Paal-Knorr synthesis of pyrroles

Some advances have been made in the Paal-Knorr synthesis of pyrroles by the condensation of primary amines with 1,4-dicarbonyl species. For instance, a new synthetic route to monosubstituted succinaldehydes allows for the facile preparation of 3-substituted pyrroles <96TL4099>. Additionally, a general method for the synthesis of 1-aminopyiroles has been devised by the condensation of commercially available 2,2,2-trichloroethyl- or 2-(tri-methylsilyl)ethylhydrazine with 1,4-dicarbonyl compounds <96JOCl 180>. A related route to such compounds involves the reaction of a-halohydrazones with p-dicarbonyl compounds <96H(43)1447>. Finally, hexamethyldisilazane (HMDS) can be utilized as the amine component in the Paal-Knorr synthesis in the presence of alumina, and this modification has been employed in the synthesis of tm azaprostacyclin analog <96S1336>. 

Ferreira developed a novel method for the preparation of masked 1,4-dicarbonyl derivatives for utilization in the Paal-Knorr synthesis of pyrroles <00SC3215>. In this process, the reaction between diazocompound 3 and n-butyl vinyl ether using dirhodium tetraacetate as catalyst provides dihydrofurans 4 which are easily converted into substituted... 

Scheme 6.1 Paal-Knorr synthesis of pyrrole 3 conducted under continuous flow in the absence of a solvent.

An attempt to employ the Paal-Knorr synthesis of pyrrole to prepare 3-benzazepines failed. For example, 40 (R = CHO) treated with n-propylamine gave the benzofulvene 104."... 

This is an example of a Paal-Knorr synthesis of pyrrole. It consists in a double condensation of a primmy amine with a 1,4-diketone, giving a cyclic bis-enmnine, which happens to be an m omatic pyrrole ring. The Ti(IV) tetra-isopropoxide acts as a Lewis acid in catalytic quantities... 

Looking at the first step of the reaction, you should recognize a Michael addition of cyclohexanone to an unsaturated ketone. (You can review this reaction in Section 18-11). The transformation in the second step looks similar to the Paal-Knorr synthesis of pyrroles... 

Scheme 4. Paal-Knorr synthesis of penta-substituted pyrrole 22.

Another example of reaction-rate enhancement was reported for the microwave-assisted Paal-Knorr synthesis of a series of tetrasubstituted pyrroles [18]. Following the standard procedure, 1,4-dicarbonyl compounds were converted to pyrrole rings via acid-mediated dehydrative cyclization in presence of primary amines. The main limitation of the standard protocol is the harsh reaction conditions (reflux in acetic acid for extended times). The use of microwaves slashes the reaction times to few minutes, giving good isolated yields of the desired products (Scheme 15.5). 

Scheme 5.23 Cl-Stetter-Paal-Knorr synthesis of furans 95 and pyrroles 98.

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>. 

This straightforward three-component approach to 1,4-diketones can readily expanded to a CIR-Stetter-Paal-Knorr synthesis of furans 24 and pyrroles 25 in the sense of a consecutive three-component or four-component reaction in a one-pot fashion. 

The Paal-Knorr Synthesis of Pyrroies. The Paal-Knorr method makes use of a 1,4-di-carbonyl compound (aldehyde or ketone) in reaction with primary amines or ammonia. Many pyrroles have been made by this general process. Alkyl and some other substituents are allowed on the dicarbonyl chain. Diketones, dialdehydes, and ketoalde-hydes all serve as reactants. Primary amines give rise to 1-alkylpyrroles. Examples of the overall process are shown in Scheme 4.2. 

Paal-Knorr synthesis of furans, thiophenes, and pyrroles... 

The efficiency of the Sila-Stetter reaction for the synthesis of 1,4-dicarbonyl compounds prompted us to extend this methodology to a single-flask protocol for the Paal-Knorr synthesis of furans and pyrroles [82, 83]. Finally, we also took advantage of acylsilanes to develop the 1,2-addition of carbanion equivalents to activated imines for the synthesis of a-amino ketones [84]. 

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). 

Paal-Knorr Synthesis. The condensation of a 1,4-diketone, for example, with ammonia or a primary amine generally gives good yields of pyrroles many syntheses have been reported (24). The lack of avaHabitity of the appropriate 1,4-diketone sometimes limits the usefiilness of the reaction. 

Paal-Knorr synthesis orgchem A method of converting a 1,4-dicarbonyl compound by cyclization with ammonia or a primary amine to a pyrrole. pol ko nor sin-... 

There are two principal routes to pyrroles. One is called the Paal-Knorr synthesis, in which pyrroles are formed by the interaction of 1,4-dicarbonyl compounds and ammonia. No intermediates have ever been isolated, so the mechanism shown in Scheme 6.13 is speculative. 

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. 

IIae Pyrroles by cyclization of 1,4-dicarbonyl compounds (Paal-Knorr synthesis) 3.06.3.2... 

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. 

Condensation of 1,3-diketones with hydrazines or hydroxyamines was conducted in a microflow system to give pyrazoles and isoxazoles in good yields [22]. High-throughput synthesis of pyrrole by the Paal-Knorr condensation of ethanolamine and acetonylacetone was achieved using the CPC CYTOS Lab System [23], The running of the system for 165 min resulted in 714 g of the pyrrole (Scheme 4.14). 

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