Paal furan

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). 

The course of the acid catalyzed dehydration of 1,4-diketones to furans, known as the Paal-Knorr method (1884CB2756), entails the formal addition of the enol of one carbonyl group to the other carbonyl. Examples which illustrate some of the routes used to make the necessary 1,4-diketones are shown in Scheme 13. Few examples are known of the preparation of the other heterocycles by this general approach using isolated intermediates, although some of the ring closures discussed in Section 3.03.3.1.1 are mechanistically equivalent. One example of the preparation of a hydroxypyrrole is included in Scheme 13 <59AC(R)2075). 

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

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. ... 

A multitude of 1,4-dicarbonyls (1) undergo the Paal-Knorr reaction with and ranging from H to alkyl, aryl, carbonyl, nitrile, and phosphonate, while R and R vary between H, alkyl, aryl, trialkylsilyl, and O-alkyl. Protic acid catalysts are typically used with sulfuric, hydrochloric, and p-toluenesulfonic acids the most popular. Conversion to the furan takes place either at room temperature or upon heating with reaction times varying from five minutes to 24 hours and yields ranging from 17-100%. 

In a series of papers in late 1884 and early 1885, Paal and Knorr demonstrated that several 1,4-dicarbonyls could be transformed into furans, pyrroles, and thiophenes. Paal first discovered this transformation and used it to prepare di-, tri-, and tetrasubstituted furans. For example, dicarbonyl 3 yielded disubstituted furan 4 upon treatment with weak acid. 

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. ... 

The most common use of the Paal-Knorr condensation begins with a 1,4-diketone and yields a 2,5-disubstituted furan. This method has been used to produce dialkyl and disilyl furans however, the most popular use of this strategy is for the production of 2,5-diaryl furans. In addition to their utility as synthetic intermediates, these compounds are under investigation for novel electronic and pharmaceutical applications. 

Several other research teams used the Paal-Knorr condensation to prepare 2,5-disubstituted furans that were investigated as potential enzyme inhibitors. Nagai produced furan 17 via treatment of dione 16 with sulfuric acid and subsequently examined the activity of 17 toward a retenoic acid receptor. Perrier discovered that furan 19, derived from dione 18, is a potent PDE4 inhibitor and may have anti-inflammatory activity. ... 

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 variety of 2,5-dialkylfurans are available via the Paal-Knorr condensation cyclization is possible for both hindered and unhindered 1,4-diketones. Fleming prepared 2-cyclohexyl-5-methylfuran (31) in 91% yield via treatment of dione 30 with catalytic p-toluenesulfonic acid in refluxing benzene. Using the same methodology, Denisenko synthesized furan 33 in 35% yield from the corresponding dione (32). ... 

Portella reported the Paal-Knorr condensation of l,4-bis(acylsilanes) 38 in the presenc( of p-toluenesulfonic acid to yield a variety of 2,5-disilylfurans 1)9. Presumably due to steri( constraints, bis(acylsilanes) substituted in the 2-position failed to undergo the Paal-Knor reaction to provide any of the expected trisubstituted furan products. 

Although it is far more common to synthesize these substrates using the Feist-Benary reaction (Section 4.1), the Paal-Knorr reaction can also be used to prepare 2,3-disubstituted furans. In a recent example, Castagnoli converted 1,4-ketoaldehyde 40 into furan 41 in 97% yield upon exposure to hot sulfuric acid. ... 

Other less common products of the Paal-Knorr condensation include 2,4-disubstituted furans. An example of such a reaction is Molander s combination of dicarbonyl 42 with hydrochloric acid to furnish 4-methyl-2-(methyldiphenylsilyl)furan (43) in 87% yield.It is important to note that this methodology can also be used to produce 2,5- and 2,3-disubstituted furans. ... 

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. 

Not surprisingly, based on the bioactivity of diaryl furans discussed in section 4.2.4.1, triaryl furans have also been investigated as enzyme inhibitors. De Laszlo prepared several 2,3,5-triarylfurans via the Paal-Knorr reactions (for example 44 to 45) and tested these compounds for their activity toward P38 kinase. ... 

A recent report demonstrates that trisubstituted furans can be prepared on a solid support using the Paal-Knorr condensation. Raghavan synthesized a variety of triaryl and alkyl diary] furans, one of which is highlighted below. Dione 50 was cyclized using p-toluenesulfonic acid in refluxing toluene followed by cleavage from the solid support to yield furan 51. ... 

The Paal-Knorr reaction offers an excellent method for the preparation of tetrasubstituted furans however, it does not work for some sterically congested substrates. Similar to di- and trisubstituted furans mentioned previously, tetrasubstituted furans have been investigated for biological acitivity. Katzenellenbogen has prepared numerous alkyl triarylfurans by the Paal-Knorr condensation (e.g. 65 to 66) and investigated their activity toward the estrogen... 

Tetraalkylfurans can be prepared via the Paal-Knorr reaction. For example, Muramatsu synthesized 2,5-diethy]-3,4-bis(trifluoromethyl)furan (72) in 94% yield by treatment of dione 71 with sulfuric acid." ... 

It is also possible to use the Paal-Knorr condensation to prepare 2,5-dialkyl-3,4-dicarbonyl substituted furans. For example, Zaleska converted diketone 73 into furan 74 in 92%... 

Numerous variations of the Paal-Knorr eondensation are known. The most popular methods use starting materials that are eonverted to 1,4-diearbonyls in situ and eyelize to yield furan produets without isolating their diearbonyl preeursors. Other more speeialized strategies have been developed for the preparation of heterosubstituted furans. 

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. 

Another variation of the Paal-Knorr eondensation involves starting with a derivative 0 2-butene-1,4-dione and performing a reduetion prior to the eyelization reaetion. For exampk Rao has reeently reported that trisubstituted furans 84 ean be produeed in high yield upo treatment of diones 83 with formic acid, catalytic sulfuric acid, catalytic palladium on carbor... 

Until 1952, it was postulated that the Paal thiophene synthesis proceeded via an initially formed furan via dehydration of the 1,4-diketone, followed by conversion of the furan to... 

The use of microwaves for the preparation of aromatic five-membered heterocycles has been intensely investigated with excellent results in terms of yields and purities of the products prepared. The Paal-Knorr reaction, namely the cyclocondensation of a 1,4-dicarbonyl compound to give furans, pyrroles and thiophenes has been successfully carried out with the aid of microwaves. 

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

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. 

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. 

Shea, K. M. Paal—Knorr Furan Synthesis In Name Reactions in Heterocyclic Chemistry, Li, J. J. Corey, E. J., Eds. Wiley Sons Hoboken, NJ, 2005, 168—181. (Review). 

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. 

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. 

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). 

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