Paal-Knorr conditions

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. ... 

Introduction of a sulfur atom has been effected in many cases with phosphorus pentasulfide for example, ring closure of 1,4-dicarbonyl compounds 81 (X = CH) under typical Paal-Knorr conditions gives fused thiophenes 82 (X = CH).75,76 Fused thiazoles [82 (X = N) and Eqs. (6), (7)] have been prepared in the same way.77-80... 

A novel transformation was observed when calix[n]arene ( = 4 or 6) was oxidized to generate the cyclic poly-1,4-diketone 11, which when subjected to Paal-Knorr conditions gave (12, n = 3) whereas, it was treated with hydrazine gave the isopyrazole-based macrocycles 13 <04T1895>. 

In the late 1970s Hara and co-workers used a similar strategy to synthesize pyrrolobenzodiazepines (33) in short order. In this report 3,4 substitution on the pyrrole was introduced using Paal-Knorr condition with substituted 1,4-diketones. 

The TBIN 38 is reduced to the corresponding amine 41 and under Paal Knorr conditions reacted with the diketone 37 (Scheme 19) 12), Through experimental design, the )deld of the Paal-Knorr cyclization was optimized and presently achieves greater than 70% yield of 42. Key conditions were defined to... 

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." ... 

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. 

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. 

A different approach toward highly substituted pyrroles involving a one-pot sila-Stetter/Paal-Knorr strategy was realized by Bharadwaj and Scheidt (Scheme 6.182) [343]. In this multicomponent synthesis, catalyzed by a thiazolium salt, an acyl anion conjugate addition reaction of an acylsilane (sila-Stetter) was coupled in situ with the conventional Paal-Knorr approach. Employing microwave conditions at 160 °C for 15 min, the acylsilane was combined with the cx/l-unsaturated ketone in... 

In addition to cydocondensation reactions of the Paal-Knorr type, cycloaddition processes play a prominent role in the construction of pyrrole rings. Thus, 1,3-dipo-lar cycloadditions of azomethine ylides with alkene dipolarophiles are very important in the preparation of pyrroles. The group of de la Hoz has studied the micro-wave-induced thermal isomerization of imines, derived from a-aminoesters, to azomethine ylides (Scheme 6.185) [346]. In the presence of equimolar amounts of /i-nitrostyrenes, three isomeric pyrrolidines (nitroproline esters) were obtained under solvent-free conditions in 81-86% yield within 10-15 min at 110-120 °C through a [3+2] cycloaddition process. Interestingly, using classical heating in an oil bath (toluene reflux, 24 h), only two of the three isomers were observed. 

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. 

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. 

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>. 

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. ... 

Similar reaction conditions as those by Bose were used for a range of other applications, for example, the synthesis of heterocycles. A combination of a microwave-assisted Paal-Knorr reaction15 with a transfer hydrogenation takes place in the preparation of 2,5-di- and 1,2,5-trisubstituted pyrroles from -l,4-diaryl-2-butene-l,4-diones in a one-pot operation. Hydrogenation was achieved with ammonium formates and 10% Pd/C as catalyst in PEG-200. Yields of up to 92% were obtained within 0.5-2 min (Scheme 4.2)16. 

Another example of reaction-rate enhancement was reported for the microwave-assisted Paal-Knorr synthesis of a series of tetrasubstituted pyrroles [18]. Following the standard procedure, 1,4-dicarbonyl compounds were converted to pyrrole rings via acid-mediated dehydrative cyclization in presence of primary amines. The main limitation of the standard protocol is the harsh reaction conditions (reflux in acetic acid for extended times). The use of microwaves slashes the reaction times to few minutes, giving good isolated yields of the desired products (Scheme 15.5). 

The reaction conditions of the classical Paal-Knorr furan synthesis can be too harsh, when labile functionality has to be preserved. In the synthesis of the 3-oxa guaianolide 4, a five-step detour proved to be more efficient than direct cyclization (Scheme 4) <2000T6331>. Cyclic carbinol amides yield a-trifluoromethyl-sulfonamido furans upon treatment with triflic anhydride (Equation 7) <20030L189>. 

In an application of the Paal-Knorr pyrrole synthesis, the synthetic equivalents 3 of 1,4-ketoaldehydes were prepared by the radical addition of ketones 4 to vinyl pivalate. Treatment of the intermediates 3 with amines gave pyrroles 5 <03SL75>. Other new extensions of this popular pyrrole synthesis include the preparation of a number of pyrroles from hexane-2,5-dione and amines under solvent-free conditions in the presence of layered zirconium phosphate or phosphonate catalysts <03TL3923>, and the development of a solid-phase variant of this reaction <03SL711>. Likewise, the preparation of iV-acylpyrroles from primary amides and 2,5-dimethoxytetrahydrofuran in the presence of one equivalent of thionyl chloride has also been reported <03S1959>. 

Butene-l,4-diones and 2-butyne-l,4-diones were converted into 2,5-diaryl- and 2,3,5-triarylfurans in high yields in the presence of HCOOH and a catalytic anaount of Pd on carbon under microwave-irradiation conditions <03JOC5392>. This procedure provides a new approach to the starting material used in the Paal-Knorr furan synthesis, as unsaturated diones are reduced to saturated diones in situ by formic acid and palladium. The solid-phase synthesis of 2,3,5-trisubstituted furans from 1,4-diketones was also reported <03SL711>. 

