Knorr’s pyrrole

Because the a-aminoketone is subject to self-condensation, the condensation with a P-dicarbonyl derivative (6) is usually carried out by generating the a-aminoketone in situ through reduction of an oximino derivative (7) 2iac ia glacial acetic acid is used as the reductant. For example, Knorr s pyrrole... 

The problems involved are exemplified here by Knorr s pyrrole synthesis (A. Gossauer, 1974). It has been known for almost a century that a-aminoketones (C2N components) react with 1,3-dioxo compounds (C2 components) to form pyrroles (C4N-heterocycles). A side-reaction is the cyclodimerization of the a-aminoketones to yield dihydropyrazines (C4Nj), but this can be minimized by keeping the concentration of the ar-aminoketone low relative to the 1,3-dioxo compound. The first step in Knorr s pyrrole synthesis is the formation of an imine. This depends critically on the pH of the solution. The nucleophilicity of the amine is lost on protonation, whereas the carbonyl groups are activated by protons. An optimum is found around pH 5, where yields of about 60% can be reached. At pH 4 or 6 the yield of the pyrrole may approach zero. The ester groups of /7-keto esters do not react with the amine under these conditions. If a more reactive 1,3-diketone is used, it has to be symmetrical, otherwise mixtures of two different imines are obtained. The imine formed rearranges to an enamine, which cyclizes and dehydrates to yield a 3-acylpyrrole as the normal Knorr product (A. Gossauer, 1974 G.W. Kenner, 1973 B). 

Bondietti, G., Lions, F. Extension of Knorr s pyrrole synthesis. Journal and Proceedings of the Royal Society of New South Wales 1933, 6 477-485. 

Zhang, Y., Jiang, Y.-Z., Liang, X.-T. A new variant of Knorr s pyrrole synthesis. Chinese Journal of Chemistry 1997,15, 371-378. 

It is believed that in the mechanism, shown for Knorr s pyrrole, an N-C-2 bond is the first formed, which implies that the nitrogen becomes attached to the more electrophilic of the two carbonyl groups of the other component. Similarly, the C-3-C-4 bond is made to the more electrophilic carbonyl group of the original a-aminocarbonyl-component, where there is a choice. 

Pyrrole reacts with aqueous formaldehyde and secondary amines in the presence of acetic acid to afford, in some cases, mixtures of products derived from attack at the 2- and 2,5-positions. The disubstitution products can be obtained in very high yields at about room temperature for example, a 92% yield of 2,5-bis(piperidylmethyl)pyrrole is obtained using this method. The same procedure apparently does not yield a Mannich base with l-methylpyrrole, but the use of aqueous formaldehyde and dimethylamine hydrochloride at 60 °C results in the formation of the 2-substitution product in 73% yield. Even highly substituted pyrroles react. Thus, ethyl 4,5-dimethylpyrrole-2-carboxylate and ethyl 2,5-dimethylpyrrole-3-carboxylate both undergo C-aminoalkylation at the unsubstituted position in 45 and 68% yields, respectively, with dimethylamine and formaldehyde in ethanolic solution. A number of tri- and tetra-substituted 2-methylpyrroles have been investigated with the exception of Knorr s pyrrole all gave side-chain substituted products with formaldehyde and a secondary amine in acetic acid. ... 

The synthesis begins with the preparation of Knorr s pyrrole (diethyl 3,5-dimethylpyrrole-2,4-dicarboxylate), which is made by the reaction of ethyl acetoacetate (ethyl 3-oxobutanoate) with ethyl 2-amino-3-oxobutanoate. The latter is made by nitrosation and subsequent reduction of ethyl acetoacetate. 

Fischer and Walach i showed that if Knorr s pyrrole is dissolved in concentrated sulphuric acid at 40° and the solution then poured on ice, 2-ethoxycarbonyl-3,5-dimethylpyrrole-4-carboxylic acid results. Probably, dissolution of the diester in concentrated sulphuric acid generates the acylium ion (77) evidence for this is the van t Hoff cryoscopic factor of 3 5 observed for such solutions a xhe process cannot be complete at the freezing point, for complete acylization would give s factor of 5. Acyli-zation 184 AacI > will be facilitated by electron-releasing substituents and will not be subject to steric factors. In the pyrrole series, a balance has to be struck between the facilitation caused by increasing alkyl substitution in the nucleus and the retardation which would accompany salt formation by... 

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