Isobutyraldehyde → Diethyl 3-(propan-2-yl)-1H-pyrrole-2,4-dicarboxylate

HRID 966142Notes

Reaction equation

HRID 966142 reaction equation
[N+:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[C-].N12[CH2:19][CH2:18][CH2:17]N=C1CCCCC2.[CH:20](=[O:24])[CH:21]([CH3:23])[CH3:22].[O:25]1CC[CH2:27][CH2:26]1>>[CH2:7]([O:6][C:4]([C:3]1[NH:1][CH:22]=[C:21]([C:20]([O:25][CH2:26][CH3:27])=[O:24])[C:23]=1[CH:18]([CH3:17])[CH3:19])=[O:5])[CH3:8]

Participants

5

Reactant 4

HCID 6561IsobutyraldehydeHCID 8028Tetrahydrofuran2×HCID 811841,8-Diazabicyclo(5.4.0)undec-7-eneHCID 533707Ethyl isocyanoacetate

Product 1

HCID 45790196Diethyl 3-(propan-2-yl)-1H-pyrrole-2,4-dicarboxylateYield 60%

Procedure

Ethyl isocyanoacetate (80 g, 0.71 mol) was dissolved in 1 L of dry tetrahydrofuran under nitrogen and 1,8-diazabicyclo[5.4.0]undec-7-ene (107.7 g, 0.71 mol) was added to the solution. A solution of isobutyraldehyde (29.7 g, 0.41 moles) in 1.5 L of dry tetrahydrofuran was added dropwise at room temperature over 3 hours. The mixture was then stirred at room temperature for 16 h. The reaction mixture was concentrated under vacuum to a brown oil. The concentrate was partitioned between 1.2 L of ethyl acetate and 0.5 L of water. The organic layer was then washed with 0.4 L of 0.1 N hydrochloric acid followed by 0.3 L of saturated sodium bicarbonate solution and then 0.3 L of saturated brine. The organic layer was dried (sodium sulfate), filtered and concentrated under vacuum to a brown oil. The residue was dissolved in toluene and added to a 1600 ml (˜800 g) column of silica gel wet with hexane. Product was eluted at 15 PSI nitrogen pressure first with 4.8 L of hexane followed by 5 L of 20% ethyl acetate in hexane. Eluent containing product by TLC analysis was combined and concentrated under vacuum to a yellow oil. The concentrate was pumped dry under high vacuum giving product A, 3-(1-methylethyl)pyrrole-2,4-dicarboxylic acid diethyl ester (54 g, 60% yield) of yellow oil that solidified on standing at room temperature. TLC silica gel:

Workup

  1. concentrationThe reaction mixture was concentrated under vacuum to a brown oil
  2. customThe concentrate was partitioned between 1.2 L of ethyl acetate and 0.5 L of water
  3. washThe organic layer was then washed with 0.4 L of 0.1 N hydrochloric acid
  4. dry with materialThe organic layer was dried (sodium sulfate)
  5. filtrationfiltered
  6. concentrationconcentrated under vacuum to a brown oil
  7. dissolutionThe residue was dissolved in toluene
  8. additionadded to a 1600 ml (˜800 g) column of silica gel wet with hexane
  9. washProduct was eluted at 15 PSI nitrogen pressure first with 4.8 L of hexane
  10. additionEluent containing product by TLC analysis
  11. concentrationconcentrated under vacuum to a yellow oil
  12. customThe concentrate was pumped dry under high vacuum

Sources & evidence

ORD record
ord-368a75b16aa04cbaa63d27e7a48f2427
Source dataset
uspto-grants-2005_10
Patent number
US06951859B2

Reaction notes

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