Knorr Pyrrole Synthesis - Related Synthesis

Related Synthesis

There are a number of important syntheses of pyrroles that are operated in the manner of the Knorr Synthesis, despite having mechanisms of very different connectivity between the starting materials and the pyrrolic product.

Fischer and Fink found that Zanetti's synthesis from 2,4-pentanedione and ethyl 2-oximinoacetoacetate gave ethyl 3,5-dimethylpyrrole-2-carboxylate as a trace byproduct. Similarly, 3-ketobutyraldehyde diethyl acetal led to the formation of ethyl 5-methylpyrrole-2-carboxylate. Both of these products resulted from the loss of the acetyl group from the inferred ethyl 2-aminoacetoacetate intermediate. An important product of the Fischer-Fink synthesis was ethyl 4,5-dimethylpyrrole-2-carboxylate, made from ethyl 2-oximinoacetoacetate and 2-methyl-3-oxobutanal, in turn made by the Claisen condensation of 2-butanone with ethyl formate.,

G.G. Kleinspehn reported that the Fischer-Fink connectivity could be forced to occur exclusively, by the use of diethyl oximinomalonate in the synthesis, with 2,4-pentanedione, or its 3-alkyl substituted derivatives. Yields were high, around 60%, and this synthesis eventually came to be one of the most important in the repertory. Yields were significantly improved, by the use of preformed diethyl aminomalonate (prepared by the hydrogenolysis of diethyl oximinomalonate in ethanol, over Pd/C), and adding a mixture of diethyl aminomalonate and the beta-diketone to actively boiling glacial acetic acid.

Meanwhile, Johnson had extended the Fischer-Fink synthesis by reacting 2-oximinoacetoacetate esters (ethyl, benzyl, or tertiary-butyl), with 3-alkyl substituted 2,4-pentanediones. Others extended the Kleinspehn synthesis by the use of unsymmetrical beta-diketones (such as 3-alkyl substituted 2,4-hexanediones), which preferentially reacted initially at the less hindered acetyl group and afforded the corresponding 5-methylpyrrole-2-carboxylate esters. N,N-Dialkyl 2-oximinoacetoacetamides also were found to give pyrroles when reacted under Knorr conditions with 3-substituted-2,4-pentanediones, in yields comparable to the corresponding esters (around 45%). However, when unsymmetrical diketones were used, it was found that the acetyl group from the acetoacetamide was retained in the product, and one of the acyl groups from the diketone had been lost. This same mechanism occurs to a minor extent in the acetoacetate ester systems, and had previously been detected radiochemically by Harbuck and Rapoport. Most of the above-described syntheses have application in the synthesis of porphyrins, bile pigments, and dipyrrins.