Paal-Knorr synthesis of furans

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 simplest method is sulfurization followed by cyclizing dehydration of 1,4-dicarbonyl compounds 14 analogous to the Paal-Knorr synthesis of furans. This cyclocondensation is carried out with P4S10 or HiS, and furnishes 2,5-disubstituted thiophenes 15 (Paul synthesis) ... 

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]. 

Scheme 12 Synthesis of furans via reductive Paal-Knorr reaction...

In an extension of traditional Stetter methodology, Miiller and co-workers have used the Stetter reaction in a one-pot multicomponent reaction for the synthesis of furans and pyrroles (Scheme 19) [85,86], The ot,P-unsaturated ketone XXVI is formed in situ and undergoes a Stetter reaction followed by a Paal-Knorr condensation. 

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). 

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. 

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 widely applicable acid-catalyzed cyclization of 1,4-dicarbonyl compounds and their surrogates, known as the Paal-Knorr furan synthesis, is frequently used in the synthesis of furan-containing compounds (Equation 1). 

Concentrated sulfuric or perchloric acids induce polymerization of the cations, while dilute acids, e.g. perchloric acid in aqueous DMSO, cause hydrolysis to 1,4-dicarbonyl compounds. Nucleophilic attack by water probably takes place at the 2-position of protonated furan. Finally, in a reversion of the Paal-Knorr synthesis (see p 58), 2-hydroxy-2,3-dihydrofuran gives rise to the 1,4-dicarbonyl compound hexane-2,5-dione as shown. 

Only a single example employing the Paal-Knorr synthesis for the generation of mono-substituted furans has been reported to date. Molander demonstrated that 2-(methyldiphenylsilyl)furan could be prepared in good yield via treatment of 4-(methyldiphenylsilyl)-4-oxobutanal with hydrochloric acid in THF. ... 

The Paal-Knorr synthesis is more commonly used for the synthesis of 2,5-disubstituted furans, especially 2,5-diaryl furans, which have shown significant antiviral activity against RNA viruses. For example, Wilson and co-workers demonstrated that diaryl-substituted diones treated with hydrochloric acid could be used to generate the corresponding 2,5-disubstituted furans in good yields. ... 

The Paal-Knorr synthesis was also used to prepare 2,5-disubstituted furans that were investigated as potential enzyme inhibitors. Reaction of a highly substituted 1,4-dione with catalytic sulfuric acid produced the corresponding furan, which was evaluated for its ability to bind to a retenoic acid receptor. ... 

The reaction of the y-diketone (42) with P4S10 did not lead to the expected thiophen derivative, but gave instead the furan (43). The Paal-Knorr synthesis has been used for the synthesis of the cyclopenta[6]thiophen derivative (43a) from (43b). ... 

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). 

Furans can be hydrolyzed under mild conditions to y-dicarbonyl compounds. The reaction may be viewed as the reverse of the Paal-Knorr-type synthesis of furans. Pyrrole polymerizes under these reaction conditions, whereas thiophene is stable. 

Treatment of 1,4-dicarbonyls (1) with catalytic acid yields substituted furans (2) and is called the Paal-Knorr furan synthesis. This method is used extensively to produce a variety of mono-, di-, tri-, and tetrasubstituted furans. ... 

Although nearly all Paal-Knorr condensations produce di-, tri-, or tetrasubstituted furans, it is possible to use this reaction to generate monosubstituted furans. Molander demonstrated the utility of this method with his synthesis of 2-(methyldiphenylsilyl)furan (11) from dicarbonyl 10. ... 

Ibers used the Paal-Knorr furan synthesis to prepare a key intermediate for the synthesis of novel porphyrin-like aromatic macrocycles. Bis yrolyljfuran 27 was available in good yield via the acid catalyzed condensation of diketone 26. ... 

The Paal-Knorr furan synthesis can also be used to prepare 2,5-arylalkylfurans, as illustrated in the following example. Salimbeni produced furan 29 from dione 28 and subsequently used the furan as an intermediate for the production of angiotensin II receptor antagonists. ... 

A multitude of 2,3,5-trisubstituted furans are available via the Paal-Knorr condensation. As with the synthesis of disubstituted furans, the scope of this version of the reaction is broad and includes incorporation of aryl, alkyl, ester, and phosphonate substituents. 

A eommon approaeh starts with a proteeted 1,4-diearbonyl and unmasks the requisite earbonyl using aeid, thus faeilitating the Paal-Knorr reaetion immediately upon deproteetion. For example, Nagai used sulfurie aeid to eonvert aeetal 77 into 2,4-disubstituted furan 78 albeit in low yield.Molander produeed a different 2,4-disubstituted furan by a similar strategy. Thioketal aeetal 79 was treated with mereury(II) ehloride and furnished furan 80 in 71% yield. Thus this strategy provides a useful approaeh for the synthesis of a variety of 2,4-disubsituted furans. 

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). 

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. 

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