Pyrimidine, 2,4-dichloro-5-methyl- → 2-chloro-5-methyl-4-[[3-(trifluoromethyl)phenyl]methyl]pyrimidine

HRID 1060520Notes

Reaction equation

HRID 1060520 reaction equation
[F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6]Br.[Cl:13][C:14]1[N:19]=[C:18](Cl)[C:17]([CH3:21])=[CH:16][N:15]=1>O1CCCC1.BrCCBr.C[Si](Cl)(C)C.[Zn].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:13][C:14]1[N:19]=[C:18]([CH2:6][C:5]2[CH:8]=[CH:9][CH:10]=[C:3]([C:2]([F:12])([F:11])[F:1])[CH:4]=2)[C:17]([CH3:21])=[CH:16][N:15]=1

Participants

8

Reactant 2

HCID 74508Pyrimidine, 2,4-dichloro-5-methyl-HCID 1230611-(Bromomethyl)-3-(trifluoromethyl)benzene

Product 1

HCID 120567142-chloro-5-methyl-4-[[3-(trifluoromethyl)phenyl]methyl]pyrimidineYield 41.9%

Reagents, catalysts & solvents 5

HCID 6397ChlorotrimethylsilaneCatalystHCID 78391,2-DibromoethaneCatalystHCID 23994ZincCatalystHCID 178418476HCID 178418476, compoundCatalystHCID 8028TetrahydrofuranSolvent2×

Procedure

To a suspension of zinc dust (2.5 g, 38 mmol) stirred in 25 mL of tetrahydrofuran were added 2 drops of 1,2-dibromoethane and the mixture was heated to reflux. The suspension was then cooled and 2 drops of trimethylsilyl chloride were added followed by portionwise addition of 3-(trifluoromethyl)benzyl bromide (6.0 g, 25 mmol) with heating. When the reaction temperature reached 55° C., a strong exotherm occurred and the reaction mixture was allowed to heat at reflux. The cooled reaction solution was decanted into a solution of 2,4dichloro-5-methylpyrimidine (3.3 g, 20 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.44 g, 0.63 mmol) stirring in 15 mL of tetrahydrofuran. Upon heating, the reaction mixture exothermed strongly again at 55° C. and was then heated to reflux. The reaction mixture was allowed to cool and partitioned between diethyl ether and water. The organic layer was separated, washed with 1 N aqueous hydrochloric acid and brine, dried over magnesium chloride and concentrated under reduced pressure to give a crude oil. Purification by flash chromatography on silica gel (15 to 25% ethyl acetate in hexane) yielded 2.4 g of the title compound of Step A as an oil. 1H NMR (CDCl3): δ8.35 (s, 1H), 7.60-7.35 (m, 4H), 4.15 (s, 2H), 2.25 (s, 3H).

Workup

  1. temperaturethe mixture was heated to reflux
  2. temperatureThe suspension was then cooled
  3. temperaturewith heating
  4. customreached 55° C.
  5. temperatureto heat
  6. temperatureat reflux
  7. customThe cooled reaction solution
  8. temperatureUpon heating
  9. customexothermed strongly again at 55° C.
  10. temperaturewas then heated to reflux
  11. temperatureto cool
  12. custompartitioned between diethyl ether and water
  13. customThe organic layer was separated
  14. washwashed with 1 N aqueous hydrochloric acid and brine
  15. dry with materialdried over magnesium chloride
  16. concentrationconcentrated under reduced pressure
  17. customto give a crude oil
  18. customPurification by flash chromatography on silica gel (15 to 25% ethyl acetate in hexane)

Sources & evidence

ORD record
ord-0d4217b8342f4eb99e962ae065451bf5
Source dataset
uspto-grants-2003_02
Patent number
US06525001B1

Reaction notes

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