5-Bromo-4-methyl-1,3-thiazole → 7-(1-Ethyl-propyl)-2,5-dimethyl-3-(4-methyl-thiazol-5-yl)-pyrazolo[1,5-a]pyrimidine

HRID 1660741Notes

Reaction equation

HRID 1660741 reaction equation
Br[C:2]1[S:6][CH:5]=[N:4][C:3]=1[CH3:7].[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]>O1CCCC1.[Zn].Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH2:8]([CH:10]([C:13]1[N:18]2[N:19]=[C:20]([CH3:23])[C:21]([C:2]3[S:6][CH:5]=[N:4][C:3]=3[CH3:7])=[C:17]2[N:16]=[C:15]([CH3:24])[CH:14]=1)[CH2:11][CH3:12])[CH3:9]

Participants

6

Reactant 2

HCID 150209975-Bromo-4-methyl-1,3-thiazoleHCID 248985233-Iodo-2,5-dimethyl-7-(pentan-3-yl)pyrazolo[1,5-a]pyrimidine

Product 1

HCID 674287127-(1-Ethyl-propyl)-2,5-dimethyl-3-(4-methyl-thiazol-5-yl)-pyrazolo[1,5-a]pyrimidineYield 79.1%

Reagents, catalysts & solvents 3

HCID 23994ZincCatalyst2×HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 8028TetrahydrofuranSolvent

Procedure

Add Rieke® zinc (10 g in 100 mL of THF, 13.2 mL, 18.48 mmol) to 5-bromo-4-methylthiazole (2.13 g, 18.48 mmol) and heat at reflux for 2 h. Cool the mixture to room temperature and settle the zinc down by centrifuge. Bubble nitrogen gas through 7-(1-ethyl-propyl)-3-iodo-2,5-dimethyl-pyrazolo[1,5-a]pyrimidine (900 mg, 2.62 mmol) in dry tetrahydrofuran (10 mL) and add the organozinc bromide solution followed by addition of [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (106 mg, 0.13 mmol). Stir the reaction mixture under reflux overnight and cool to room temperature. Add ammonium chloride solution to the reaction mixture and extract with dichloromethane. Dry the organic portion over sodium sulfate, filter, and remove the solvent under vacuum. Purify the crude product by silica gel column chromatography, elueting with hexane/ethyl acetate (3/1) to obtain the title compound (652 mg, 79%). 1H NMR (400 MHz, CDCl3): δ 8.80 (s, 1H), 6.48 (s, 1H), 3.63 (m, 1H), 2.57 (s, 3H), 2.43 (s, 3H), 2.40 (s, 3H), 1.85 (m, 4H), 0.90 (t, 6H, J=7.3Hz). ES/MS m/z 315 (M+1)+.

Workup

  1. temperatureheat
  2. temperatureat reflux for 2 h
  3. temperatureunder reflux overnight
  4. temperaturecool to room temperature
  5. extractionAdd ammonium chloride solution to the reaction mixture and extract with dichloromethane
  6. dry with materialDry the organic portion over sodium sulfate
  7. filtrationfilter
  8. customremove the solvent under vacuum
  9. customPurify the crude product by silica gel column chromatography

Sources & evidence

ORD record
ord-718a48d476884e51a2b7c3b89c1b7d8c
Source dataset
uspto-grants-2011_10
Patent number
US08030304B2

Reaction notes

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