Synthesis Paal-Knorr

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, 4, 118, 329 Pariser-Parr-Pople approach, 4, 157 PE spectroscopy, 4, 24, 188-189 photoaddition reactions with aliphatic aldehydes and ketones, 4, 232 photochemical reactions, 4, 67, 201-205 with aliphatic carbonyl compounds, 4, 268 with dimethyl acetylenedicarboxylate, 4, 268 Piloty synthesis, 4, 345 Piloty-Robinson synthesis, 4, 110-111 polymers, 273-274, 295, 301, 302 applications, 4, 376 polymethylation, 4, 224 N-protected, 4, 238 palladation, 4, 83 protonation, 4, 46, 47, 206 pyridazine synthesis from, 3, 52 pyridine complexes NMR, 4, 165... 

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>. 

Finally, Scharf and Wolters report a method said to be superior to both the Paal-Knorr synthesis (starting materials more easily accessible) and the Feist-Benary synthesis (freer choice for 3-substituent). Thermal rearrangement-elimination by alkylated dioxolanes at 230 C gives alkyl substituted furans. Yields can be nearly quantitive since the only serious by-products also give the furans under proton-catalyzed thermolysis (Scheme 25).124 Photochemical methods are outlined in Section VII. 

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. 

Dehydrations of dione (61) via the Paal-Knorr synthesis lead to heterophanes (58)-(60) (68TL2181, 69T5357). Dione (61) is readily prepared from cyclododecanone by conventional procedures (64E620). 

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. 

Paal-Knorr synthesis can also be used to synthesize furan and thiophene ring systems. A simple dehydration of a 1,4-dicarbonyl compound provides the furan system, whereas thiophene or substituted thiophenes can be prepared by treating 1,4-dicarbonyl compounds with hydrogen sulphide (H2S) and hydrochloric acid (HCl). 

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. 

The acid-catalyzed cyclization of 1,4-dicarbonyl compounds known as the Paal-Knorr synthesis is one of the most important methods for the preparation of furans. As many methods for the synthesis of 1,4-diones have recently been developed, the synthetic utility of the Paal-Knorr reaction has improved. 

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 forward process is known as the Paal-Knorr synthesis. This is a very straightforward synthesis limited only by the accessibility of the 1,4-dicarbonyl precursors. 

The Paal-Knorr synthesis can similarly be applied to thiophenes, e.g. compounds 2.17 - 2.20. 

Our retrosynthetic analysis of the Paal-Knorr synthesis leads to a problem when applied to furan, as it implies addition of a water molecule, followed by elimination of two water molecules. In practice, simple dehydration of a 1,4-dicarbonyl compound leads to furans as in the preparation of 2.21. 

The thioamides themselves are conveniently prepared from the corresponding amides by treatment with phosphorus (V) sulphide (see the Paal—Knorr synthesis of thiophenes, Chapter 2, for this type of conversion). A variation of the Hantzsch reaction utilises thioureas, where R3 in 3.30 is a nitrogen and not a carbon substituent. For instance, thiourea itself is used in the preparation of 2-aminothiazoles such as 3.32. 

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