Heterocycle synthesis Knorr pyrrole

Paal-Knorr synthesis It is a useful and straightforward method for the synthesis of five-membered heterocyclic compounds, e.g. pyrrole, furan and thiophene. However, necessary precursors, e.g. dicarbonyl compounds, are not readily available. Ammonia, primary amines, hydroxylamines or hydrazines are used as the nitrogen component for the synthesis of pyrrole. 

Standard heterocyclic syntheses tend to have a name associated with them and it is simply not worth while learning these names. Few chemists use any but the most famous of them we will mention the Knorr pyrrole synthesis, the Hantzsch pyridine synthesis, and the Fischer and Reissert indole syntheses. We did not mention that the synthesis of furans from 1,4-dicarbonyl compounds is known as the Feist-Benary synthesis, and there are many more like this. If you are really interested in these other names we suggest you consult a specialist book on heterocyclic chemistry. 

Hamby, J. M., Hodges, J. C. a-Amino ketones from amino acids as precursors for the Knorr pyrrole synthesis. Heterocycles 1993, 35, 843-850. 

Knoevenagel reactions are used in the synthesis of a wide variety of O- and N-heterocycles. In the typical Knorr pyrrole synthesis, a 1,3-dicarbonyl compound is condensed with an oximino- or azimino-1,3-dicarbonyl compound followed by reductive cyclization. Thus, catalytic hydrogenation of benzyl acetoacetate (243) and diethyl oximinoacetonedicarboxylate (242) affords pyrrole (244), which is transformed to (245) by another Knoevenagel reaction (Scheme 49). A rational synthesis of all four uropor-phyrines has been achieved by cyclization of appropriate pyrroles such as (245). ° Another typical preparation of a heterocycle that involves a Knoevenagel condensation is the Hantzsch 1,4-dihydro-pyridine synthesis. Here, an aldehyde and two molecules of a 1,3-dicarl30nyl compound react in the... 

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). 

Approaches to the synthesis and medicinal importance of pyrroles have been reviewed. The synthesis of pyrroles using multicomponent reactions was reviewed and advances in this area from mid-2009 to the end of 2013 are covered (14CSR4633). Another review covered the synthesis of pyrroles using the Paal-Knorr reaction (14AHC95).The synthetic approaches and biosynthetic hypotheses of pyrrole—imidazole alkaloids were discussed in another report (14CC8628). Synthesis of pyrrole-based heterocyclic molecules through metal triflate-catalyzed addition reactions of pyrrole to C—C and C-N bonds was reviewed (14PAC925). 

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. 

Syntheses of the heterocyclopentadienes use a variety of cyclization strategies. A general approach is the Paal-Knorr synthesis (for pyrroles) and its variations (for the other heterocycles). The target molecule is made from an enolizable y-dicarbonyl compound that is treated with an amine derivative (for pyrroles) or P2O5 (for furans) or P2S5 (for thiophenes). 

The Knoevenagel condensation also plays a part in a number of prominent heterocycle syntheses including the Knorr pyrrole synthesis/ Hantzsch dihydropyridine synthesis/ Feist-Benary furan synthesis and the Gewald reaction, which is used to make 2-aminothiophenes. 

Cribble, G. W. Knorr and Paal-Knorr Pyrrole Synthesis. In Name Reactions in Heterocyclic Chemistry, Li, J. J., Ed. John Wiley Sons Hoboken, NJ, 2005 pp 79-88. 

Simple and efficient, the Stetter hydroacylation reaction quickly became a popular route for the production of 1,4-dicarbonyl compounds as precursors for the synthesis of pyrrole, furan, and pyridazine heterocycles. The Parke-Davis route to atorvastatin (Lipitor ) illustrates the use of a Stetter/Paal-Knorr sequence to access a high value pharmaceutical intermediate (16) from 4-fluorobenzaldehyde 12 and benzylidine amide 13. ... 

Similar reaction conditions as those by Bose were used for a range of other applications, for example, the synthesis of heterocycles. A combination of a microwave-assisted Paal-Knorr reaction15 with a transfer hydrogenation takes place in the preparation of 2,5-di- and 1,2,5-trisubstituted pyrroles from -l,4-diaryl-2-butene-l,4-diones in a one-pot operation. Hydrogenation was achieved with ammonium formates and 10% Pd/C as catalyst in PEG-200. Yields of up to 92% were obtained within 0.5-2 min (Scheme 4.2)16. 

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). 

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. 

The Paal-Knorr synthesis of furans as well as thiophenes and pyrroles has been carried out on solid support and a library of heterocyclic compounds has been prepared <2003SL711>. It has been shown that the acid-catalyzed synthesis of 2,3>4-substituted furans from 1,4-diketones can be assisted by microwave irradiation <20040L389>. 

Pyrrole is one of the most prominent heterocycles in several natural products and synthetic pharmaceuticals. The most common approach to pyrroles is the Paal-Knorr reaction. Taddei and coworkers have investigated a rapid and versatile synthesis of tetrasubstituted pyrroles in few highly efficient steps ... 

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