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

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Reaction Steps

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:

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