In 1884, C. Paal and L. Knorr almost simultaneously reported that 1,4-diketones upon treatment with strong mineral acids underwent dehydration to form substituted furans. This transformation soon became widely used and now it is referred to as the Paal-Knorr furan synthesis. The general features of the method are 1) virtually any 1,4-dicarbonyl compound (mainly aldehydes and ketones) or their surrogates are suitable substrates 2) the dehydration is affected by strong mineral acids such as hydrochloric acid or sulfuric acid, but often Lewis acids and dehydrating agents (e.g., phosphorous pentoxide, acetic anhydride, etc.) can be used and 3) the yields are usually moderate to good. The two major drawbacks of the reaction are the relative difficulty to obtain the 1,4-dicarbonyl substrates, and the sensitivity of many functionalities to acidic conditions. 

Even though the Paal-Knorr pyrrole synthesis has been around for 120 years, its precise mechanism was the subject of debate. In 1991, V. Amarnath et al. investigated the intermediates of the reaction and determined the most likely mechanistic pathway. The formation of pyrroles was studied on various racemic and meso-3,4-diethyl-2,5-hexanediones. The authors found that the rate of cyclization was different for the racemic and meso compounds and the racemic isomers reacted considerably faster than the meso isomers. There were two crucial observations 1) the stereoisomers did not interconvert under the reaction conditions and 2) there was no primary kinetic isotope effect for the hydrogen atoms at the C3 and C4 positions. These observations led to the conclusion that the cyclization of the hemiaminal intermediate is the rate-determining (slow) step. 

F.H. Kohnke and co-workers prepared novel heterocyclophanes from cyclic poly-1,4-diketones, which were obtained by the oxidation of calix[6]furan and calix[4]furan. " One of the heterocyclophanes, calix[6]pyrrole, was prepared by the Paal-Knorr pyrrole synthesis from the corresponding dodecaketone. The substrate was heated with excess ammonium acetate in absolute ethanol. Interestingly, the analogous synthesis of calix[4]pyrrole under identical conditions failed, while calix[5]pyrrole is obtained only in 1% yield. 

The formal total synthesis of roseophilin was accomplished by B.M. Trost et al. who used the Paal-Knorr pyrrole synthesis to install the trisubstituted pyrrole moiety.The 1,4-diketone substrate was reacted with various primary amines to obtain A/-substituted pyrroles. The best yield was obtained when benzylamine was used as the amine component, but the A/-deprotection of the product proved to be problematic. This forced the researchers to prepare the otherwise unstable A/-unprotected pyrrole under carefully controlled conditions and protect it immediately with SEM-chloride. 

In the laboratory of A. Millar, the convergent enantloselective synthesis of CI-981, a potent and tissue-selective Inhibitor of HMG-CoA reductase was achieved. The central tetrasubstituted pyrrole ring was prepared via the Paal-Knorr pyrrole synthesis. The required 1,4-diketone precursor was efficiently prepared by the Stetter reaction between p-fluorobenzaldehyde and an unsaturated amide. Interestingly, the A/-benzyl thiazolium chloride catalyst afforded only the benzoin condensation product and none of the desired diketone. However, when the A/-ethyl thiazolium bromide catalyst was employed, under anhydrous and concentrated reaction conditions, the 1,4-diketone was formed in good yield. The authors also noted that the simple dilution of the reaction mixture resulted in a dramatic increase in the formation of the undesired benzoin condensation product. 

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. 

In the reaction of y -keto esters with a-halo ketones, the possible competition between C-alkylation (followed by reaction of the Paal-Knorr type) and aldol addition (followed by reaction of the Feist-Benary type) can result in mixtures of isomeric fiirans. Regioselectivity can, however, sometimes be controlled by the reaction conditions, as for instance in the interaction of chloroacetone with an aceto-acetic acid ester, leading to the furan-3-carboxylates 18/19 ... 

The Paal-Knorr furan synthesis involves the treatment of a 1,4-dicarbonyl with catalytic acid to generate the corresponding furan. A variety of differentially substituted 1,4-dicarbonyls have been used in the Paal-Knorr reaction to synthesize the corresponding mono-, di-, tri-, and tetrasubstituted flirans. Commonly employed acids include sulfuric, hydrochloric, and p-toluenesulfonic acid. The reaction generally takes place at room temperature or under thermal conditions. 

The compounds core comprises a pentasubstituted pyrrole, which results from a convergent synthesis with a Paal-Knorr reaction as its crucial step. This succeeds only under specially designed conditions the reaction faced initially a seemingly insurmountable obstacle, and therefore a range of linear syntheses had been developed as weU. Although they are scientifically very interesting, they will not be discussed here in any greater detail. [395,396]... 

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... 

Figure 4.4 Maximization of the production rate of the Paal-Knorr reaction (Scheme 4.1) with different optimization strategies. Values of the objective function are given by the color bar at right. Control variable boundaries are denoted by dashed red lines. The initial conditions are boxed in black at the bottom...

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. 

Crabtree and co-workers discovered the dehydrogenative Paal-Knorr synthesis the reaction of 1,4-diols with primary amines in the presence of a Ru diphosphine diamine complex at 125 °C to afford 2,5-disubstituted pyrroles (Scheme 12.37)." Kempe and Milstein developed dehydrogenative conditions for the synthesis of pyrroles via C-N and C-C coupling of alcohols with vicinal amino alcohols (Scheme 12.37). These reactions require the use of KOfBu, which may facilitate a-deprotonation of the intermediate imine. 

Paal and Knorr cyelisation [63] of 1, 4-diketone to give pyrroles was speeded up by microwave irradiation. The reaction was carried out under microwave solvent-free conditions and was completed within 2 min (Scheme 11.8). R was taken as... 

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