Paal-Knorr-pyrrole synthesis

5-trimethyl-1H-pyrrole-3-carboxylic acid ethyl ester 

OH ammonia precursors NH4OAC, (NH4)2C03 catalyst zeolite, AI2O3, p-TSOH, CSA, Ti(0/-Pr)4, microwave solvent MeOH, EtOH, H2O, toluene, DMF, ionic liquid 

Even though the Paal-Knorr pyrrole synthesis has been around for 120 years, its precise mechanism was the subject of debate. In 1991, V. Amarnath et al. investigated the intermediates of the reaction and determined the most likely mechanistic pathway. The formation of pyrroles was studied on various racemic and meso-3,4-diethyl-2,5-hexanediones. The authors found that the rate of cyclization was different for the racemic and meso compounds and the racemic isomers reacted considerably faster than the meso isomers. There were two crucial observations 1) the stereoisomers did not interconvert under the reaction conditions and 2) there was no primary kinetic isotope effect for the hydrogen atoms at the C3 and C4 positions. These observations led to the conclusion that the cyclization of the hemiaminal intermediate is the rate-determining (slow) step. 

Kohnke and co-workers prepared novel heterocyclophanes from cyclic poly-1,4-diketones, which were obtained by the oxidation of calix[6]furan and calix[4]furan. One of the heterocyclophanes, calix[6]pyrrole, was prepared by the Paal-Knorr pyrrole synthesis from the corresponding dodecaketone. The substrate was heated with excess ammonium acetate in absolute ethanol. Interestingly, the analogous synthesis of calix[4]pyrrole under identical conditions failed, while calix[5]pyrrole is obtained only in 1% yield. 

The formal total synthesis of roseophilin was accomplished by B.M. Trost et al. who used the Paal-Knorr pyrrole synthesis to install the trisubstituted pyrrole moiety.The 1,4-diketone substrate was reacted with various primary amines to obtain A/-substituted pyrroles. The best yield was obtained when benzylamine was used as the amine component, but the A/-deprotection of the product proved to be problematic. This forced the researchers to prepare the otherwise unstable A/-unprotected pyrrole under carefully controlled conditions and protect it immediately with SEM-chloride. 

The other major route to pyrroles is the interaction of a 1,4-dicarbonyl compound with ammonia. The 

however, that this synthesis gives furans if no ammonia is included. This would involve nucleophilic attack of an enol tautomer of the substrate on to the other carbonyl to give a hemiketal. 

Reaction between 1,4-ketones and primary amines (or ammonia) to give pyrroles. O 

Quiclet-Sire, B. Quintero, L. Sanchez-Jimenez, G. Zard, Z. Synlett 2003,75. 

Discovered more than a century ago, the Paal-Knorr pyrrole synthesis is similar to the Knorr synthesis. It is the intermolecular condensation of a primary amine (or ammonia) with a 1,4-diketone (or 1,4-dialdehyde) to give pyrroles.  

L-167307 is an orally bioavailable inhibitor of p38 kinase. In vivo, it reduces secondary paw swelling in the rat adjuvant arthritis model with an ID50 of 7.4 mg/kg/day. Triarylpyrrole L-167307 was assembled using the Paal-Knorr pyrrole synthesis of a 1,4-diketone and ammonium acetate.  

Celecoxib (Celebrex) is a selective cyclooxygenase-2 (COX-2) inhibitor prescribed as a nonsteroidal anti-inflammatory drug (NSAID). The Paal-Knorr cyclization was the crucial step in preparing tri-substituted keto-pyrroles as COX-2 inhibitors. Here, the tri-ketone substrates were prepared in situ from phenacyl bromide and 1,3-diketone.  

The Paal-Knorr cyclization was employed to produce highly aryl-substituted pyrrole carboxylates as useful medicinal chemistry leads. Therefore, l,4-diketone-2,3-diester was assembled from an Sn2 displacement of ethyl 2-bromoacetoacetate with the anion of the ketoester. Condensation with an aniline then provided a library of fully substituted pyrroles. 

When Paal and Knorr discovered the pyrrole synthesis more than a century ago, they had no idea that the reaction bearing their names would have contributed greatly to the manufacture of atorvastatin (Lipitor). Indeed, synthesis of Lipitor is probably the tour de force for the Paal-Knorr pyrrole synthesis. 

Corwin, A. H. Heterocyclic Compounds Vol. 1, Wiley, NY, 1950 Chapter 6. (Review). 

The Chemistry of Pyrroles, Academic Press, Lxjndon, 1977, pp 51-57, 74-79. (Review). 

Gribble, G. W. Knorr and Paal—Knorr Pyrrole Syntheses In Name Reactions in Heterocyclic Chemistry, Eds, Li, J. J. Corey, E. J. Wiley Sons Hoboken, NJ, 2005, 79-88. (Review). 

Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8 189, Springer-Verlag Berlin Heidelberg 2009 

40 C or RNH2. AcOH, NaOAc, toluene, 60 C or 

Name Reactions A Collection of Detailed Mechanisms and Synthetic Applications, DOI 10.1007/978-3-319-03979-4 202, Springer International Publishing Switzerland 2014 

Exanple 5, Furan ring opening-pyrrole ring closure  

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PAAL - KNORR Pyrrole Synthesis Pyrrole synthesis from 1,4-butanedlone and amines. 

