Knorr pyrrole syntheses

Formation of pyrroles by condensation of ketones with a-aminoketones 

By a condensation reaction of an a-aminoketone 1 with a ketone 2, a pyrrole 3 can be obtained. This reaction is known as the Knorr pyrrole synthesis. 

A mechanism has been formulated, starting with a condensation to give the imine 4, that can tautomerize to the corresponding enamine 5. The latter can be isolated in some cases, thus supporting the formulated mechanism. A cyclization and subsequent dehydration leads to the imine 6, which tautomerizes to yield the aromatic pyrrole 3  

The aminoketone 1, required as starting material, can be obtained by a Neber rearrangement from a A -tosylhydrazone. Another route to a-aminoketones starts with the nitrosation of an a-methylene carbonyl compound—often in situ—to give the more stable tautomeric oxime 7, which is then reduced in a subsequent step to yield 1  

With excess ketone, the preparation of the aminoketone and subsequent condensation to a pyrrole can be conducted in one pot. In a side-reaction a-aminoketones can undergo a self-condensation to give pyrazines 8  

5-dimethyl-1 H-pyrrole-2,4-dicarboxylic acid diethyl ester 

Condensation of the amino ketone and ketone to give an imine  

A useful modification of the Knorr pyrrole synthesis was developed in the laboratory of J.M. Hamby for the construction of tetrasubstituted pyrroles. The necessary a-amino ketones were prepared from A/-methoxy-A/-methylamides of amino acids (Weinreb amides). These Weinreb amides were prepared by the mixed anhydride method and treated with excess methylmagnesium bromide in ether to afford the corresponding Cbz-protected a-amino ketones in excellent yield. The Cbz group is removed by catalytic hydrogenation in the presence of the active methylene compound (e.g., acetoacetic ester), the catalyst is then filtered and the resulting solution is heated to reflux to bring about the condensation. 

The two-step one-pot total synthesis of Ro 22-1319, an antipsychotic agent featuring a rigid pyrrolo[2,3-g]isoquinoline skeleton, was accomplished by D.L. Coffen and co-workers. The cyclic 1,3-diketone precursor was prepared from arecoline and dimethyl malonate, and in the same reaction vessel an amino ketone hydrochloride was added. The pH of the reaction mixture was adjusted to 4 in order to initiate the formation of the pyrrole. 

The Knorr pyrrole synthesis involves the reaction between an a-amino ketone and a second carbonyl compound, having a reactive a-methylene group, to give a pyrrole. The amine is often generated in situ by reduction of an oximino group. 

The mechanism of the original Knorr pyrrole synthesis entails in situ reduction of the oxime moiety to an amine, condensation with the second carbonyl compound, and cyclization with loss of a second molecule of water to give a pyrrole Several studies have demonstrated that different pathways and pyrrole products obtain depending on the substrates. 

The Knorr pyrrole synthesis was applied to make butyrophenone analogues of molindone, a typical anti-psychotic first marketed in the United States in 1974. The Knorr condensation of 2-hydroxyimino-3-pentanone with 1,3-cyclohexadione in 70% acetic acid in the presence of zinc powder at 

QF-0400B, typical antipsychotic molindone, typical antipsychotic 

The same tactic was employed to prepare new cyclic butyrophenone derivatives in the indole series as potential atypical anti-psychotics. The Knorr pyrrole synthesis provided a simple and practical access of 6-aminomethyltetrahydroindol-4-ones and their affinities for D2, and 5-HT2a receptors were evaluated for their potential as atypical anti-psychotics. As 

This approach to the five-membered pyrrole ring reacts an a-aminoketone with a P-ketoester. The mechanism will probably involve imine formation then cyclization via an aldol-type reaction using the enamine nucleophile. Dehydration leads to the pyrrole. Only the key parts of this sequence are shown below. 

The synthesis works well only with an activated ester like ethyl acetoacetate. Otherwise, self-condensation 

A modification of the Feist-Benary furan synthesis (pi34). Reaction between a-aminoketones, derived fron a-haloketones and ammonia, and P-ketoesters assembles pyrroles. 

