Hydrochloric Acid → 4-Bromo-5-(chloroacetyl)thiophene-2-carbonitrile

HRID 1436387Notes

Reaction equation

HRID 1436387 reaction equation
C([Li])CCC.[Br:6][C:7]1[CH:8]=[C:9]([C:12]#[N:13])[S:10][CH:11]=1.C(=O)=O.CC(C)=O.[Cl:21][CH2:22][C:23](N(OC)C)=[O:24].Cl>O1CCCC1>[Br:6][C:7]1[CH:8]=[C:9]([C:12]#[N:13])[S:10][C:11]=1[C:23](=[O:24])[CH2:22][Cl:21]

Participants

7

Reactant 5

HCID 313Hydrochloric AcidHCID 27347162-Chloro-N-methoxy-N-methylacetamideHCID 142923554-Bromothiophene-2-carbonitrileHCID 18522661Acetone cardice3×HCID 178418339Butyllithium

Product 1

HCID 866185894-Bromo-5-(chloroacetyl)thiophene-2-carbonitrileYield 22%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

Butyllithium (2.5 M solution in hexanes; 14.5 mL, 36.3 mmol) was added under nitrogen over approximately 5 min to a solution of 4-bromo-thiophene-2-carbonitrile (5.95 g, 31.6 mmol) in 300 mL of anhydrous tetrahydrofuran at dry ice-acetone temperature. After the addition, the reaction was stirred at dry ice-acetone temperature for 30 min. 2-Chloro-N-methoxy-N-methyl acetamide (4.80 g, 32.7 mmol) in 40 mL of anhydrous tetrahydrofuran was then added dropwise over 30 min. After the addition, the reaction was stirred at dry ice-acetone temperature for 4 h. 6 M HCl (36 mL) was added and the reaction allowed to warm to room temperature. The reaction was concentrated under reduced pressure to remove the tetrahydrofuran. The residue was partitioned between ethyl acetate and water. Saturated sodium chloride was added to aid in the separation of an emulsion. The organic layer was separated, washed with water, saturated sodium chloride, dried (MgSO4), filtered and the solvent removed under reduced pressure. The residue was purified on 800 g of silica gel (230-400 mesh) using a gradient of 30% methylene chloride in hexane to 60% methylene chloride in hexane as the eluent. Isolation of the major component gave 4-bromo-5-(chloroacetyl)thiophene-2-carbonitrile (1.81 g, 22%) as a white solid, mp 126-128° C.; MS (ESI) m/z 262.

Workup

  1. additionAfter the addition
  2. additionAfter the addition
  3. concentrationThe reaction was concentrated under reduced pressure
  4. customto remove the tetrahydrofuran
  5. customThe residue was partitioned between ethyl acetate and water
  6. additionSaturated sodium chloride was added to aid in the separation of an emulsion
  7. customThe organic layer was separated
  8. washwashed with water, saturated sodium chloride
  9. dry with materialdried (MgSO4)
  10. filtrationfiltered
  11. customthe solvent removed under reduced pressure
  12. customThe residue was purified on 800 g of silica gel (230-400 mesh)

Sources & evidence

ORD record
ord-a114069fa683406fbcfd68aa52a21bc7
Source dataset
uspto-grants-2009_11
Patent number
US07618990B2

Reaction notes

Loading…