Water → HCID 22718090, compound

HRID 2227729Notes

Reaction equation

HRID 2227729 reaction equation
[N:1]#[C:2]Br.[F:4][C:5]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:6]=1[O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:15]=[CH:16][N:17]([CH3:19])[CH:18]=2)=[CH:10][CH:9]=1.O.CCOC(C)=O>CN(C)C1C=CN=CC=1.CN(C=O)C>[C:2]([C:16]1[N:17]([CH3:19])[CH:18]=[C:14]([C:11]2[CH:10]=[CH:9][C:8]([O:7][C:6]3[CH:20]=[CH:21][C:22]([F:24])=[CH:23][C:5]=3[F:4])=[CH:13][CH:12]=2)[N:15]=1)#[N:1].[C:2]([C:14]1([C:11]2[CH:10]=[CH:9][C:8]([O:7][C:6]3[CH:20]=[CH:21][C:22]([F:24])=[CH:23][C:5]=3[F:4])=[CH:13][CH:12]=2)[CH2:18][N:17]([CH3:19])[CH:16]=[N:15]1)#[N:1]

Participants

8

Reactant 4

HCID 962WaterHCID 8857Ethyl AcetateHCID 10476Cyanogen BromideHCID 22718134HCID 22718134, compound

Product 2

HCID 22718090HCID 22718090, compoundHCID 22718112HCID 22718112, compound

Reagents, catalysts & solvents 2

HCID 142844-(Dimethylamino)pyridineCatalystHCID 6228DimethylformamideSolvent

Conditions

Temperature
60 °C

Procedure

2-Cyano-4-[4-(2,4-difluorophenoxy)phenyl]-1-methyl-1H-imidazole. A mixture of crude 4-[4-(2,4-difluorophenoxy)phenyl]-1H-imidazole (prepared from 4.14 g of 2-bromo-1-[4-(2,4-difluorophenoxy)phenyl]ethanone and 35 mL of formamide as described above), solid KOH (2.57 g) and MeI (1 mL) was heated at reflux overnight. After filtration, the reaction was concentrated to dryness and the residue was purified by flash chromatography, affording 4-[4-(2,4-difluorophenoxy)phenyl]-1-methyl-1H-imidazole as a solid. A solution of 4-(dimethylamino)pyridine (1.34 g, 10.9 mmol) in 30 mL of dry DMF at −10° C. was added cyanogen bromide (5.0 M solution in MeCN; 2.1 mL, 10.5 mmol), giving a pale yellow precipitate. Solid 4-[4-(2,4-difluorophenoxy)phenyl]-1-methyl-1H-imidazole (1.39 g, 4.86 mmol) was added and the reaction was heated at 60° C. overnight. The reaction was allowed to cool to room temperature and added to water and EtOAc. The separated aqueous layer was extracted twice with EtOAc and the pooled organic layers were washed with water (3×), dried (Na2SO4), filtered and concentrated. The oily residue was purified by flash chromatography (gradient from 8.5/2.5 to 7/3 hexane/EtOAc) affording 713 mg of 2-cyano-4-[4-(2,4-difluorophenoxy)phenyl]-1-methyl-1H-imidazole as a solid, mp 109-110° C. (Rf 0.42, 7/3 hexane/EtOAc) along with 122 mg of 4-cyano-4-[4-(2,4-difluorophenoxy)phenyl]-1-methyl-1H-imidazole, mp 169-170° C. (Rf 0.32, 7/3 hexane/EtOAc). 1H NMR (2-cyano; CDCl3): δ7.65 (d, 2H, J=9.0 Hz), 7.16 (s, 1H), 7.06 (dt, 1H, J=9.3, 5.4 Hz), 6.93 (d, 2H, J=8.7 Hz), 6.98-6.80 (m, 2H), 3.65 (s, 3H). 1H NMR (4-cyano; CDCl3): δ7.69 (d, 2H, J=8.7 Hz), 7.27 (s, 1H), 7.09 (dt, J=8.7, 5.7 Hz), 6.96 (d, 2H, J=8.7 Hz), 7.00-6.82 (m, 2H), 3.90 (s, 3H).

Workup

  1. customgiving a pale yellow precipitate
  2. temperatureto cool to room temperature
  3. extractionThe separated aqueous layer was extracted twice with EtOAc
  4. washthe pooled organic layers were washed with water (3×)
  5. dry with materialdried (Na2SO4)
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customThe oily residue was purified by flash chromatography (gradient from 8.5/2.5 to 7/3 hexane/EtOAc)

Sources & evidence

ORD record
ord-a07d5207b4524dcc877573d7e3628b7d
Source dataset
uspto-grants-2002_07
Patent number
US06414011B1

Reaction notes

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