C:14]([C:24]3[C:23]([Cl:22])=[CH:28][N:27]=[C:26]([S:29][CH3:30])[N:25]=3)=[CH:15][C:16]=2[CH2:17][CH2:18][OH:19])=[CH:9][CH:8]=1

Participants

8

Reactant 5

HCID 67752,3-Dichloro-5,6-dicyano-1,4-benzoquinoneHCID 14798Sodium HydroxideHCID 47370635-Chloro-2-(methylthio)pyrimidineHCID 574288302-(2-(4-Fluorobenzyl)thiophen-3-yl)ethanolHCID 178418339Butyllithium

Product 1

HCID 602044632-(2-(4-Fluoro-benzyl)-5-(5-chloro-2-(methylthio)pyrimidin-4-yl)thiophen-3-yl)ethanolYield 28%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent3×

Conditions

Temperature
-78 °C

Procedure

n-Butyllithium (5.4 mL, 1.6 M in hexanes, 8.63 mmol) was added dropwise to a solution of 2-(2-(4-fluorobenzyl)thiophen-3-yl)ethanol (0.97 g, 4.11 mmol) in anhydrous tetrahydrofuran (15 mL) at −78° C. The resulting mixture was stirred at −78° C. for 1 h and then a solution of 5-chloro-2-(methylthio)pyrimidine (0.79 g, 4.93 mmol) in 1 mL of tetrahydrofuran was added slowly. The mixture was stirred at −78° C. for 1 h and then at −40° C. for 2 h. The reaction was quenched with a solution (1.1 mL) of acetic acid and methanol (1:1) at −40° C. and then a solution of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (0.1.1 g, 4.93 mmol) in tetrahydrofuran (1 mL) was added. After complete addition the reaction was stirred at −40° C. for 1 h, then warmed to rt. 10 mL of aqueous sodium hydroxide (2 M) and 50 mL of water were added and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (80 mL), dried over anhydrous sodium sulfate and filtered. The solvent was evaporated in vacuo and the product purified by flash chromatography eluting with ethyl acetate/hexane (1:4) to afford the title compound (0.45 g, 28%). MS (M+H)+ 395/397.

Workup

  1. stirringThe mixture was stirred at −78° C. for 1 h
  2. waitat −40° C. for 2 h
  3. customThe reaction was quenched with a solution (1.1 mL) of acetic acid and methanol (1:1) at −40° C.
  4. additionAfter complete addition the reaction
  5. stirringwas stirred at −40° C. for 1 h
  6. temperaturewarmed to rt
  7. extractionthe mixture was extracted with ethyl acetate (3×50 mL)
  8. washThe combined organic layers were washed with brine (80 mL)
  9. dry with materialdried over anhydrous sodium sulfate
  10. filtrationfiltered
  11. customThe solvent was evaporated in vacuo
  12. customthe product purified by flash chromatography
  13. washeluting with ethyl acetate/hexane (1:4)

Sources & evidence

ORD record
ord-01b52c9df02548bca13060d153729ded
Source dataset
uspto-grants-2010_08
Patent number
US07786132B2

Reaction notes

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