Knorr condensation

Knorr condensation of ethyl trifluoroacetylacetate with a variety of partners serves as a facile route to the preparation of a variety of trifluoromethylated pyrroles [25, 26] (equation 15)... 

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>. 

It is therefore recommended that the glycosyl halide should be added slowly to a solution of the alcohol in order to maintain as high a concentration of the latter as possible. Further, it was suggested that for maximum efficiency the activity of the silver salt should be ascertained before use by polarimetric means so that optimal reaction times can be employed. The beneficial effects of iodine which is often used in the reaction are suggested to result from the specific inhibition of the side reactions. Rather surprisingly, however, the Koenigs-Knorr condensation was found to occur more slowly in the presence of iodine than in its absence, so the effect would not appear to be direct. 

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. ... 

Finan and Warren12 conducted a Koenigs-Knorr condensation of benzyl 3,5,6-tri-O-benzyl-a-D-glucofuranoside with tetra-O-acetyl-a-D-glucopyranosyl bromide, and obtained a derivative in which the reducing residue of sophorose was present as its benzyl furanoside. 

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). 

Kiss and coworkers78,79 synthesized some minor D-glucosiduronic acid metabolites of phenacetin (isolated from the urine of patients sensitive to phenacetin), namely, the conjugates of 2-acetamido-5-eth-oxyphenol and 5-acetamido-2-ethoxyphenol (33 and 35) by the platinum-catalyzed oxidation of the corresponding /3-D-glucopyranosides, and by the Koenigs-Knorr condensation of 1 with the appropriate ni-... 

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. 

Solvent effect. Because of its high dielectric constant (39), nitromethane is recommended as solvent for Koenig-Knorr condensation of glycosyl bromides with ethanol in the presence of silver carbonate to yield jS-glycosides. In less polar solvents the o-glycoside can be the major product. 

V. Magnus, D. Vikic-Topic, S. Iskric, and S. Kveder, Competitive formation of peracetylated a-L-arabinopyranosides andjS-L-arabinose l,2-(alkyl orthoactetates) in Koenigs-Knorr condensations, Carbohydr. Res., 114 (1983) 209-224. 

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-... 

Some selectivity of acylation or alkylation has been observed in several other cases however, the structures of the products could not be unambiguously estimated.642,692,693 Low selectivity is characteristic of Koenigs-Knorr condensations of acetylated glycosyl halides with 1,6-anhydrohexopyranoses (see Sect. X,l,b). 

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