2-Trimethylsilylthiazole → 2,5-Dimethyl-7-(1-propyl-butyl)-3-thiazol-5-yl-pyrazolo[1,5-a]pyrimidine

HRID 1660739Notes

Reaction equation

HRID 1660739 reaction equation
C[Si](C)(C)[C:3]1[S:4][CH:5]=[CH:6][N:7]=1.C([Li])CCC.[CH2:15]([CH:18]([C:22]1[N:27]2[N:28]=[C:29]([CH3:32])[C:30](I)=[C:26]2[N:25]=[C:24]([CH3:33])[CH:23]=1)[CH2:19][CH2:20][CH3:21])[CH2:16][CH3:17]>C1COCC1.[Cl-].[Zn+2].[Cl-].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:32][C:29]1[C:30]([C:5]2[S:4][CH:3]=[N:7][CH:6]=2)=[C:26]2[N:25]=[C:24]([CH3:33])[CH:23]=[C:22]([CH:18]([CH2:19][CH2:20][CH3:21])[CH2:15][CH2:16][CH3:17])[N:27]2[N:28]=1

Participants

7

Reactant 3

HCID 5884532-TrimethylsilylthiazoleHCID 248985247-(1-Propyl-butyl)-3-iodo-2,5-dimethyl-pyrazolo[1,5-a]pyrimidineHCID 178418339Butyllithium

Product 1

HCID 674278072,5-Dimethyl-7-(1-propyl-butyl)-3-thiazol-5-yl-pyrazolo[1,5-a]pyrimidineYield 42.3%

Reagents, catalysts & solvents 3

HCID 3007855ZincchlorideCatalystHCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
-78 °C

Procedure

Charge an oven dried flask with 2-trimethylsilanylthiazole (1.765 g, 11.24 mmol) dissolved in anhydrous THF (30 mL) and chill under an inert atmosphere to −78° C. Slowly add n-butyl lithium (2.5 M hexane solution, 4.5 mL, 11.24 mmol) and stir 30 min at −78° C. Add anhydrous zinc chloride (2.26 g, 16.58 mmol) in one aliquot and stir 30 min at −78° C. Allow the reaction to rise to room temperature, stir 30 min, and add 7-(1-propyl-butyl)-3-iodo-2,5-dimethyl-pyrazolo[1,5-a]pyrimidine (1.624 g, 5.18 mmol) and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane (0.423 g, 0.518 mmol). Reflux overnight in an oil bath (90° C.) under an inert atmosphere. Cool the reaction to room temperature, quench with saturated sodium bicarbonate, and dilute with ethyl acetate (150 mL). Separate and extract the aqueous with ethyl acetate (75 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% (30% THF/hexane) to 0% hexane/100% (30% THF/hexane) in a step gradient of 10% increments to give a white solid (0.720 g, 42%). ES/MS m/z 329.0 (M+1)+.

Workup

  1. additionCharge an oven
  2. customthe reaction
  3. customto rise to room temperature
  4. temperatureReflux overnight in an oil bath (90° C.) under an inert atmosphere
  5. temperatureCool
  6. customthe reaction to room temperature
  7. customquench with saturated sodium bicarbonate
  8. additiondilute with ethyl acetate (150 mL)
  9. customSeparate
  10. extractionextract the aqueous with ethyl acetate (75 mL)
  11. dry with materialCombine the organic phases, dry over anhydrous magnesium sulfate
  12. filtrationfilter
  13. concentrationconcentrate under reduced pressure
  14. customPurify the resulting residue
  15. washeluting with 100% hexane/0% (30% THF/hexane) to 0% hexane/100% (30% THF/hexane) in a step gradient of 10% increments

Sources & evidence

ORD record
ord-4643d4c65952478886d7f763cc52ec94
Source dataset
uspto-grants-2011_10
Patent number
US08030304B2

Reaction notes

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