1,4-Dioxane → 2-(Chloroacetyl)thiophene

HRID 324520Notes

Reaction equation

HRID 324520 reaction equation
C[Si](C=[N+]=[N-])(C)C.[CH:8]1[CH:12]=[C:11]([CH2:13][C:14]([Cl:16])=O)[S:10][CH:9]=1.[O:17]1CCOCC1>>[Cl:16][CH2:14][C:13]([C:11]1[S:10][CH:9]=[CH:8][CH:12]=1)=[O:17]

Participants

4

Reactant 3

HCID 312751,4-DioxaneHCID 1623622-Thiopheneacetyl chlorideHCID 167693Trimethylsilyldiazomethane2×

Product 1

HCID 27579252-(Chloroacetyl)thiopheneYield 42%

Procedure

Trimethylsilyl diazomethane (TMSCHN2, 2M in hexanes, 100 ml, 0.200 mole) was added dropwise, over a period of 20 minutes, to an ice bath solution of thiophene-2-acetyl chloride (0.192 mole, 28.1 g) in 100 ml of dry 1,4-dioxane. The slush disappeared upon addition of TMSCHN2. The reaction mixture was slowly warmed to room temperature and stirred for 24 hours. The reaction mixture was cooled in an ice bath and HCl gas was bubbled for 0.5 hour and stirred at room temperature for 2 days. The solvent was removed under reduced pressure, the residue partitioned between 100 ml of aqueous saturated NaHCO3 solution and 250 ml of ethyl acetate and separated. The organic phase was washed with 100 ml of aqueous saturated NaHCO3 solution, dried (Na2SO4) and the solvent was removed under reduced pressure. The crude product was chromatographed on 200 g of silica packed with 2.5% EtOAc-hexanes and the column was eluted with increasing amounts of ethyl acetate in hexanes (2.5%, 1 L, 5%, 1 L; 7.5%, 1 L, 10%, 1 L; 12.5%, 1 L; 15%, 1 L) to give 12.8 g of the desired product which was slightly contaminated: 42% yield; 1H NMR (CDCl3) δ 7.80 (dd, 1H, J=0.9, 3.9 Hz), 7.74 (dd, 1H, J=0.9, 5.0 Hz average), 7.19 (dd, 1H, J=0.9, 5.0 Hz average), 4.61 (s, 2H). This product turned yellow and then brown over time and therefore was used in the formation of the 2-amino-1,3-thiazole derivatives as soon as possible.

Workup

  1. temperatureThe reaction mixture was cooled in an ice bath
  2. customHCl gas was bubbled for 0.5 hour
  3. stirringstirred at room temperature for 2 days
  4. customThe solvent was removed under reduced pressure
  5. customthe residue partitioned between 100 ml of aqueous saturated NaHCO3 solution and 250 ml of ethyl acetate
  6. customseparated
  7. washThe organic phase was washed with 100 ml of aqueous saturated NaHCO3 solution
  8. dry with materialdried (Na2SO4)
  9. customthe solvent was removed under reduced pressure
  10. customThe crude product was chromatographed on 200 g of silica
  11. washthe column was eluted with increasing amounts of ethyl acetate in hexanes (2.5%, 1 L, 5%, 1 L; 7.5%, 1 L, 10%, 1 L; 12.5%, 1 L; 15%, 1 L)

Sources & evidence

ORD record
ord-25aca57a7b5249a8b26801a77f5d3129
Source dataset
uspto-grants-2001_04
Patent number
US06218408B1

Reaction notes

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