2-Chloropyrimidine → 4-(4-bromo-2-tert-butyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)-2-chloropyrimidine

HRID 1043728Notes

Reaction equation

HRID 1043728 reaction equation
[Li]CCCC.[Br:6][C:7]1[N:8]=[C:9]([C:21]([CH3:24])([CH3:23])[CH3:22])[N:10]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:11]=1Br.[Cl:25][C:26]1[N:31]=[CH:30][CH:29]=[CH:28][N:27]=1>C1COCC1.O=[Mn]=O>[Br:6][C:7]1[N:8]=[C:9]([C:21]([CH3:24])([CH3:23])[CH3:22])[N:10]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:11]=1[C:28]1[CH:29]=[CH:30][N:31]=[C:26]([Cl:25])[N:27]=1

Participants

6

Reactant 3

HCID 744042-ChloropyrimidineHCID 665910814,5-dibromo-2-tert-butyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazoleHCID 178418339Butyllithium

Product 1

HCID 866514104-(4-bromo-2-tert-butyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)-2-chloropyrimidineYield 39.2%

Reagents, catalysts & solvents 2

HCID 14801Manganese dioxideCatalystHCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-78 °C

Procedure

n-BuLi (1.5 M in hexane, 40 mL, 60 mmol) was added dropwise to a cooled solution of 4,5-dibromo-2-tert-butyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (23.6 g, 57.2 mmol) in anhydrous THF (250 mL) at −78° C. After 30 minutes at −78° C., a solution of 2-chloropyrimidine (7.21 g, 63.0 mmol) in anhydrous THF (2 mL) was added dropwise and the reaction was stirred at −78° C. for 1 hour. The reaction was quenched by the addition of saturated aqueous NH4Cl solution and allowed to warm to room temperature. The mixture was partitioned with EtOAc and the layers separated. The aqueous portion was extracted with EtOAc (3×) and the combine organic layers were washed with water, brine, dried (MgSO4), and concentrated. The resulting residue was dissolved in EtOAc, treated with MnO2 (5.2 g, 60 mmol), and heated to reflux for 3 hours. The reaction was allowed to cool to room temperature and filtered through Celite. The filter cake was washed thoroughly with EtOAc and the combine filtrates were concentrated. The remaining residue was purified by flash chromatography (SiO2, 0-10% EtOAc in hexanes) to give 10 g (37%) of 4-(4-bromo-2-tert-butyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)-2-chloropyrimidine: LCMS (m/z): 445. 0 (MH+), tR=1.35 minutes. 1H NMR (400 MHz, CDCl3) δ 8.64 (d, J=5.3 Hz, 1H), 7.83 (d, J=5.3 Hz, 1H), 5.85 (s, 2H), 3.45 (m, 2H), 1.49 (s, 9H), 0.76 (m, 2H), −0.08 (s, 9H).

Workup

  1. customThe reaction was quenched by the addition of saturated aqueous NH4Cl solution
  2. temperatureto warm to room temperature
  3. customThe mixture was partitioned with EtOAc
  4. customthe layers separated
  5. extractionThe aqueous portion was extracted with EtOAc (3×)
  6. washthe combine organic layers were washed with water, brine
  7. dry with materialdried (MgSO4)
  8. concentrationconcentrated
  9. dissolutionThe resulting residue was dissolved in EtOAc
  10. temperatureheated
  11. temperatureto reflux for 3 hours
  12. temperatureto cool to room temperature
  13. filtrationfiltered through Celite
  14. washThe filter cake was washed thoroughly with EtOAc
  15. concentrationthe combine filtrates were concentrated
  16. customThe remaining residue was purified by flash chromatography (SiO2, 0-10% EtOAc in hexanes)

Sources & evidence

ORD record
ord-eceaaa14edb84cc8a73745eedc0ca17a
Source dataset
uspto-grants-2013_10
Patent number
US08563553B2

Reaction notes

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