2-Bromo-3-chlorothiophene → HCID 24758884, compound

HRID 1639656Notes

Reaction equation

HRID 1639656 reaction equation
Br[C:2]1[S:3][CH:4]=[CH:5][C:6]=1[Cl:7].[CH2:8]([CH:10]([C:13]1[N:18]2[N:19]=[C:20]([CH3:23])[C:21](I)=[C:17]2[N:16]=[C:15]([CH3:24])[CH:14]=1)[CH2:11][CH3:12])[CH3:9]>C1COCC1.[Zn]>[Cl:7][C:6]1[CH:5]=[CH:4][S:3][C:2]=1[C:21]1[C:20]([CH3:23])=[N:19][N:18]2[C:13]([CH:10]([CH2:8][CH3:9])[CH2:11][CH3:12])=[CH:14][C:15]([CH3:24])=[N:16][C:17]=12

Participants

5

Reactant 2

HCID 27245612-Bromo-3-chlorothiopheneHCID 248985233-Iodo-2,5-dimethyl-7-(pentan-3-yl)pyrazolo[1,5-a]pyrimidine

Product 1

HCID 24758884HCID 24758884, compoundYield 80.9%

Reagents, catalysts & solvents 2

HCID 23994ZincCatalyst2×HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
85 °C

Procedure

Suspend Reike® zinc (5 g/100 mL THF, 20 mL, 15.0 mmol) in anhydrous THF (10 mL) and add 2-bromo-3-chlorothiophene (1.98 g, 10.0 mmol). Reflux the mixture under an inert atmosphere in an oil bath (85° C.) for 3 h. Cool the reaction to room temperature and centrifuge the remaining zinc metal. Canulate off the reagent solution into a new vessel under positive argon pressure and add 7-(1-ethyl-propyl)-3-iodo-2,5-dimethyl-pyrazolo[1,5-a]pyrimidine (1.72 g, 5.0 mmol). Degas the solution by positive argon pressure for 10-15 min and add dichloro[1,1′-bis(diphenyl-phosphino)ferrocene]palladium (II) dichloromethane (0.225 g, 0.275 mmol). Stir at reflux temperature overnight under an inert atmosphere. Cool the reaction to room temperature, quench with saturated ammonium chloride, and dilute with ethyl acetate (75 mL). Separate and extract the aqueous portion with ethyl acetate (50 mL), combine the organic phases, dry over anhydrous magnesium sulfate, filter, and concentrate under reduced pressure. Purify the resulting residue using flash chromatography, eluting with 100% hexane/0% (15% ethyl acetate/hexane) to 0% hexane/100% (15% ethyl acetate/hexane) in a step gradient of 10% increments to give a yellow solid (1.35 g, 40%). ES/MS m/z (35Cl) 334.4 (M+1)+.

Workup

  1. temperatureCool
  2. customthe reaction to room temperature
  3. customDegas the solution by positive argon pressure for 10-15 min
  4. temperatureat reflux temperature overnight under an inert atmosphere
  5. temperatureCool
  6. customthe reaction to room temperature
  7. customquench with saturated ammonium chloride
  8. additiondilute with ethyl acetate (75 mL)
  9. customSeparate
  10. extractionextract the aqueous portion with ethyl acetate (50 mL)
  11. dry with materialdry over anhydrous magnesium sulfate
  12. filtrationfilter
  13. concentrationconcentrate under reduced pressure
  14. customPurify the resulting residue
  15. washeluting with 100% hexane/0% (15% ethyl acetate/hexane) to 0% hexane/100% (15% ethyl acetate/hexane) in a step gradient of 10% increments

Sources & evidence

ORD record
ord-eadf10d992094a6fba4e3a9dad77f8af
Source dataset
uspto-grants-2012_02
Patent number
US08110580B2

Reaction notes

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