Tetrahydrofuran → 6-(2-(Pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)quinoxaline

HRID 751286Notes

Reaction equation

HRID 751286 reaction equation
C1COCC1.Br[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][CH:11]=[N:10]2.[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[C:24](B(O)O)=[C:25]2[CH2:30][CH2:29][CH2:28][N:26]2[N:27]=1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CN(C=O)C.C1COCC1>[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[C:24]([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[N:13]=[CH:12][CH:11]=[N:10]3)=[C:25]2[CH2:30][CH2:29][CH2:28][N:26]2[N:27]=1

Participants

7

Reactant 4

HCID 8028TetrahydrofuranHCID 11430Potassium CarbonateHCID 6109396-BromoquinoxalineHCID 59710031(2-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-boronic acid

Product 1

HCID 103582146-(2-(Pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)quinoxalineYield 30.1%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalyst2×HCID 21974620tetrahydrofuran N,N-dimethylformamideSolvent

Procedure

Add THF (2.2 mL) to 6-bromo-quinoxaline (Yamamoto, T. et al., J. Am. Chem. Soc. 1996, 118, 3930-3936; 219 mg, 1.05 mmol) and purge the solution with nitrogen for 10 min. Add tris(dibenzylideneacetone)dipalladium(0) (80 mg, 0.087 mmol) and bis(1,2-bis(diphenylphosphino)ethane)palladium(0) (78 mg, 0.087 mmol), purge the reaction with nitrogen for 2 min, and stir the reaction at room temperature for 20 min. Add (2-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-boronic acid (Preparation 5; 200 mg, 0.87 mmol) in 1:1 DMF/THF (2 mL each) and stir for 10 min. Add 2.0M aqueous potassium carbonate (1.04 mL, 2.1 mmol) and heat the reaction to 65° C. Add additional tris(dibenzylideneacetone)dipalladium(0) (80 mg, 0.087 mmol) after 1 h and 3 h. Stir the reaction at 65° C. for 18 h, filter through Celite® with methanol/chloroform, and concentrate in vacuo. Purify by flash column chromatography followed by reverse-phase preparative HPLC. Concentrate the pure fractions from the preparative HPLC in vacuo, take up in methanol, treat with MP-carbonate beads, filter, and concentrate in vacuo to provide the title compound (82 mg, 30%) as a clear, colorless oil. MS ESI+ m/e 314 (M+1). 1H NMR (CDCl3) δ 8.86 (m, 3H), 8.11 (m, 1H), 8.05 (m, 2H), 7.79 (m, 2H), 7.47 (m, 1H), 4.33 (m, 2H), 3.11 (m, 2H), 2.72 (m, 2H). HPLC: 98.5%, Rt=13.61 min. TLC (SiO2): Rf0.3 (1:3 [80:18:2 chloroform/methanol/concentrated aqueous ammonium hydroxide]/dichloromethane).

Workup

  1. custompurge the solution with nitrogen for 10 min
  2. customthe reaction with nitrogen for 2 min
  3. customthe reaction at room temperature for 20 min
  4. temperatureheat
  5. customthe reaction to 65° C
  6. custom3 h
  7. stirringStir
  8. customthe reaction at 65° C. for 18 h
  9. filtrationfilter through Celite® with methanol/chloroform
  10. concentrationconcentrate in vacuo
  11. customPurify by flash column chromatography
  12. concentrationConcentrate the pure fractions from the preparative HPLC in vacuo
  13. additiontreat with MP-carbonate beads
  14. filtrationfilter
  15. concentrationconcentrate in vacuo

Sources & evidence

ORD record
ord-09eae8e44a1c4457a56bf1cff02bae44
Source dataset
uspto-grants-2008_07
Patent number
US07405299B2

Reaction notes

Loading…