Isopropyl Acetate → Ethyl 4-cyano-3-[4-(2-cyanophenyl)phenyl]-5-ethyl-1-methylpyrrole-2-carboxylate

HRID 1865077Notes

Reaction equation

HRID 1865077 reaction equation
CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]#[N:22])=[CH:11][CH:10]=2)O1.[CH2:24]([O:26][C:27]([C:29]1[N:30]([CH3:39])[C:31]([CH2:37][CH3:38])=[C:32]([C:35]#[N:36])[C:33]=1I)=[O:28])[CH3:25].C(OC(C)C)(=O)C.C(=O)([O-])[O-].[K+].[K+]>O.[Pd].CC([O-])=O.CC([O-])=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd+2].C(O)C>[C:35]([C:32]1[C:33]([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]#[N:22])=[CH:13][CH:14]=2)=[C:29]([C:27]([O:26][CH2:24][CH3:25])=[O:28])[N:30]([CH3:39])[C:31]=1[CH2:37][CH3:38])#[N:36]

Participants

9

Reactant 4

HCID 7915Isopropyl AcetateHCID 11430Potassium Carbonate2×HCID 579750002-[4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]benzenecarbonitrileHCID 57975348HCID 57975348, compound

Product 1

HCID 69020544Ethyl 4-cyano-3-[4-(2-cyanophenyl)phenyl]-5-ethyl-1-methylpyrrole-2-carboxylateYield 62.7%

Reagents, catalysts & solvents 4

HCID 23938PalladiumCatalystHCID 84538Palladium(2+) acetate--triphenylphosphane (1/2/2)CatalystHCID 702EthanolSolventHCID 962WaterSolvent2×

Conditions

Temperature
75 °C

Procedure

Add 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]benzenecarbonitrile (0.916 grams, 0.003 moles, prepared in preparation 58), 4-cyano-5-ethyl-3-iodo-1-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (0.996 grams, 0.003 moles, prepared in preparation 38), isopropyl acetate (14 mL) and ethanol (6 mL) to a 100 mL 3-neck flask. Stir the mixture under a nitrogen atmosphere and add palladium black (0.0319 grams, 0.0003 moles). Add a solution of potassium carbonate (0.663 grams, 0.0048 moles) in water (6 mL). Heat the mixture to reflux at 75° C. for 135 minutes. Add bis(acetato)bis(triphenylphosphine)palladium (II) (0.045 grams, 0.00006 moles) and continue heating at reflux for an additional 105 minutes. Add a solution of potassium carbonate (0.16 grams, 0.00116 moles) in water and continue heating at reflux for an additional 195 minutes. Cool the mixture to room temperature and stir for about 16 hours. Warm the mixture to 75° C. and filter to remove palladium black. Transfer the filtrate to a separatory funnel and add acetone (20 mL) to redissolve a precipitate and then separate the phases. Discard the aqueous phase. Concentrate the organic phase to a solid under reduced pressure (15-25 mm) and suspend the solid in ethanol (3 mL) and water (7 mL). Filter the suspension to recover the solid, and transfer the solid to a 20 mL vial. Add ethanol (12 mL) and warm to reflux. Slowly cool the resulting solution to about 23° C. and filter the resulting suspension to recover the precipitate. Dry the solid at 45° C. under reduced pressure (15-25 mm) to provide the title compound (0.72 g, 0.00188 moles) in 62.6% yield. 1H NMR (CDCl3, 500 MHz): δ 7.77 (app d, 2H, J=8); 7.66 (app. td, 1H. J=117.5): 7.57 (m, 3H), 7.49-7.43 (m,3H); 4.10 (q, 2H, J=6.5); 3.91 (s, 3H); 2.87 (q, 2H, J=8); 1.32 (t, 3H, J=7.5); 1.04 (t, 3H, J=7).

Workup

  1. temperatureHeat the mixture
  2. temperatureat reflux for an additional 105 minutes
  3. temperaturecontinue heating
  4. temperatureat reflux for an additional 195 minutes
  5. temperatureCool the mixture to room temperature
  6. stirringstir for about 16 hours
  7. temperatureWarm the mixture to 75° C.
  8. filtrationfilter
  9. customto remove palladium black
  10. additionadd acetone (20 mL)
  11. dissolutionto redissolve a precipitate
  12. customseparate the phases
  13. concentrationConcentrate the organic phase to a solid under reduced pressure (15-25 mm)
  14. filtrationFilter the suspension
  15. customto recover the solid
  16. temperatureAdd ethanol (12 mL) and warm to reflux
  17. temperatureSlowly cool the resulting solution to about 23° C.
  18. filtrationfilter the resulting suspension
  19. customto recover the precipitate
  20. customDry the solid at 45° C. under reduced pressure (15-25 mm)

Sources & evidence

ORD record
ord-2147e6138bb249a2b19dd67e9bd23f6d
Source dataset
uspto-grants-2009_12
Patent number
US07625932B2

Reaction notes

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