Dimethylformamide → ethyl 4-chloro-3-cyano-5-methyl-1H-pyrrole-2-carboxylate

HRID 655753Notes

Reaction equation

HRID 655753 reaction equation
Br[C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10].[CH3:14][N:15](C=O)C>[C-]#N.[C-]#N.[Zn+2].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].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.[Fe+2]>[Cl:7][C:6]1[C:2]([C:14]#[N:15])=[C:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[NH:4][C:5]=1[CH3:8]

Participants

6

Reactant 2

HCID 6228DimethylformamideHCID 66707680ethyl 3-bromo-4-chloro-5-methyl-1H-pyrrole-2-carboxylate2×

Product 1

HCID 66707683ethyl 4-chloro-3-cyano-5-methyl-1H-pyrrole-2-carboxylate

Reagents, catalysts & solvents 3

HCID 11186Zinc cyanide (Zn(CN)2)Catalyst2×HCID 635956Ferrocene-1,1'-bis-(diphenylphosphine)Catalyst2×HCID 9811564Bis(dibenzylideneacetone)palladiumCatalyst2×

Conditions

Temperature
130 °C

Procedure

Nitrogen gas was bubbled through a mixture of 1.4 g (5.25 mmol) of ethyl 3-bromo-4-chloro-5-methyl-1H-pyrrole-2-carboxylate (Intermediate 14), 470 g (4 mol) Zn(CN)2, 250 mg (0.26 mmol) Pd2(dba)3 and 302 mg (0.26 mmol) dppf in 15 ml DMF for 15 min. The mixture was heated at 130° C. for 1 h. Additional Zn(CN)2 (1 g), Pd2(dba)3 (500 mg) and dppf (604 mg) were added. After bubbling through N2 for 15 min and heating at 130° C. for 2 h, additional Zn(CN)2 (0.5 g), Pd2(dba)3 (250 mg) and dppf (302 mg) were added. Heating was continued at 130° C. for 2 h. Solvent was removed and the residue was partitioned between EtOAc and water. The EtOAc was separated and washed with brine. Combined aqueous layers were extracted again with EtOAc, which was washed with brine. Combined EtOAc extracts were dried (MgSO4) and concentrated. The residue was purified by silica gel chromatography (100% CH2Cl2 followed by gradient elution to 5% MeOH in CH2Cl2) to afford 750 mg of product as a solid. MS (ES) (MH+): 213 for C9H9ClN2O2; NMR (d6-DMSO): 1.3 (t, 3H), 2.2 (s, 3H), 4.3 (q, 2H), 13.1 (s, 1H).

Workup

  1. customAfter bubbling through N2 for 15 min
  2. temperatureheating at 130° C. for 2 h
  3. additionadditional Zn(CN)2 (0.5 g), Pd2(dba)3 (250 mg) and dppf (302 mg) were added
  4. temperatureHeating
  5. customSolvent was removed
  6. customthe residue was partitioned between EtOAc and water
  7. customThe EtOAc was separated
  8. washwashed with brine
  9. extractionCombined aqueous layers were extracted again with EtOAc, which
  10. washwas washed with brine
  11. dry with materialCombined EtOAc extracts were dried (MgSO4)
  12. concentrationconcentrated
  13. customThe residue was purified by silica gel chromatography (100% CH2Cl2 followed by gradient elution to 5% MeOH in CH2Cl2)

Sources & evidence

ORD record
ord-f4d77ddc35694c908ffc45179fdd0833
Source dataset
uspto-grants-2011_12
Patent number
US08071605B2

Reaction notes

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