Knorr Pyrrole Synthesis - Method

Method

The mechanism requires zinc and acetic acid as catalysts. It will proceed at room temperature. Because α-amino-ketones self-condense very easily, they must be prepared in situ. The usual way of doing this is from the relevant oxime.

The original Knorr synthesis employed two equivalents of ethyl acetoacetate, one of which was converted to ethyl 2-oximinoacetoacetate by dissolving it in glacial acetic acid, and slowly adding one equivalent of saturated aqueous sodium nitrite, under external cooling. Zinc dust was then stirred in, reducing the oxime group to the amine. This reduction consumes two equivalents of zinc and four equivalents of acetic acid.

Modern practice is to add the oxime solution resulting from the nitrosation and the zinc dust gradually to a well-stirred solution of ethyl acetoacetate in glacial acetic acid. The reaction is exothermic, and the mixture can reach the boiling point, if external cooling is not applied. The resulting product, diethyl 3,5-dimethylpyrrole-2,4-dicarboxylate, has been called Knorr's Pyrrole ever since. In the Scheme above, R2 = COOEt, and R1 = R3 = Me represent this original reaction.

Knorr's pyrrole can be derivatized in a number of useful manners. One equivalent of sodium hydroxide will saponify the 2-ester selectively. Dissolving Knorr's Pyrrole in concentrated sulfuric acid, and then pouring the resulting solution into water will hydrolyze the 4-ester group selectively. The 5-methyl group can be variously oxidized to chloromethyl, aldehyde, or carboxylic acid functionality by the use of stoichiometric sulfuryl chloride in glacial acetic acid. Alternatively, the nitrogen atom can be alkylated. The two ester positions can be more smoothly differentiated by incorporating benzyl or tertiary-butyl groups via the corresponding acetoacetate esters. Benzyl groups can be removed by catalytic hydrogenolysis over palladium on carbon, and tertiary-butyl groups can be removed by treatment with trifluoroacetic acid, or boiling aqueous acetic acid. R1 and R3 (as well as R2 and "Et") can be varied by the application of appropriate beta-ketoesters readily made by a synthesis emanating from acid chlorides, Meldrum's acid, and the alcohol of one's choice. Ethyl and benzyl esters are easily made thereby, and the reaction is noteworthy in that even the highly hindered tertiary-butyl alcohol gives very high yields in this synthesis.

Levi and Zanetti extended the Knorr synthesis in 1894 to the use of acetylacetone (2,4-pentanedione) in reaction with ethyl 2-oximinoacetoacetate. The result was ethyl 4-acetyl-3,5-dimethylpyrrole-2-carboxylate, where "OEt" = R1 = R3 = Me, and R2 = COOEt. The 4-acetyl group could easily be reduced to a 4-ethyl group by use of the Wolff-Kishner reduction (hydrazine and alkali, heated); hydrogenolysis, or the use of diborane. Benzyl or tertiary-butyl acetoacetates also work well in this system, and with close temperature control, the tertiary-butyl system gives a very high yield (close to 80%). N,N-dialkyl pyrrole-2- and/or 4-carboxamides may be prepared by the use of N,N-dialkyl acetoacetamides in the synthesis. Even thioesters have been successfully prepared, using the method. As for the nitrosation of beta-ketoesters, despite the numerous literature specifications of tight temperature control on the nitrosation, the reaction behaves almost like a titration, and the mixture can be allowed to reach even 40 degrees Celsius without significantly impacting the final yield.