Knorr’s pyrrole synthesis

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. 

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. 

Tamura, Y., Kato, S., Ikeda, M. One-Step Knorr pyrrole synthesis with hydroxylamine 0-sulfonic acid. Chem. Ind. 1971,767. 

Quiclet-Sire, B., Quintero, L., Sanchez-Jimenez, G., Zard, S. Z. A practical variation on the Paal-Knorr pyrrole synthesis. Synlett 200Z, 75-78. 

Heterocycles are almost invariably formed by inter- and intramolecular Schiff base or lactam formation. We cite here the classical Knorr pyrrole synthesis (see Scheme 1.3.4) and Baeyer s barbituric acid synthesis, where the amide nitrogen atoms of urea are nucleophilic enough to add to malonic acid esters (Scheme 1.4.2). 

The condensation of carbonyl compounds with a-aminoketones gives pyrroles by a Ilac cycli-zation known as the Knorr pyrrole synthesis. In most examples the carbonyl compounds are fi-ketoesters or )S-diketones (Scheme 45). 

The key step for budding the 1,4- diketone, subsequently used in the Paal- Knorr pyrrole synthesis, is a Stetter reaction, whereby p-fluorobenzaldehyde is added to a )S-ketoamide in presence of a thiazohum salt. 

Torok and co-workers312 have reported the one-pot synthesis of /V-arylsulfonyl heterocycles through the reaction of primary aromatic sulfonamides with 2,5-dimethoxytetrahydrofuran. When triflic acid is used in catalytic amount, IV-arylsulfonylpyrroles are formed (Scheme 5.34). Equimolar amount of triflic acid results in the formation of N- ary I s u I fo n y I i n do I e s, whereas /V-arylsu Ifonylcar-bazoles are isolated in excess acid (Scheme 5.34). In the reaction sequence 1,4-butanedial formed in situ from 2,5-dimethoxytetrahydrofurane reacts with the sulfonamide to give the pyrrole derivative (Paal-Knorr synthesis). Subsequently, one of the formyl groups of 1,4-butanal alkylates the pyrrole ring followed by a second, intramolecular alkylation (cyclialkylation) step. 

Yu, S.-X., Le Quesne, P. W. Quararibea metabolites. 3. Total synthesis of ( )-funebral, a rotationally restricted pyrrole alkaloid, using a novel Paal-Knorr reaction. Tetrahedron Lett. 1995, 36, 6205-6208. 

Construction of the phosphole ring, with one useful exception, is accomplished by methods that are quite different from those employed for the N, S, O ring systems. Because of fundamental differences in the chemistry of phosphines versus amines, none of the familiar carbonyl condensation processes are known to be applicable to phosphole synthesis. Thus an attempt to use the Paal-Knorr condensation of 1,4-dicarbonyl compounds with PhPH2 <65JCS2184> and with PH3 <88ZOB783> failed to give phospholes. The only successful method known to the present that is common to both the phosphole and pyrrole ring systems is the condensation of 1,3-diynes with primary phosphines... 

Veisi, H., Azadbakht, R., Ezadifar, M., and Hemmati, S. (2013). An efficient and green procedure for synthesis of pyrrole derivatives by Paal-Knorr condensation using sodium dodecyl sulfate in aqueous micellar. 7. Heterocyclic Chem., 50, E241-E246. 

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