Org Prep Daily

September 15, 2010

Knorr pyrrole synthesis

Filed under: procedures — milkshake @ 1:31 pm

A solution of tert-butyl acetoacetate 31.65g (200mmol) in acetic acid 40 mL was cooled on ice bath to 5C and a solution of NaNO2 14.00g (1 eq.) in water 20mL was injected slowly under the level of the reaction mix with cooling and vigorous stirring, over a 20 min period, so that the internal temperature did not exceed +15C. The syringe was washed with water (2 x 3 mL) and the washings also added to the mix. The reaction mix was stirred on melting ice bath to RT in an open flask overnight (16 hours).

Separately, in a 3-necked 1L round bottom flask with a large egg-shaped stirbar and internal thermometer and an addition funnel, anhydrous sodium acetate 20g and ethyl acetoacetate 29.0g (1.1 eq.) were dissolved in acetic acid 100mL on a 60C oil bath. With vigorous stirring, Zn dust 10g (Aldrich, < 10micrometer) was then added followed by dropwise addition of the nitrosated mixture (from tBu acetoacetate and sodium nitrite). This addition was carried out over a 45 min period, while an additional Zn dust 40g was simultaneously added to the mix in approx 5 g portions few minutes apart. Each Zn addition was accompanied by a temperature spike, the internal temperature in the flask was kept below +85C. (The bath temperature was 60C and the the internal temperature in the flask was controlled by the rate of addition of Zn dust and the nitrosation mix. The total quantity of used Zn dust was 50g). At the end, the addition funnel was washed with additional acetic acid (3 x 10 mL) and this was added to the mix and continued for 1 more hour at 60C. The resulting foamy reaction mixture was finally diluted by addition of water, 100mL, and the mixture was stirred for one more hour at 60C. The reaction mix was then poured into a large beaker, diluted with water 0.5L, some crushed ice was added (total mix volume was 1.5L) and the slurry was placed on ice bath and stirred for 1 hour. The precipitate was collected by filtration, washed thoroughly with water and dried by suction.

The obtained crude product was dissolved in a 1:1 mix of ethanol+ethyl acetate (0.5L) with gentle heating, the solution was filtered from the leftover Zn dust (Zn washed with EtOAc on Buchner) and the filtrates were evaporated to dryness. The solid residue was suspended in acetonitrile 60mL and the slurry was placed into a freezer (-20C) overnight. The precipitate was collected by filtration, washed with cold acetonitrile, dried by suction and on highvac. Y=35.55g (66.5%) of a white sugar-like crystalline solid.

1H(CDCl3, 400MHz): 8.93 (br s, 1H), 4.29 (q, 7.1Hz, 2H), 2.53(s, 3H), 2.50(s, 3H), 1.57(s, 9H), 1.36(t, 7.1Hz, 3H)

Note: There were couple more grams of the product left in the supernatants that could be likely isolated on a column, or doing a fractional crystallization from MeCN, but it was not worth the trouble.

3 Comments »

  1. Thank you for sharing your work. You have put my mind at ease. I am doing a similar synthesis using almost the same pyrrole as a precursor to a porphyrin complex. The only synthesis I found similar to this one is on scifinder but it uses ethyl acetoacetate. I was wondering if the steric hindrance of the tert-butyl group would make the yield lower but it seems that it does not.

    Comment by Josh — August 16, 2011 @ 8:53 pm

  2. Try sodium dithionite in a near neutral then slightly alkaline solution instead of zinc dust/essigsaure! (Old German paper by Kleinspein)

    Reduction occurs at room temp, yields are up (80% I think), and purity is much better with good clean crystals. (Just filter reaction mixture).

    Did it in ’74 at Uni!

    Awesome!

    Comment by Dr John — June 2, 2013 @ 8:09 pm

    • Ha! Gro├čartig!

      (in ’74, my biggest achievement was crawling out of the womb)

      Comment by milkshake — June 2, 2013 @ 9:30 pm


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