Pyrroles, Paal-Knorr synthesis

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. 

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... 

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. 

The Paal-Knorr synthesis utilizes 1,4-diketones to generate furans, thiophenes and pyrroles, 1,5-diketones to generate pyridines, and 1,3-diketones to generate subunits containing two heteroatoms. 

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. 

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

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

Paal synthesis thiophenes, 4, 884-885 Paal-Knorr synthesis furan synthesis by, 4, 97 in heterophane synthesis, 7, 770 pyrroles, 4, 118... 

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. 

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. 

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."... 

The Paal-Knorr synthesis, in which 1,4-dicarbonyl compounds are treated with NH3 or primary amines (or with ammonium or alkylammonium salts) in ethanol or acetic acid, leads to 2,5-disubstituted pyrroles, and is universally applicable. For instance, hexane-2,5-dione 8 reacts with NH3 to yield 2,5-dimethylpyrrole 9 ... 

Paal-Knorr synthesis Synthesis of pyrrole by cycliz.aiion of a y-dicarboiiyl compound. 

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. 

Chapter 4 discussed two of the traditional methods of pyrrole synthesis, the Paal-Knorr synthesis and the Knorr synthesis. The basic reactions are repeated here as Scheme 9.3. Details of the mechanisms were given in sections 4.2.1 and 4.2.3, respectively. 

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