Iodine → 2-Iodo-1-methyl-4-(5-methylthiophen-2-yl)-1H-imidazole

HRID 1429114Notes

Reaction equation

HRID 1429114 reaction equation
[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[S:8][C:9]([CH3:12])=[CH:10][CH:11]=2)[N:4]=[CH:3]1.[Li]CCCC.[I:18]I.[NH4+].[Cl-]>C1COCC1>[I:18][C:3]1[N:2]([CH3:1])[CH:6]=[C:5]([C:7]2[S:8][C:9]([CH3:12])=[CH:10][CH:11]=2)[N:4]=1

Participants

6

Reactant 4

HCID 807IodineHCID 25517Ammonium ChlorideHCID 600466101-Methyl-4-(5-methylthiophen-2-yl)-1H-imidazoleHCID 178418339Butyllithium

Product 1

HCID 675118002-Iodo-1-methyl-4-(5-methylthiophen-2-yl)-1H-imidazoleYield 106.5%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
-40 °C

Procedure

A mixture of 1-methyl-4-(5-methylthiophen-2-yl)-1H-imidazole 5 (2.36 g, 13.3 mmol) in THF (0.100 mL) was cooled −78° C. nBuLi (9.53 mL of a 1.6 M solution in hexanes, 15.2 mmol) was added dropwise (˜2 min) and the pale yellow solution was allowed to warm to −40° C. (over ˜1 h) and then re-cooled to −78° C. I2 (2.74 g, 10.4 mmol) was added and the mixture was allowed to warm to room temperature (over ˜2 h) and stirred overnight. Saturated aqueous NH4Cl (2 mL) was added and the mixture was concentrated to ˜10 mL. The mixture was diluted with CH2Cl2. H2O, saturated aqueous Na2S2O3 and the organic phase was separated. The aqueous phase was re-extracted (CH2Cl2) and the combined organics were washed (saturated aqueous NaCl), dried (MgSO4), filtered and concentrated to give a residue. The residue was purified by flash chromatography (EtOAc/hexanes 10:90 then 15:85 then 25:75) to give 2-iodo-1-methyl-4-(5-methylthiophen-2-yl)-1H-imidazole 6 (3.37 g, 84%) as a colourless solid. 1H NMR (CDCl3, 400 MHz) δ2.46 (d, J=0.8 Hz, 3H), 3.59 (s, 3H), 6.62-6.66 (m, 1H), 7.04 (d, J=3.5 Hz, 1H), 7.11 (s, 1H); 13C NMR (CDCl3, 100 MHz) δ15.3, 36.8, 91.0, 118.7, 122.2, 125.5, 134.3, 138.1, 140.5; HRMS (EI) m/z 303.9533 C9H9N21S [M]+. requires 303.9526.

Workup

  1. additionwas added dropwise (˜2 min)
  2. temperaturere-cooled to −78° C
  3. temperatureto warm to room temperature (over ˜2 h)
  4. concentrationthe mixture was concentrated to ˜10 mL
  5. additionThe mixture was diluted with CH2Cl2
  6. customH2O, saturated aqueous Na2S2O3 and the organic phase was separated
  7. extractionThe aqueous phase was re-extracted (CH2Cl2)
  8. washthe combined organics were washed (saturated aqueous NaCl)
  9. dry with materialdried (MgSO4)
  10. filtrationfiltered
  11. concentrationconcentrated
  12. customto give a residue
  13. customThe residue was purified by flash chromatography (EtOAc/hexanes 10:90

Sources & evidence

ORD record
ord-0b25505f74f2460da2483bea162baa44
Source dataset
uspto-grants-2015_01
Patent number
US08937303B2

Reaction notes

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