Paal-Knorr reactions

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%. 

Jones and Civcir prepared a variety of alternating oligomeric furanipyridine compounds and studied their NMR chemical shifts as well as the pKa values for the corresponding conjugate acids. All of these compounds were synthesized by Paal-Knorr reactions of 1,4-diketones with hot polyphosphoric acid. A representative example is the conversion of 24 into 25 in 82% yield. ... 

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. ... 

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. ... 

Diaryl bisfurans are available from two sequential Paal-Knorr reactions of tetraketones. For example, Barba converted 46 into 3,3"-bis-2,5-diphenylfuran (47) in good yield upon treatment with sulfuric acid and acetic anhydride. ... 

Several groups have used the Paal-Knorr reaction to synthesize trialkylfurans. Ballini prepared a series of 3-alkyl-2,5-dimethylfurans (53) in 60-94% yield by treatment of the corresponding diones (52) with tosic acid. Weirsum produced the sterically congested tri-r-butylfuran 55 from dione 54, but was unable to use the same strategy to furnish the tetra-t-butyl derivative. ... 

Both 2,5-dialkyl-3-furoates and 2,5-dialkyl-3-phosphonofurans can be produced using the Paal-Knorr reaction. Methyl 2,5-diisopropyl-3-furoate (62) is available upon treatment of dione 61 with sulfuric acid. Phosphonodiones 63 can be efficiently converted into 2-substituted-3-diethylphosphono-5-methylfurans 64 by exposure to Amberlyst in refluxing toluene. ... 

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." ... 

Another important route to pyrroles is offered by the Paal-Knorr reaction, where the pyrrole system is formed by condensation of a 1,4-diketone 9... 

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. 

Two other examples of microwave-assisted Paal-Knorr reactions were reported in 2004, describing the synthesis of a larger set of pyrroles with different substituents around the ring. The methods differ mainly in the syntheses employed to produce the 1,4 dicarbonyl compounds required for the cyclization. A variation of the Stetter reaction between an acyl silane and dif-... 

Scheme 3 Synthesis of 1,4-disubstituted pyrroles via Paal-Knorr reaction...

A two-step procedure was required for the preparation of a diverse set of pyrrole-3-carboxylic acid derivatives. The diketone 15 was prepared using a functional homologation of a 6-ketoester 14 with different aldehydes followed by oxidation with PCC. The Paal-Knorr reaction was carried out in AcOH in a sealed tube under microwave irradiation (180 °C, 5-10 min) to give differently substituted pyrroles with a COOMe group in position 3 (Scheme 5). This group was further transformed to expand the diversity of the products prepared with this method [32]. 

The synthesis of 2,3,5-trialkylpyrroles can be easily achieved by conjugate addition of nitroalkanes to 2-alken-l,4-dione (prepared by oxidative cleavage of 2,5-dialkylfuran) with DBU in acetonitrile, followed by chemoselective hydrogenation (10% Pd/C as catalyst) of the C-C- double bond of the enones obtained by elimination of HN02 from the Michael adduct. The Paal-Knorr reaction (Chapter 10) gives 2,3,5-trialkylpyrroles (Eq. 4.124).171... 

Needing 2,5-dimethylfuran as a masked 1,4-dicarbonyl equivalent, Scott and Naples found that the ion-exchange resin Amberlyst 15 is extremely effective in catalyzing the cyclization of hexane-2,5-dione to this compound.31 Some unusual Paal-Knorr reactions have been described. In one, phos-phorus(V) sulfide gave none of the expected thiophene when it acted upon the diketoester 3, the thioester 4 being obtained instead.32 Against all... 

The retro-Paal-Knorr ring opening reaction leading to 1,4-dicarbonyl compounds was accomplished by heating iV-substituted pyrroles in a citrate buffer <06SL1428>. The sequence was coupled with a forward Paal-Knorr reaction enabling the exchange of the N-substituent on pyrroles. 

One of the most common approaches to pyrrole synthesis is the Paal-Knorr reaction, in which 1,4-dicarbonyl compounds are converted to pyrroles by acid-mediated dehydrative cyclization in the presence of a primary amine. The group of Taddei has reported a microwave-assisted variation of the Paal-Knorr procedure, whereby a small array of tetrasubstituted pyrroles was obtained (Scheme 6.181) [342], The pyrroles were effectively synthesized by heating a solution of the appropriate 1,4-dicarbonyl compound in the presence of 5 equivalents of the primary amine in acetic acid at 180 °C for 3 min. The same result was obtained by heating an identical mixture under open-vessel microwave conditions (reflux) for 5 min. Interestingly, the authors were unable to achieve meaningful product yields when attempting to carry out the same transformation by oil-bath heating. 

The Paal-Knorr reaction was also employed by Steglich in likely biomimetic approaches to the marine alkaloids lamellarin L <00CEJ1147> as well as purpurone and ningalin C <00TL9477>. The overall approach employed herein involved initial oxidative coupling of two arylpyruvic acids followed by condensation of the resulting 1,4-diketones with suitable... 

Alternatively, Ballini devised a new strategy to synthesize tri-alkylated pyrroles from 2,5-dialkylfurans and nitroalkanes <00SL391>. This method involves initial oxidation of 2,5-dimethylfuran with magnesium monoperoxyphthalate to cA-3-hexen-2,5-dione (6). Conjugate addition of the nitronate anion derived from the nitro compound 7 to 6 followed by chemoselective hydrogenation of the C-C double bond of the resulting enones 8 (obtained by elimination of nitrous acid from the Michael adduct) completes the conversion to the alkylated y-diketones 9. Final cyclization to pyrroles 10 featured improved Paal-Knorr reaction conditions involving reaction of the diketones with primary amines in a bed of basic alumina in the absence of solvent. 

C=N bond formation has also been achieved starting from two additional carbonyl functions properly installed in an Ugi component. Cyclization has been accomplished in this case through a Paal-Knorr reaction of the dicarbonyl compound generated by the Ugi condensation, leading to pyrazinones [107]. 

The Paal Knorr reaction provides an efficient synthesis of l,3,7-triaryl-6-phenyl-2-thioxo-l,2,3,7-tetrahydropyr-rolo[2,3- pyrimidin-4-one derivatives from 2-thiobarbituric acids under microwave conditions <2006JHC1231>. 

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. 

Scheme 27 Exothermic Paal-Knorr reaction conducted in a CYTOS flow reactor.

Scheme 15.5 Synthesis of tetrasubstituted pyrroles by microwave-assisted Paal-Knorr reaction.

The 2-aroylaziridines (303), on thermolysis, provide aroylazomethine ylides which undergo [3 + 2] cycloadditions with various dipolarophiles. Whereas imines are normally inert to dipole synthons, Lown and Landberg reported that the polarized A -sulfonyl-a-acylimines afford initially the 1-sulfonyl-4,5-diacylimidazolines (304) which undergo cyclodehydration (Paal-Knorr reaction) to the furo[3,4-fi ]imidazolines (305) (Scheme 57). A further variant with other substituted A-sulfonylimines (R1 = 4-ClC6H4S02) and sequential amination affords the l,5-dihydropyrrolo[3,4-. 

This is an example of the Paal-Knorr reaction and is discussed (1). 

Polshettiwar V, Varma RS (2010) Nano-organocatalyst magnetically retrievable ferrite-anchored glutathione for microwave-assisted Paal-Knorr reaction, aza-Michael addition, and pyrazole synthesis. Tetrahedron 66 1091-1097... 

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