4-trifluoromethyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole → HCID 71240810, compound

HRID 1774610Notes

Reaction equation

HRID 1774610 reaction equation
C([Li])CCC.[F:6][C:7]([F:22])([F:21])[C:8]1[N:9]=[CH:10][N:11]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH:12]=1.Cl[C:24]1[CH:29]=[C:28]([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([Cl:37])[CH:31]=2)[N:27]=[CH:26][N:25]=1>C1COCC1.CC(OC)(C)C.[Cl-].[Cl-].[Zn+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:37][C:32]1[CH:31]=[C:30]([C:28]2[CH:29]=[C:24]([C:10]3[N:11]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:18])([CH3:19])[CH3:20])[CH:12]=[C:8]([C:7]([F:21])([F:6])[F:22])[N:9]=3)[N:25]=[CH:26][N:27]=2)[CH:35]=[CH:34][C:33]=1[Cl:36]

Participants

8

Reactant 3

HCID 136002324-trifluoromethyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazoleHCID 24902229HCID 24902229, compoundHCID 178418339Butyllithium

Product 1

HCID 71240810HCID 71240810, compoundYield 68.8%

Reagents, catalysts & solvents 4

HCID 3007855ZincchlorideCatalystHCID 178418397HCID 178418397, compoundCatalystHCID 8028TetrahydrofuranSolventHCID 15413tert-Butyl methyl etherSolvent

Procedure

n-Butyl lithium (2.5M solution in hexane, 0.11 ml, 0.27 mmol) was added dropwise to a cold (−78° C.) stirred solution of 4-trifluoromethyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole (0.067 g, 0.25 mmol) in THF (5 ml) and the mixture was stirred at this temperature under a nitrogen atmosphere for 30 minutes. After this time, ZnCl2 (1M solution in Et2O, 0.58 ml, 0.58 mmol) was added in one portion and the solution was allowed to warm to room temperature. 4-Chloro-6-(3,4-dichloro-phenyl)-pyrimidine (0.05 g, 0.19 mmol) and Pd(PPh3)4 (0.045 g, 0.01 mol) were added sequentially and the resulting mixture was heated to reflux and stirred for a further 4 hours. After this time the mixture was diluted with TBME (100 ml) and washed with 1M HCl (50 ml). The layers were separated and the aqueous extracted with TBME (50 ml). The organic layers were combined, dried (MgSO4), filtered and concentrated. The resulting residue was purified using a Biotage Isolera (10 g silica column eluting with 100% heptane to 20% ethyl acetate/80% heptane) to afford the title compound (0.064 g, 68% yield) as a white solid. δH (250 MHz, CDCl3) 9.26 (d, J=1.22 Hz, 1H), 8.60 (d, J=1.37 Hz, 1H), 8.37 (d, J=2.13 Hz, 1H), 8.06 (dd, J=2.13, 8.53 Hz, 1H), 7.52-7.75 (m, 2H), 6.13 (s, 2H), 3.65 (dd, J=7.77, 8.68 Hz, 2H), 0.79-1.05 (m, 2H), −0.03 (s, 9H). Tr=2.66 min m/z (ES+) (M+H+) 489, 491.

Workup

  1. temperaturethe resulting mixture was heated
  2. temperatureto reflux
  3. stirringstirred for a further 4 hours
  4. washwashed with 1M HCl (50 ml)
  5. customThe layers were separated
  6. extractionthe aqueous extracted with TBME (50 ml)
  7. dry with materialdried (MgSO4)
  8. filtrationfiltered
  9. concentrationconcentrated
  10. customThe resulting residue was purified
  11. washa Biotage Isolera (10 g silica column eluting with 100% heptane to 20% ethyl acetate/80% heptane)

Sources & evidence

ORD record
ord-8b61e2c76cf043ae9a3bd94e223abe5f
Source dataset
uspto-grants-2016_02
Patent number
US09260422B2

Reaction notes

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