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 2267345Notes

Reaction equation

HRID 2267345 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-2991c4b5c8114b56a0430dfb172f657a
Source dataset
uspto-grants-2010_12
Patent number
US07858785B2

Reaction notes

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