Tetrahydrofuran → 3-hydroxy-2,2-dimethyl-1-[2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-propan-1-one

HRID 1677470Notes

Reaction equation

HRID 1677470 reaction equation
I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=3)[N:9]=2)[N:4]([Si](C(C)C)(C(C)C)C(C)C)[CH:3]=1.[Li]CCCC.CO[C:40]([CH3:48])([CH3:47])[C:41](N(OC)C)=[O:42].CCCC[N+](CCCC)(CCCC)CCCC.[F-].[O:67]1CCC[CH2:68]1>>[OH:67][CH2:68][C:40]([CH3:47])([CH3:48])[C:41]([C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:12]=[C:13]([O:21][CH3:22])[C:14]([O:19][CH3:20])=[C:15]([O:17][CH3:18])[CH:16]=3)[N:9]=2)[NH:4][CH:3]=1)=[O:42]

Participants

6

Reactant 5

HCID 8028Tetrahydrofuran3×HCID 2724141Tetrabutylammonium FluorideHCID 595405257-iodo-5-triisopropylsilanyl-2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazineHCID 86646687N,2-Dimethoxy-N,2-dimethylpropanamideHCID 178418339Butyllithium

Product 1

HCID 595406983-hydroxy-2,2-dimethyl-1-[2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-propan-1-oneYield 11%

Procedure

A solution of 7-iodo-5-triisopropylsilanyl-2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazine (233 mg, 0.410 mmol) in anhydrous tetrahydrofuran (3 ml) was cooled to −78° C. and treated with nBuLi (2.29M in hexanes, 0.25 ml, 0.57 mmol) dropwise. The solution was stirred for 30 seconds and then 2,N-dimethoxy-2,N-dimethyl-propionamide (198 mg, 1.23 mmol), dissolved in THF (5 ml), was added dropwise. The reaction mixture was stirred at −78° C. for 30 minutes and then at room temperature 30 minutes. The reaction mixture was quenched with saturated aqueous NaHSO4 and then partitioned between EtOAc/water. The organic layers were collected, dried over MgSO4, filtered, and concentrated giving a brown oil. The oil was purified by silica gel chromatography using 10-50% EtOAc in hexanes as eluant providing a yellow solid. The yellow solid was dissolved in THF (5 ml) and treated with TBAF (1M in THF, 5.3 ml, 5.3 mmol) and refluxed for 6 hours. The reaction mixture was partitioned between EtOAc/1N HCl. The organic layers were collected, dried over MgSO4, filtered, and concentrated giving a yellow solid. The crude product was purified by preparative thin layer chromatography using 10% [5% NH4OH:MeOH]/DCM as eluant providing 30 mg (11%) of 3-hydroxy-2,2-dimethyl-1-[2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-propan-1-one as a pale yellow solid. MP 227-229° C., M+H=386.

Workup

  1. additionwas added dropwise
  2. stirringThe reaction mixture was stirred at −78° C. for 30 minutes
  3. customat room temperature
  4. custom30 minutes
  5. customThe reaction mixture was quenched with saturated aqueous NaHSO4
  6. custompartitioned between EtOAc/water
  7. customThe organic layers were collected
  8. dry with materialdried over MgSO4
  9. filtrationfiltered
  10. concentrationconcentrated
  11. customgiving a brown oil
  12. customThe oil was purified by silica gel chromatography
  13. customproviding a yellow solid
  14. temperaturerefluxed for 6 hours
  15. customThe reaction mixture was partitioned between EtOAc/1N HCl
  16. customThe organic layers were collected
  17. dry with materialdried over MgSO4
  18. filtrationfiltered
  19. concentrationconcentrated
  20. customgiving a yellow solid
  21. customThe crude product was purified by preparative thin layer chromatography

Sources & evidence

ORD record
ord-60776891d40c424fab97daf55d409f8d
Source dataset
uspto-grants-2011_08
Patent number
US08008298B2

Reaction notes

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