Acetic Acid → 1H-Pyrrole-2-carboxylic acid, 5-methyl-, ethyl ester

HRID 1948374Notes

Reaction equation

HRID 1948374 reaction equation
O=[C:2]([CH3:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:10](O)(=O)[CH3:11].[N:14]([O-])=O.[Na+].COC(OC)CC(=O)C>[Zn].CCCCCCC>[CH2:7]([O:6][C:4]([C:3]1[NH:14][C:10]([CH3:11])=[CH:9][CH:2]=1)=[O:5])[CH3:8]

Participants

7

Reactant 4

HCID 176Acetic AcidHCID 8868Ethyl AcetoacetateHCID 2285484,4-Dimethoxy-2-butanoneHCID 23668193Sodium Nitrite

Product 1

HCID 965981H-Pyrrole-2-carboxylic acid, 5-methyl-, ethyl esterYield 13.6%

Reagents, catalysts & solvents 2

HCID 23994ZincCatalyst3×HCID 8900HeptaneSolvent

Conditions

Temperature
0 °C

Procedure

To a 4-neck 22 L round bottom flask equipped with an overhead stirrer, liquid addition funnel, nitrogen inlet and an internal temperature probe was charged ethyl 3-oxobutanoate (1952 g, 15.0 mol) and glacial acetic acid (5 L). The resulting solution was cooled to 0° C. with an ice water bath and an aqueous solution of sodium nitrite (1242 g, 18.0 mol, 1.2 eq, in 1875 ml of water) was added slowly (4.5 h) not allowing the internal temperature above 10° C. The homogeneous red solution was allowed to warm to ambient and stirred for 48 h. The solution color changed from light red to yellow. Reaction vessel was then placed in a heating mantle, fitted with a reflux condenser and acetylacetaldehyde dimethyl acetal (1982 g, 15.0 mol, 1 eq) was added in one portion (the top of the reflux condenser was left open to air to allow for the rapid gas evolution during the addition of the zinc). Zinc (dust, 2156 g, 33 mol, 2.2 eq) was added in portions (at a rate such that gas evolution was controlled) over 4 h. The addition of zinc brought the reaction to reflux and after addition the dark red solution was heated at reflux for an additional 1.5 h. Contents of the reaction were poured hot into a 50 L container with 20 kg of ice and allowed to stir for 16 h. Resulting suspension was filtered, dried in convection oven and recrystallized with hot heptane yielding a light yellow solid (312 g, 13.6% yield).

Workup

  1. customTo a 4-neck 22 L round bottom flask equipped with an overhead stirrer, liquid addition funnel, nitrogen inlet
  2. customthe internal temperature above 10° C
  3. temperatureto warm to ambient and
  4. customReaction vessel
  5. customfitted with a reflux condenser
  6. waitwas left open to air
  7. customover 4 h
  8. customthe reaction
  9. temperatureto reflux
  10. additionafter addition the dark red solution
  11. temperaturewas heated
  12. temperatureat reflux for an additional 1.5 h
  13. stirringto stir for 16 h
  14. customResulting suspension
  15. filtrationwas filtered
  16. customdried in convection oven

Sources & evidence

ORD record
ord-82b2d852b0c94c40aad52baf15a321c8
Source dataset
uspto-grants-2013_03
Patent number
US08399489B2

Reaction notes

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