Anderson, L. R. Kirk-Othmer Encycl. Chem. TechnoL 3rd Ed. 1982,19, 499. (Review). 

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Knoevenagel reaction Knorr pyrrole synthesis. Kolbe>Schmitt reaction Leuckart reaction Mannich reaction... 

The exploration of the chemistry of azirines has led to the discovery of several pyrrole syntheses. From a mechanistic viewpoint the simplest is based upon their ability to behave as a-amino ketone equivalents in reactions analogous to the Knorr pyrrole synthesis cf. Section 3.03.3.2.2), as illustrated in Schemes 91a and 91b for reactions with carbanions. Parallel reactions with enamines or a-keto phosphorus ylides can be effected with electron-deficient 2//-azirines (Scheme 91c). Conversely, electron-rich azirines react with electron deficient alkynes (Scheme 91d). 

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

The Paal-Knorr pyrrole synthesis is the condensation of a primary amine 4 (or ammonia) with a 1,4-diketone 5 (or 1,4-dialdehyde) to give a pyrrole 6. ... 

Knorr discovered that treatment of ethyl a-oximinoacetoacetate (7) and ethyl acetoacetate (8) with zinc and acetic acid affords 2,4-dicarboethoxy-3,5-dimethylpyrrole (9). Extensive modifications of this reaction over the past 100 years have elevated the Knorr pyrrole synthesis to one of exceptional generality and versatility. 

Paal and Knorr independently discovered the straightforward reaction of primary amines (or ammonia) with 1,4-diketones to give pyrroles following loss of water7 Like the Knorr pyrrole synthesis, the PK method is a powerful and widely used method of constructing pyrroles (vide infra). 

The major development in the Knorr pyrrole synthesis has been access to the amine component. For example, use of preformed diethyl aminomalonate with 1,3-diketones affords much higher yields of pyrroles 14. Reaction of 6-dicarbonyl compounds with hydroxylamine 0-sulfonic acid gives pyrroles 15 in one step. Weinreb a-aminoamides have found use in the Knorr pyrrole synthesis of a wide variety of pyrroles 16. °... 

A zinc-free alternative to the Knorr pyrrole synthesis employs catalytic hydrogenation, as for 17 + 18 to 19. Oximes such as 17 are readily prepared by nitrosation (NaNOa, HO Ac) of the active methylene group. 

The major application of the Knorr pyrrole synthesis is in the construction of porphyrins, and many examples exist,particularly from the work of Lash, who also demonstrated the formation of novel pyrroles, such as Cyanopyrroles are available... 

An important extension of the Knorr pyrrole synthesis developed by Cushman utilizes ketone enolates and BOC-protected a-amino aldehydes and ketones. Two examples (37, 38) are shown. 

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). 

Mainly C-substituted pyrroles have been synthesized by application of the Knorr pyrrole synthesis however N-substituted pyrroles can also be prepared, when starting with secondary aminoketones, e.g. bearing an N-methyl or N-phenyl substituent. 

In a process related to the Knorr pyrrole synthesis, condensation of p-amino alcohols 10 with p-dicarbonyl compounds 11 affords p-hydroxy enamines 12 which are then oxidized to the pyrroles 13 <96TL9203>. 

The large scale preparation of orthogonally protected pyrrole tricarboxylic acid derivatives (i.e., 92) was reported. A key step was the selective a-chlorination of a 2,4-dimethylpyrrole intermediate that was derived from the Knorr pyrrole 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). 

The first step is formation of a pyrrole ring system from two identical aminoketones. It is actually a Knorr pyrrole synthesis, but we do not need to identify it as such, just approach it logically. In fact, if we look back at the Knorr pyrrole synthesis, we shall see that, under chemical conditions, the reagents used here are not sufficiently reactive for the pyrrole synthesis we need a more activated compound, like ethyl acetoacetate. Furthermore, we could not possibly proceed without masking the carboxyls as esters. This underlines how a biosynthetic sequence might differ somewhat from a purely chemical synthesis. 

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