Paal-Knorr condensation

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. ... 

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. 

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. 

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... 

Several groups have employed the Paal-Knorr condensation for the preparation of disubstituted diarylfurans. Miyashita converted dione 67 into 3,4-disubstituted-2,5-diarylfuran 68 in good yield using standard Paal-Knorr conditions. Lai demonstrated that 2,5-disubstituted-3,4-diarylfurans like 70 are available from dione 69 upon exposure to phosphorous pentoxide. ... 

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%... 

Perumal investigated a novel variation that involved the combination of a Vilsmeier reaction with a Paal-Knorr condensation. Reaction of 3-benzoylpropionic acid (87) under Vilsmeier conditions furnished chloroformylfuran 88 in 75% yield, while reaction of acetonylacetone (89) provided formylfuran 90 in 60% yield." ... 

Ketoamides can participate in a variation of the Paal-Knorr condensation to yield 5-alkyl-2-aminofurans. Boyd described the cyclization of 1,4-ketoamides 91 upon exposure to acetic anhydride and perchloric acid to yield imminium salts 92 that furnished aminofurans 93 after treatment with triethylamine. ... 

An interesting family of polycyclic pyrroles was described in 2005 using again the synthetic sequence of a Stetter reaction for the preparation of the starting 1,4 diketones followed by a microwave-assisted Paal-Knorr condensation [35]. For example, cyclopentenone 23 (obtained in a Pauson-Khand cyclization) reacted imder Stetter reaction conditions to give the amino ketone 25 (Scheme 8). The microwave-assisted Paal-Knorr cyclization of 25 with different amines gave a small collection of tricychc pyrrole 2-carbox-amides. 

As will be discussed later, the novel pentacyclic antitumor alkaloid roseophilin continues to attract much synthetic effort and several approaches relied on the venerable Paal-Knorr condensation for construction of the pyrrole moiety. For instance, Trost utilized this reaction upon diketone 1 to afford the tricyclic core 2 of roseophilin in a strategy featuring an enyne metathesis as a key step <00JA3801>, while another formal synthesis of this alkaloid utilized a radical macrocyclization to produce the ketopyrrole core <00JCS(P1)3389>. 

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. 

Reaction of 3,3-disubstituted-l,4-pentadiene 92 with a primary amine under cyclohydrocarbonylation conditions yielded cyclopenta[. ]pyrrole 96 as the predominant product accompanied by a small amount of cyclopentanone 95 (Scheme 15). This unique reaction is proposed to proceed through a cascade hydrocarbonylation-carbonylation process. The first hydrocarbonylation of 92 and the subsequent carbocyclization formed cyclopentanoylmethyl-Rh complex 93. If 93 immediately reacts with molecular hydrogen, 2-methylcyclopentanone 95 is formed. However, if CO insertion takes place faster than the hydrogenolysis, cyclopentanoylacetyl-Rh complex 94 is generated, which undergoes the Paal-Knorr condensation with a primary amine to yield cyclopenta[. ]pyrrole 96. ... 

The TBIA (4) is then used in a Paal-Knorr condensation to provide the pyrrole (Scheme 31.3). This reaction is slow. Deprotection, saponification, and cyclization then provide the atorvastatin lactone (6). Conversion to the final calcium salt form of 1 is achieved by base treatment and addition... 

When considering the synthesis of phospholes, one has to forget most of the classical and powerful methods employed for the preparation of thiophenes and pyrroles. For example, Paal-Knorr condensation, direct ortho-lithiation, halogenation with NBS or I2/Hg2+ and Vilsmeier-Haack formylation are not operative in phosphole chemistry. Likewise, no chemical or electrochemical oxidative polymerization... 

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). 

Wang, B., Gu, Y., Luo, C., Yang, T., Yang, L., Suo, J. Pyrrole synthesis in ionic liquids by Paal-Knorr condensation under mild conditions. Tetrahedron Lett. 2004, 45, 3417-3419. 

The most general method to synthesize 2,5-disubstituted N-aminopyrroles consists of a modified Paal-Knorr condensation [20] starting from 1,4-diketones and a mono-protected hydrazine (Scheme 3.2). 

Paal-Knorr condensation of these 1,4-diketones with protected hydrazines gives access to the corresponding N-protected N-aminopyrroles 1-8 in a simple proce-... 

Construction of the phosphole ring, with one useful exception, is accomplished by methods that are quite different from those employed for the N, S, O ring systems. Because of fundamental differences in the chemistry of phosphines versus amines, none of the familiar carbonyl condensation processes are known to be applicable to phosphole synthesis. Thus an attempt to use the Paal-Knorr condensation of 1,4-dicarbonyl compounds with PhPH2 <65JCS2184> and with PH3 <88ZOB783> failed to give phospholes. The only successful method known to the present that is common to both the phosphole and pyrrole ring systems is the condensation of 1,3-diynes with primary phosphines... 

Type of reaction C-N bond formation Reaction conditions Aqueous micellar, room temperature Synthetic strategy One-step Paal-Knorr condensation Catalyst Sodium dodecyl sulfate (SDS) as surfactant... 

Keywords Amines, 2,5-hexanedione, sodium dodecyl sulfate (SDS), surfactant, water, micelles, room temperature, Paal-Knorr condensation, pyrrole derivatives... 

Veisi, H., Azadbakht, R., Ezadifar, M., and Hemmati, S. (2013). An efficient and green procedure for synthesis of pyrrole derivatives by Paal-Knorr condensation using sodium dodecyl sulfate in aqueous micellar. 7. Heterocyclic Chem., 50, E241-E246. 

In recent years, synthesis of pyrroles has drawn the attention of chemists. Traditional methods used for pyrrole synthesis include the Hantzsch reaction [45] and the Paal-Knorr condensation reaction [46,47], The latter is the most widely used method, which involves the cyclocondensation reaction of 1,4-dicarbonyl compounds with primary amines to produce substituted pyrroles. In addition, there are several methods such as 1,3-dipolar cydoaddition reaction, aza-Wittig reaction, reductive coupling, and titanium-catalyzed hydroamination of diynes. Scheme 1 shows several catalysts used in this type of reaction [44]. 

An efficient and highly versatile microwave-assisted Paal-Knorr condensation of various 1,4-diketones gave furans, pyrroles and thiophenes in good yields. In addition, transformations of the methoxycarbonyl moiety, such as Curtius rearrangement, hydrolysis to carboxylic acid, or the conversion into amine by reaction with a primary amine in the presence of Me3Al, are described by Minetto et al. (2005). 

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