Cesium carbonate → 1-(2,4-difluorophenyl)-1H-imidazole-4-carbaldehyde

HRID 57513Notes

Reaction equation

HRID 57513 reaction equation
[NH:1]1[CH:5]=[C:4]([CH:6]=[O:7])[N:3]=[CH:2]1.[F:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1I.C([O-])([O-])=O.[Cs+].[Cs+].CN[C@@H]1CCCC[C@H]1NC>CN(C=O)C.[Cu]I>[F:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[N:1]1[CH:5]=[C:4]([CH:6]=[O:7])[N:3]=[CH:2]1

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 764281H-Imidazole-4-carbaldehydeHCID 1375192,4-Difluoro-1-iodobenzeneHCID 2733821trans-N,N'-dimethyl-1,2-cyclohexanediamine

Product 1

HCID 904235051-(2,4-difluorophenyl)-1H-imidazole-4-carbaldehydeYield 74.5%

Reagents, catalysts & solvents 2

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 6228DimethylformamideSolvent

Conditions

Temperature
110 °C

Procedure

To 1H-imidazole-4-carbaldehyde (3.01 g, 31.3 mmol), 2,4-difluoro-1-iodobenzene (1.008 g, 4.20 mmol), Cs2CO3 (2.281 g, 7.00 mmol) in DMF (50 mL) was added copper(I) iodide (0.033 g, 0.175 mmol) and (1R,2R)—N1,N2-dimethylcyclohexane-1,2-diamine (0.100 g, 0.700 mmol). The reaction was heated to 110° C. for 18 hours. The reaction mixture was then cooled to room temperature and filtered, and washed with EtOAc (100 mL). The organic was washed with water (2×30 mL) and brine (30 mL), dried (Na2SO4) and concentrated. The residue was purified by silica gel chromotography to give 1-(2,4-difluorophenyl)-1H-imidazole-4-carbaldehyde (651 mg), to which was added (S)-2-methylpropane-2-sulfinamide (0.424 g, 3.5 mmol), CuSO4 (0.798 g, 5 mmol) and DCE (10 mL). The reaction was heated to 65° C. for 18 hours. The reaction was cooled to rt, filtered and concentrated to give (S,E)-N-((1-(2,4-difluorophenyl)-1H-imidazol-4-yl)methylene)-2-methylpropane-2-sulfinamide, to which was added DCM (20 mL). The reaction mixture was cooled to −70° C. and methylmagnesium bromide (1.667 ml, 5 mmol) was added dropwise to the solution. The reaction was stirred for two hours and the cold bath was then removed, and the reaction was allowed to warm to rt and stir for 30 minutes. The reaction was cooled to 0° C. and HCl (1M) was added cautiously to quench until aqueous pH=8. The phases were separated and the aqueous layer was extracted with DCM (2×30 mL). Combined organic was dried (Na2SO4) and concentrated to give (S)—N—((S)-1-(1-(2,4-difluorophenyl)-1H-imidazol-4-yl)ethyl)-2-methylpropane-2-sulfinamide (230 mg), which was then dissolved in MeOH (5 mL) and HCl (0.5 mL, 4M) was added. The reaction was stirred for one hour and concentrated to give product (212 mg). LCMS m/z 224.1 (M+H)+; Rt-0.39 min.

Workup

  1. temperatureThe reaction mixture was then cooled to room temperature
  2. filtrationfiltered
  3. washwashed with EtOAc (100 mL)
  4. washThe organic was washed with water (2×30 mL) and brine (30 mL)
  5. dry with materialdried (Na2SO4)
  6. concentrationconcentrated
  7. customThe residue was purified by silica gel chromotography

Sources & evidence

ORD record
ord-7d7bc62b952141f7a743accb10283567
Source dataset
uspto-grants-2016_09
Patent number
US09434719B2

Reaction notes

Loading…