Separately, Paal and Knorr described the initial examples of condensation reactions between 1,4-diketones and primary amines, which became known as the Paal-Knorr pyrrole synthesis. Paal also developed a furan synthesis in related studies. The central theme of these reactions involves cyclizations of 1,4-diketones, either in the presence of a primary amine (Paal-Knorr pyrrole synthesis), in the presence of a sulfur(II) source (Paal thiophene synthesis), or by dehydration of the diketone itself (Paal furan synthesis). 

Scheme 6.182 Sila-Stetter/Paal-Knorr pyrrole synthesis.

In analogy to the Paal-Knorr pyrrole synthesis described by Taddei and coworkers [342] (Scheme 6.181), similar reaction conditions were used by these authors to cyclize 1,4-dicarbonyl compounds to give furans (Scheme 6.190). Thus, heating a solution of a 1,4-dicarbonyl compound in ethanol/water in the presence of a catalytic amount of hydrochloric acid at 140 °C for 3 min provided an excellent yield of the corresponding trisubstituted furan derivative. 

Reaction of hydrazine or substituted hydrazine with 1,3-dicarbonyl compounds to provide the pyrazole or pyrazolone ring system. Cf. Paal-Knorr pyrrole synthesis (page 333). 

A cntical component of this effort was an extensive investigation of the classical Paal-Knorr pyrrole synthesis" that finally resulted in a successful cyclodehydration in a model system when a full equivalent of pivalic acid was used as catalyst (Scheme 4). Thus condensation of commercially available isobutyrylacetanilide 18 with benzaldehyde in the presence of p-alanine and acetic acid afforded the enone 19 in 85% yield. 

One of the most general pyrrole syntheses is the cyclizative condensation of 1,4-dicarbonyl compounds with ammonia, a primary amine or related compound. The mechanistic pattern involves formation of carbinolamine and imine intermediates followed by aromatization. This method is sometimes referred to as the Paal-Knorr pyrrole synthesis (equation 65) (B-77MI30601). Once the dicarbonyl compound is available, the cyclization normally proceeds in good yield, so ease of access to the diketone is of major importance in determining the applicability of this method to specific pyrroles. Pyrrole formation usually takes place on heating the diketone in a solvent such as benzene or toluene with a catalytic amount of acid. An alternative method involves heating the dicarbonyl compound and an amine salt... 

The Paal-Knorr Pyrrole Synthesis is the condensation of a 1,4-dicarborivl compound with an excess of a primary amine or ammonia to give a pyrrole. 

In an application of the Paal-Knorr pyrrole synthesis, the synthetic equivalents 3 of 1,4-ketoaldehydes were prepared by the radical addition of ketones 4 to vinyl pivalate. Treatment of the intermediates 3 with amines gave pyrroles 5 <03SL75>. Other new extensions of this popular pyrrole synthesis include the preparation of a number of pyrroles from hexane-2,5-dione and amines under solvent-free conditions in the presence of layered zirconium phosphate or phosphonate catalysts <03TL3923>, and the development of a solid-phase variant of this reaction <03SL711>. Likewise, the preparation of iV-acylpyrroles from primary amides and 2,5-dimethoxytetrahydrofuran in the presence of one equivalent of thionyl chloride has also been reported <03S1959>. 

PAAL KNORR Pyrrole synthesis 284 PADWA Annulation 285 PAQUETTE Olelination 286 PARHAM Cycle ether synthesis 287 PARNES Gemnal dimethylation 288 Pames 223... 

In the laboratory of D.F. Taber, the large-scale preparation of a tetrasubstituted pyrrole, a key precursor for the preparation of hemes and porphyrins, was achieved. The 1,4-dicarbonyl substrate was generated from a ketal via hydrolysis and was immediately subjected to the Paal-Knorr pyrrole synthesis by heating it with ammonium carbonate in DMF. The resulting 1/-/-pyrrole was formylated with trimethyl orthoformate in trifluoroacetic acid. 

The titanium isopropoxide mediated Paal-Knorr pyrrole synthesis was used as the key step in the first total synthesis of magnolamide by W. Le Quesne et al. ... 

In the laboratory of A. Millar, the convergent enantloselective synthesis of CI-981, a potent and tissue-selective Inhibitor of HMG-CoA reductase was achieved. The central tetrasubstituted pyrrole ring was prepared via the Paal-Knorr pyrrole synthesis. The required 1,4-diketone precursor was efficiently prepared by the Stetter reaction between p-fluorobenzaldehyde and an unsaturated amide. Interestingly, the A/-benzyl thiazolium chloride catalyst afforded only the benzoin condensation product and none of the desired diketone. However, when the A/-ethyl thiazolium bromide catalyst was employed, under anhydrous and concentrated reaction conditions, the 1,4-diketone was formed in good yield. The authors also noted that the simple dilution of the reaction mixture resulted in a dramatic increase in the formation of the undesired benzoin condensation product. 

Paal-Knorr pyrrole synthesis Condensation of primary amines with 1,4-dicarbonyl compounds to form substituted pyrroles. 328... 

Paal-Knorr pyrrole synthesis. Formation of pyrroles by heating 1,4-dicarbonyl compounds with ammonia or primary amines in a sealed tube. 

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