2,2-Diethylpropanedioate → 5,6-dichloro-1H-pyrrolo[3,2-b]pyridin-2(3H)-one

HRID 2394343Notes

Reaction equation

HRID 2394343 reaction equation
C([O:3][C:4]([CH:6](C(OCC)=O)[C:7]1[C:12]([N+:13]([O-])=O)=[CH:11][C:10]([Cl:16])=[C:9]([Cl:17])[N:8]=1)=O)C.C(OC(C(C(OCC)=O)C1C(Cl)=CC([N+]([O-])=O)=C(Cl)N=1)=O)C.C(C(CC)(C([O-])=O)C([O-])=O)C.NC1C(C(C(OCC)=O)C(OCC)=O)=NC(Cl)=C(Cl)C=1.NC1(Cl)C=CC(Cl)=NC1C(C(OCC)=O)C(OCC)=O>C(O)C.[Ni].O.Cl.CCCCCC.C(OCC)(=O)C>[Cl:17][C:9]1[N:8]=[C:7]2[C:12](=[CH:11][C:10]=1[Cl:16])[NH:13][C:4](=[O:3])[CH2:6]2

Participants

11

Reactant 5

HCID 69515632,2-DiethylpropanedioateHCID 10594057HCID 10594057, compoundHCID 10829571HCID 10829571, compoundHCID 11792215136888-77-2HCID 18973096HCID 18973096, compound

Product 1

HCID 106319655,6-dichloro-1H-pyrrolo[3,2-b]pyridin-2(3H)-oneYield 71%

Reagents, catalysts & solvents 5

HCID 935NickelCatalystHCID 313Hydrochloric AcidSolventHCID 702EthanolSolvent2×HCID 962WaterSolventHCID 21226206Ethyl acetate hexaneSolvent

Procedure

The mixture of 2-bis(ethoxycarbonyl)methyl-5,6-dichloro-3-nitropyridine, 2-bis(ethoxycarbonyl)methyl-3,6-dichloro-5-nitropyridine and diethylmalonate was dissolved in ethanol (100 mL) and added to a suspension of 50% Raney nickel in water (30 g) diluted with ethanol (10 mL). The mixture was hydrogenated in a Parr shaker at 3 atmospheres pressure for 5 hours and then filtered through diatomaceous earth (Celite (trademark)) to remove the catalyst. The solvent was removed in vacuo to leave an oil which was subjected to flash chromatography on silica gel eluting with 4:1 hexane/ethyl acetate. Each of the fractions was separately concentrated and the residues examined by 1H NMR in deuterochloroform. Eluted after diethylmalonate was the desired product, 3-amino-2-bis(ethoxycarbonyl)methyl-5,6-dichloropyridine, followed closely thereafter by the unwanted isomer, 5-amino-2-bis(ethoxycarbonyl)methyl-3,6-dichloropyridine. Although clean separation from diethyl malonate was achieved, the bulk of the mass of desired product and the isomer eluted as mixed fractions. Leading fractions containing only 3-amino-2-bis(ethoxycarbonyl)methyl-5,6-dichloropyridine and mixed fractions containing at least 10% of this material were combined to afford a solid consisting of 3-amino-2-bis(ethoxycarbonyl)methyl-5,6-dichloropyridine (3.17 g) and the unwanted isomer, 3-amino-2-bis(ethoxycarbonyl)methyl-3,6-dichloropyridine (4.03 g). This mixture was taken up in 6N HCl solution (120 mL) and heated at reflux for 3 hours. After cooling to room temperature the volatiles were removed in vacuo. Ethanol was added and then evaporated to help remove water. This process was repeated. The resulting brown solid was subjected to flash chromatography on silica gel using 9:1 chloroform/methanol as eluant. All fractions containing the desired product were combined and concentrated to leave a solid which was triturated with methanol to afford 5,6-dichloro-4-azaoxindole (1.42 g, 71%) from 3-amino-2-bis(ethoxycarbonyl)methyl-5,6-dichloropyridine, 13% overall from 3-nitro-2,5,6-trichloropyridne). M.p. 230°-233° C. (dec).

Workup

  1. filtrationfiltered through diatomaceous earth (Celite (trademark))
  2. customto remove the catalyst
  3. customThe solvent was removed in vacuo
  4. customto leave an oil which
  5. concentrationEach of the fractions was separately concentrated
  6. washEluted after diethylmalonate
  7. customAlthough clean separation from diethyl malonate
  8. washthe bulk of the mass of desired product and the isomer eluted
  9. additionas mixed fractions
  10. additionLeading fractions containing only 3-amino-2-bis(ethoxycarbonyl)methyl-5,6-dichloropyridine
  11. additionmixed fractions
  12. additioncontaining at least 10% of this material
  13. customto afford a solid
  14. temperatureheated
  15. temperatureat reflux for 3 hours
  16. customwere removed in vacuo
  17. additionEthanol was added
  18. customevaporated
  19. customto help remove water
  20. additionAll fractions containing the desired product
  21. concentrationconcentrated
  22. customto leave a solid which
  23. customwas triturated with methanol

Sources & evidence

ORD record
ord-7a50a3ca2ea0424d8dd8fdf65d4b2941
Source dataset
uspto-grants-1998_09
Patent number
US05811432

Reaction notes

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