4-Chlorobenzaldehyde → ethyl 2-bromo-5-((4-chlorophenyl)(hydroxy)methyl)-1-isopropyl-1H-imidazole-4-carboxylate

HRID 2410094Notes

Reaction equation

HRID 2410094 reaction equation
[Li+].CC([N-]C(C)C)C.[CH2:9]([O:11][C:12]([C:14]1[N:15]=[C:16]([Br:22])[N:17]([CH:19]([CH3:21])[CH3:20])[CH:18]=1)=[O:13])[CH3:10].[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=[O:29])=[CH:26][CH:25]=1.CCOCC.CCCCCC>C1COCC1>[CH2:9]([O:11][C:12]([C:14]1[N:15]=[C:16]([Br:22])[N:17]([CH:19]([CH3:21])[CH3:20])[C:18]=1[CH:28]([C:27]1[CH:30]=[CH:31][C:24]([Cl:23])=[CH:25][CH:26]=1)[OH:29])=[O:13])[CH3:10]

Participants

6

Reactant 4

HCID 77264-ChlorobenzaldehydeHCID 2724682Lithium diisopropylamideHCID 21584099Diethylether hexaneHCID 86707750ethyl 2-bromo-1-isopropyl-1H-imidazole-4-carboxylate2×

Product 1

HCID 86707749ethyl 2-bromo-5-((4-chlorophenyl)(hydroxy)methyl)-1-isopropyl-1H-imidazole-4-carboxylate

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-20 °C

Procedure

LDA (63 mL, 2M solution in THF, 126 mmol) was slowly (over 30 min) added to a solution of 2-bromo-1-isopropyl-1H-imidazole-4-carboxylic acid ethyl ester (intermediate A; 11.0 g, 42.1 mmol) in THF (200 mL) at −78° C. After 2 h at −78° C., a solution of 4-chlorobenzaldehyde (8.9 g, 63.2 mmol) in THF (10 mL) was slowly added and the reaction mixture was allowed to warm to −20° C. over 30 min. The reaction mixture was quenched at −20° C. with 6 ml of acetic acid, concentrated and taken up in EtOAc/water, extracted twice with EtOAc. The combined organic extracts were washed with water and brine, dried (Na2SO4) and concentrated. The crude material was purified by chromatography (hexane/EtOAc, 60:40) to afford an orange foam. This was treated with 100 ml of 10% Et2O/hexane overnight and the resulting solid was filtered and rinsed with hexane to give the title compound as a white solid. ESI-MS: 403.1 [M+H]+ (LC-MS 2); 1H-NMR (DMSO-d6, 400 MHz) δ ppm 0.90 (d, J=7.04 Hz, 3 H) 1.26 (t, J=7.04 Hz, 3 H) 1.45 (d, J=7.04 Hz, 3 H) 4.25 (qd, J=7.04, 3.13 Hz, 2 H) 4.69 (quin, J=7.04 Hz, 1 H) 6.73 (d, J=4.30 Hz, 1 H) 6.83 (d, J=4.30 Hz, 1 H) 7.27 (m, J=8.60 Hz, 2 H) 7.41 (m, J=8.60 Hz, 2 H); Rf=0.15 (hexane/EtOAc, 60:40)

Workup

  1. custom(over 30 min)
  2. customThe reaction mixture was quenched at −20° C. with 6 ml of acetic acid
  3. concentrationconcentrated
  4. extractionextracted twice with EtOAc
  5. washThe combined organic extracts were washed with water and brine
  6. dry with materialdried (Na2SO4)
  7. concentrationconcentrated
  8. customThe crude material was purified by chromatography (hexane/EtOAc, 60:40)
  9. customto afford an orange foam
  10. filtrationthe resulting solid was filtered
  11. washrinsed with hexane

Sources & evidence

ORD record
ord-0d83044cf1ba41f1b8b67aae227da3f5
Source dataset
uspto-grants-2014_08
Patent number
US08815926B2

Reaction notes

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