Acetic Acid → 5-Bromo-2-chloro-4-(thiophen-2-yl)pyrimidine

HRID 2267444Notes

Reaction equation

HRID 2267444 reaction equation
[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[Li].[Br:7][C:8]1[CH:9]=[N:10][C:11]([Cl:14])=[N:12][CH:13]=1.C(O)(=O)C.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1COCC1.CO>[Br:7][C:8]1[C:9]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[N:10][C:11]([Cl:14])=[N:12][CH:13]=1

Participants

7

Reactant 4

HCID 176Acetic AcidHCID 67752,3-Dichloro-5,6-dicyano-1,4-benzoquinoneHCID 6066655-Bromo-2-chloropyrimidineHCID 178418439HCID 178418439, compound

Product 1

HCID 574288715-Bromo-2-chloro-4-(thiophen-2-yl)pyrimidine

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 8028TetrahydrofuranSolvent3×

Conditions

Temperature
-78 °C

Procedure

Thienyl lithium (1.0 M in THF, 26 mL, 26 mmol) was diluted with anhydrous THF (65 mL) and the mixture cooled down to −78° C. under a nitrogen atmosphere. 5-Bromo-2-chloropyrimidine, dissolved in 10 mL of tetrahydrofuran, was added to the reaction mixture dropwise. The reaction was allowed to stir for 1 h and then warmed to −20° C. Acetic acid (1.5 mL) and methanol (1.2 mL) were successively added to the reaction mixture. The reaction was stirred for 15 min and a solution of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (5.9 g, 20 mmol) in 10 mL of THF was added. The reaction was stirred for an additional 15 min and then the cooling bath was removed. The mixture was stirred for 1 h and then cooled to 0° C. with an ice bath. 5 N sodium hydroxide (5.2 mL) was added to the reaction mixture and stirred for 5 min. The reaction was then diluted with ethyl acetate (50 mL) and water (50 mL). The organic layer was washed with saturated aqueous sodium bicarbonate, water and brine. The organic layer was then dried with sodium sulfate, concentrated and purified by flash chromatography on silica gel using 5% ethyl acetate in hexanes as an eluent to obtain a yellow solid. Yield=3.6 g. MS (M+H)+ 275/277.

Workup

  1. additionwas added to the reaction mixture dropwise
  2. temperaturewarmed to −20° C
  3. stirringThe reaction was stirred for 15 min
  4. stirringThe reaction was stirred for an additional 15 min
  5. customthe cooling bath was removed
  6. stirringThe mixture was stirred for 1 h
  7. temperaturecooled to 0° C. with an ice bath
  8. addition5 N sodium hydroxide (5.2 mL) was added to the reaction mixture
  9. stirringstirred for 5 min
  10. additionThe reaction was then diluted with ethyl acetate (50 mL) and water (50 mL)
  11. washThe organic layer was washed with saturated aqueous sodium bicarbonate, water and brine
  12. dry with materialThe organic layer was then dried with sodium sulfate
  13. concentrationconcentrated
  14. custompurified by flash chromatography on silica gel using 5% ethyl acetate in hexanes as an eluent
  15. customto obtain a yellow solid

Sources & evidence

ORD record
ord-e84345478ff1401b87f3f0efa71ae2a0
Source dataset
uspto-grants-2010_12
Patent number
US07858785B2

Reaction notes

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